Researchers Database

minami kouichirou

    Anesthesiology&CriticalCareMedicineAnesthesiology Assistant Professor
Last Updated :2021/12/04

Researcher Information

Degree

  • (BLANK)(1995/03)

J-Global ID

Research Interests

  • 胸骨圧迫   職域救急   疼痛機序   麻酔機序   蘇生   麻酔科学   

Research Areas

  • Life sciences / Emergency medicine
  • Life sciences / Anesthesiology
  • Life sciences / Pharmacology

Academic & Professional Experience

  • 2006/09 - Today  一般財団法人 救急振興財団救急救命東京研修所教授
  • 2006/09 - Today  自治医科大学麻酔科学講座・救急医学講座講師
  • 2013/05 - 2019/02  国立がん研究センター研究所がん病態生理研究部外来研究員
  • 2000/03 - 2006/08  産業医科大学麻酔科講師
  • 1997/10 - 2000/03  産業医科大学麻酔科助手
  • 1995/10 - 1997/09  University of Colorado Health Sciences CenterDepartment of PharmacologyPostdoctoral fellow
  • 1995/04 - 1995/09  産業医科大学麻酔科助手
  • 1989/07 - 1991/03  新日本製鐵八幡製鉄所病院麻酔科臨床研修医
  • 1989/05 - 1989/06  産業医科大学病院臨床研修医

Education

  • 1991/04 - 1995/03  University of Occupational and Environmental Health, Japan  School of Medicine  生体情報系専攻
  • 1983/04 - 1989/03  University of Occupational and Environmental Health, Japan  Faculty of Medicine  医学科

Association Memberships

  • 臨床救急医学会   日本救急医学会   日本麻酔学会   

Published Papers

  • Reiko Horishita, Yuichi Ogata, Ryo Fukui, Ryo Yamazaki, Kuniaki Moriwaki, Susumu Ueno, Nobuyuki Yanagihara, Yasuhito Uezono, Yuka Yokoyama, Kouichiro Minami, Takafumi Horishita
    Anesthesia and analgesia 132 (6) 1756 - 1767 2021/06 
    BACKGROUND: The transient receptor potential vanilloid subtype 3 (TRPV3) channel is activated by innocuous temperature and several chemical stimuli. It is proposed to be involved in pathological pain development and is therefore considered a potential target for treating pain. Local anesthetics have been used for patients with both acute and chronic pain. Although blockage of the voltage-gated sodium channel is the primary mechanism by which local anesthetics exert their effects, they cannot be explained by this mechanism alone, especially in pathologic states such as chronic pain. Indeed, the effects of local anesthetics on multiple targets involved in the pain pathway have been reported. It has also been suggested that modulating the function of transient receptor potential (TRP) channels (eg, TRPV1 and transient receptor potential ankyrin 1 [TRPA1]) is one of the mechanisms of action of local anesthetics. However, the effects of local anesthetics on TRPV3 have not been reported. METHODS: We expressed TRPV3 in Xenopus oocytes and investigated the effects of local anesthetics on 2-aminoethoxydiphenyl borate (2APB)-induced currents using 2-electrode voltage-clamp techniques. RESULTS: Clinically used local anesthetics inhibited the 2APB-activated currents from the TRPV3 channel in a concentration-dependent manner at pharmacologically relevant concentrations with half maximal inhibitory concentration (IC50) values of 2.5 (lidocaine), 1.4 (mepivacaine), 0.28 (ropivacaine), and 0.17 (bupivacaine) mmol/L, respectively. Conversely, these local anesthetics also directly induced currents at higher concentrations, although these currents were quite small compared to the 2APB-induced currents. We found that the inhibition of TRPV3 by lidocaine is noncompetitive and independent of intracellular signaling cascades. 2APB-induced TRPV3 currents were reduced by extracellular N-(2,6-dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314) but not by intracellular QX-314 nor benzocaine. Moreover, lidocaine showed a use-dependent block in TRPV3 inhibition. Finally, QX-314 appeared to slightly permeate the activated TRPV3 channel pore based on examination of oocytes coexpressing TRPV3 and a sodium channel. These results suggest that local anesthetics could inhibit TRPV3 channel function by extracellular interactions of their charged forms with the channel pore. CONCLUSIONS: Local anesthetics inhibited TRPV3 2APB-induced currents at pharmacologically relevant concentrations when TRPV3 was expressed in Xenopus oocytes. These effects seem to occur via an extracellular interaction between the charged form of the anesthetic with the TRPV3 channel pore. These results help to elucidate the mechanisms of action of local anesthetics.
  • Kanako Miyano, Katsuya Ohbuchi, Yuka Sudo, Kouichiro Minami, Toru Yokoyama, Masahiro Yamamoto, Miaki Uzu, Miki Nonaka, Seiji Shiraishi, Hiroaki Murata, Yoshikazu Higami, Yasuhito Uezono
    Journal of pharmacological sciences 143 (4) 320 - 324 2020/08 [Refereed][Not invited]
     
    Cellular dielectric spectroscopy (CDS) is a novel technology enabling pharmacological evaluation of multiple receptor types with a label-free cell-based assay. We evaluated activities of a family of ligand-gated channels, transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) channels by an electrical impedance-based biosensor (CellKey™ system) using CDS. Measures of both potency (EC50) and efficacy (Emax) of these agonists with CellKey™ were almost identical to those made using the traditional Ca2+ influx assay in TRPV1- or TRPA1-expressing cells, suggesting that CellKey™ is a simpler and easier means of evaluating TRP activities.
  • Takafumi Horishita, Yuichi Ogata, Reiko Horishita, Ryo Fukui, Kuniaki Moriwaki, Susumu Ueno, Nobuyuki Yanagihara, Yasuhito Uezono, Yuka Sudo, Kouichiro Minami
    Journal of pharmacological sciences 142 (4) 140 - 147 2020/04 [Refereed][Not invited]
     
    Carvacrol is the predominant monoterpene in essential oils from many aromatic plants. Several animal studies showing analgesic effects of carvacrol indicate potential of carvacrol as a new medication for patients with refractory pain. Voltage-gated sodium channels (Nav) are thought to have crucial roles in the development of inflammatory and neuropathic pain, but there is limited information about whether the analgesic mechanism of carvacrol involves Nav. We used whole-cell, two-electrode, voltage-clamp techniques to examine the effects of carvacrol on sodium currents in Xenopus oocytes expressing α subunits of Nav1.2, Nav1.3, Nav1.6, Nav1.7, and Nav1.8. Carvacrol dose-dependently suppressed sodium currents at a holding potential that induced half-maximal current. The half-maximal inhibitory concentration values for Nav1.2, Nav1.3, Nav1.6, Nav1.7, and Nav1.8 were 233, 526, 215, 367, and 824 μmol/L, respectively, indicating that carvacrol had more potent inhibitory effects towards Nav1.2 and Nav1.6 than Nav1.3, Nav1.7, and Nav1.8. Gating analysis showed a depolarizing shift of the activation curve and a hyperpolarizing shift of the inactivation curve in all five α subunits following carvacrol treatment. Furthermore, carvacrol exhibits a use-dependent block for all five α Nav subunits. These findings provide a better understanding of the mechanisms associated with the analgesic effect of carvacrol.
  • Kouichiro Minami, Yota Kokubo
    Journal of anesthesia 33 (4) 567 - 567 2019/08 [Refereed][Not invited]
  • Kanako Miyano, Seiji Shiraishi, Koichiro Minami, Yuka Sudo, Masami Suzuki, Toru Yokoyama, Kiyoshi Terawaki, Miki Nonaka, Hiroaki Murata, Yoshikazu Higami, Yasuhito Uezono
    International journal of molecular sciences 20 (13) 2019/07 [Refereed][Not invited]
     
    Carboplatin, an anticancer drug, often causes chemotherapy-induced peripheral neuropathy (PN). Transient receptor potential ankyrin 1 (TRPA1), a non-selective cation channel, is a polymodal nociceptor expressed in sensory neurons. TRPA1 is not only involved in pain transmission, but also in allodynia or hyperalgesia development. However, the effects of TRPA1 on carboplatin-induced PN is unclear. We revealed that carboplatin induced mechanical allodynia and cold hyperalgesia, and the pains observed in carboplatin-induced PN models were significantly suppressed by the TRPA1 antagonist HC-030031 without a change in the level of TRPA1 protein. In cells expressing human TRPA, carboplatin had no effects on changes in intracellular Ca2+ concentration ([Ca2+]i); however, carboplatin pretreatment enhanced the increase in [Ca2+]i induced by the TRPA1 agonist, allyl isothiocyanate (AITC). These effects were suppressed by an inhibitor of protein kinase A (PKA). The PKA activator forskolin enhanced AITC-induced increase in [Ca2+]i and carboplatin itself increased intracellular cyclic adenosine monophosphate (cAMP) levels. Moreover, inhibition of A-kinase anchoring protein (AKAP) significantly decreased the carboplatin-induced enhancement of [Ca2+]i induced by AITC and improved carboplatin-induced mechanical allodynia and cold hyperalgesia. These results suggested that carboplatin induced mechanical allodynia and cold hyperalgesia by increasing sensitivity to TRPA1 via the cAMP-PKA-AKAP pathway.
  • Toru Yokoyama, Kiyoshi Terawaki, Kouichiro Minami, Kanako Miyano, Miki Nonaka, Miaki Uzu, Yohei Kashiwase, Kazuyoshi Yanagihara, Yoichi Ueta, Yasuhito Uezono
    Journal of neuroendocrinology 30 (9) e12630  2018/09 [Refereed][Not invited]
     
    In cancer cachexia, abnormal metabolism and neuroendocrine dysfunction cause anorexia, tissue damage and atrophy, which can in turn alter body fluid balance. Arginine vasopressin, which regulates fluid homeostasis, is secreted by magnocellular neurosecretory cells (MNCs) of the hypothalamic supraoptic nucleus. Arginine vasopressin secretion by MNCs is regulated by both excitatory and inhibitory synaptic activity, alterations in plasma osmolarity and various peptides, including angiotensin II. In the present study, we used whole-cell patch-clamp recordings of brain slices to determine whether hyperosmotic stimulation and/or angiotensin II potentiate excitatory synaptic input in a rat model of cancer cachexia, similar to their effects in normal (control) rats. Hyperosmotic (15 and 60 mmol L-1   mannitol) stimulation and angiotensin II (0.1 μmol L-1 ) increased the frequency, but not the amplitude, of miniature excitatory postsynaptic currents in normal rats; in model rats, both effects were significantly attenuated. These results suggest that cancer cachexia alters supraoptic MNC sensitivity to osmotic and angiotensin II stimulation.
  • Kouichiro Minami, Yota Kokubo, Ichinosuke Maeda, Shingo Hibino
    Journal of anesthesia 31 (1) 152 - 155 2017/02 [Refereed][Not invited]
     
    In chest compression for cardiopulmonary resuscitation (CPR), the lower half of the sternum is pressed according to the American Heart Association (AHA) guidelines 2010. These have been no studies which identify the exact location of the applied by individual chest compressions. We developed a rubber power-flexible capacitive sensor that could measure the actual pressure point of chest compression in real time. Here, we examined the pressure point of chest compression by ambulance crews during CPR using a mannequin. We included 179 ambulance crews. Chest compression was performed for 2 min. The pressure position was monitored, and the quality of chest compression was analyzed by using a flexible pressure sensor (Shinnosukekun™). Of the ambulance crews, 58 (32.4 %) pressed the center and 121 (67.6 %) pressed outside the proper area of chest compression. Many of them pressed outside the center; 8, 7, 41, and 90 pressed on the caudal, left, right, and cranial side, respectively. Average compression rate, average recoil, average depth, and average duty cycle were 108.6 counts per minute, 0.089, 4.5 cm, and 48.27 %, respectively. Many of the ambulance crews did not press on the sternal lower half definitely. This new device has the potential to improve the quality of CPR during training or in clinical practice.
  • Kouichiro Minami, Yota Kokubo, Ichinosuke Maeda, Shingo Hibino
    The American journal of emergency medicine 34 (5) 899 - 902 2016/05 [Refereed][Not invited]
     
    BACKGROUND: Feedback devices are used to improve the quality of chest compression (CC). However, reports have noted that accelerometers substantially overestimate depth when cardiopulmonary resuscitation (CPR) is performed on a soft surface. Here, we determined whether a flexible pressure sensor could correctly evaluate the depth CC performed on a mannequin placed on a mattress. METHODS: Chest compression was performed 100 times/min by a compression machine on the floor or a mattress, and the depth of CC was monitored using a flexible pressure sensor (Shinnosukekun) and CPRmeter(™). The depth of machine-performed CC was consistently 5cm. We compared data from the feedback sensor with the true depth of CC using dual real-time auto feedback system that incorporated an infrared camera (CPR evolution(™)). RESULTS: On the floor, the true depth of CC was 5.0±0.0cm (n=100), or identical to the depth of CC performed by the machine. The Shinnosukekun(™) measured a mean (±SD) CC depth of 5.0±0.1cm (n=100), and the CPRmeter(™) measured a depth of 5.0±0.2cm (n=100). On the mattress, the true depth of CC was 4.4±0.0cm (n=100). The Shinnosukekun(™) measured a mean CC depth of 4.4±0.0cm (n=100), and the CPRmeter(™) measured a depth of 4.7±0.1cm (n=100). The data of CPRmeter(™) were overestimated (P<.0001 between the true depth and the CPRmeter(™)-measured depth). CONCLUSION: The Shinnosukekun(™) could correctly measure the depth of CC on a mattress. According to our present results, the flexible pressure sensor could be a useful feedback system for CC performed on a soft surface.
  • Kouichiro Minami, Yota Kokubo, Ichinosuke Maeda, Shingo Hibino
    Resuscitation 99 e11-2  2016/02 [Refereed][Not invited]
  • Kouichiro Minami, Junichi Ogata, Yasuhito Uezono
    Naunyn-Schmiedeberg's archives of pharmacology 388 (10) 999 - 1007 2015/10 [Refereed][Not invited]
     
    Tramadol is an analgesic that is used worldwide for pain, but its mechanisms of action have not been fully elucidated. The majority of studies to date have focused on activation of the μ-opioid receptor (μOR) and inhibition of monoamine reuptake as mechanisms of tramadol. Although it has been speculated that tramadol acts primarily through activation of the μOR, no evidence has revealed whether tramadol directly activates the μOR. During the past decade, major advances have been made in our understanding of the physiology and pharmacology of ion channels and G protein-coupled receptor (GPCR) signaling. Several studies have shown that GPCRs and ion channels are targets for tramadol. In particular, tramadol has been shown to affect GPCRs. Here, the effects of tramadol on GPCRs, monoamine transporters, and ion channels are presented with a discussion of recent research on the mechanisms of tramadol.
  • Kouichiro Minami, Yuka Sudo, Kanako Miyano, Robert S Murphy, Yasuhito Uezono
    Journal of anesthesia 29 (3) 475 - 479 2015/06 [Refereed][Not invited]
     
    Tramadol has been used as an analgesic for several decades. µ-Opioid receptors (µORs) are the major receptors that mediate the analgesic effects of opioids. Although µORs have been thought to be one of the sites of action of tramadol, there has been no report that directly proves whether tramadol is an agonist of μOR or not. In this study, we examined the effects of tramadol and its main active metabolite O-desmethyltramadol (M1), on the function of µORs using Xenopus oocytes expressing cloned human µORs. The effects of tramadol and M1 were evaluated using the Ca(2+)-activated Cl(-) current assay method for G(i/o)-protein-coupled receptors by using a µOR fused to G(qi5) (µOR-G(qi5)) in Xenopus oocytes. DAMGO [(D-Ala(2), N-MePhe(4), Gly(5)-ol)-enkephalin] evoked Cl(-) currents in oocytes expressing µOR-G(qi5) in a concentration-dependent manner. Tramadol and M1 also evoked Cl(-) currents in the oocytes expressing µOR-G(qi5); however, relatively higher concentrations (compared to DMAGO) were necessary to induce such currents. Tramadol and M1 had a direct effect on µORs expressed in Xenopus oocytes. Although the monoamine uptake system and several types of ligand-gated ion channels are thought to be one of the targets for tramadol, tramadol-induced antinociception may be mediated at least in part, by the direct activation of µORs.
  • Kanako Miyano, Kouichiro Minami, Toru Yokoyama, Katsuya Ohbuchi, Takuhiro Yamaguchi, Satoshi Murakami, Seiji Shiraishi, Masahiro Yamamoto, Motohiro Matoba, Yasuhito Uezono
    Anesthesia and analgesia 120 (4) 790 - 8 2015/04 [Refereed][Not invited]
     
    BACKGROUND: The transient receptor potential vanilloid 1 (TRPV1) and the transient receptor potential ankyrin 1 (TRPA1), which are expressed in sensory neurons, are polymodal nonselective cation channels that sense noxious stimuli. Recent reports showed that these channels play important roles in inflammatory, neuropathic, or cancer pain, suggesting that they may serve as attractive analgesic pharmacological targets. Tramadol is an effective analgesic that is widely used in clinical practice. Reportedly, tramadol and its metabolite (M1) bind to μ-opioid receptors and/or inhibit reuptake of monoamines in the central nervous system, resulting in the activation of the descending inhibitory system. However, the fundamental mechanisms of tramadol in pain control remain unclear. TRPV1 and TRPA1 may be targets of tramadol; however, they have not been studied extensively. METHODS: We examined whether and how tramadol and M1 act on human embryonic kidney 293 (HEK293) cells expressing human TRPV1 (hTRPV1) or hTRPA1 by using a Ca imaging assay and whole-cell patch-clamp recording. RESULTS: Tramadol and M1 (0.01-10 μM) alone did not increase in intracellular Ca concentration ([Ca]i) in HEK293 cells expressing hTRPV1 or hTRPA1 compared with capsaicin (a TRPV1 agonist) or the allyl isothiocyanate (AITC, a TRPA1 agonist), respectively. Furthermore, in HEK293 cells expressing hTRPV1, pretreatment with tramadol or M1 for 5 minutes did not change the increase in [Ca]i induced by capsaicin. Conversely, pretreatment with tramadol (0.1-10 μM) and M1 (1-10 μM) significantly suppressed the AITC-induced [Ca]i increases in HEK293 cells expressing hTRPA1. In addition, the patch-clamp study showed that pretreatment with tramadol and M1 (10 μM) decreased the inward currents induced by AITC. CONCLUSIONS: These data indicate that tramadol and M1 selectively inhibit the function of hTRPA1, but not that of hTRPV1, and that hTRPA1 may play a role in the analgesic effects of these compounds.
  • Toru Yokoyama, Kouichiro Minami, Kiyoshi Terawaki, Kanako Miyano, Junichi Ogata, Takashi Maruyama, Mamoru Takeuchi, Yasuhito Uezono, Yoichi Ueta
    Brain research 1583 45 - 54 2014/10 [Refereed][Not invited]
     
    Kisspeptin is the natural ligand of the G protein-coupled receptor -54 and plays a major role in gonadotropin-releasing hormone secretion in the hypothalamus. Kisspeptin-10 is an endogenous derivative of kisspeptin and has 10 -amino acids. Previous studies have demonstrated that central administration of kisspeptin-10 stimulates the secretion of arginine vasopressin (AVP) in male rats. We examined the effects of kisspeptin-10 on- excitatory synaptic inputs to magnocellular neurosecretory cells (MNCs) including AVP neurons in the supraoptic nucleus (SON) by obtaining in vitro whole-cell patch-clamp recordings from slice preparations of the rat brain. The application of kisspeptin-10 (100 nM-1 μM) significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) in a dose-related manner without affecting the amplitude. The kisspeptin-10-induced potentiation of the mEPSCs was significantly attenuated by previous exposure to the kisspeptin receptor antagonist kisspeptin-234 (100 nM) and to the protein kinase C inhibitor bisindolylmaleimide I (20 nM). These results suggest that kisspeptin-10 participates in the regulation of synaptic inputs to the MNCs in the SON by interacting with the kisspeptin receptor.
  • Kouichiro Minami, Masaki Yoshie, Takemitsu Aoki, Yoshiharu Ito
    Resuscitation 84 (10) e137-8  2013/10 [Refereed][Not invited]
  • Kouichiro Minami, Yasuhito Uezono
    Journal of anesthesia 27 (2) 284 - 92 2013/04 [Refereed][Not invited]
     
    The exact mechanisms of action behind anesthetics and analgesics are still unclear. Much attention was focused on ion channels in the central nervous system as targets for anesthetics and analgesics in the 1980s. During the 1990s, major advances were made in our understanding of the physiology and pharmacology of G protein coupled receptor (GPCR) signaling. Thus, several lines of studies have shown that G protein coupled receptors (GPCRs) are one of the targets for anesthetics and analgesics and especially, that some of them inhibit the functions of GPCRs, i.e,, muscarinic receptors and substance P receptors. However, these studies had been focused on only G(q) coupled receptors. There has been little work on G(s)- and G(i)-coupled receptors. In the last decade, a new assay system, using chimera G(i/o)-coupled receptor fused to Gq(i5), has been established and the effects of anesthetics and analgesics on the function of G(i)-coupled receptors is now more easily studied. This review highlights the recent progress of the studies regarding the effects of anesthetics and analgesics on GPCRs.
  • Toshihiko Yanagita, Shinya Satoh, Yasuhito Uezono, Kiyotaka Matsuo, Takayuki Nemoto, Toyoaki Maruta, Norie Yoshikawa, Tomomi Iwakiri, Kouichiro Minami, Manabu Murakami
    Neuropharmacology 61 (8) 1265 - 74 2011/12 [Refereed][Not invited]
     
    Insulin-like growth factor-1 (IGF-1) plays important roles in the regulation of neuronal development. The electrical activity of Na(+) channels is crucial for the regulation of synaptic formation and maintenance/repair of neuronal circuits. Here, we examined the effects of chronic IGF-1 treatment on cell surface expression and function of Na(+) channels. In cultured bovine adrenal chromaffin cells expressing Na(V)1.7 isoform of voltage-dependent Na(+) channels, chronic IGF-1 treatment increased cell surface [(3)H]saxitoxin binding by 31%, without altering the Kd value. In cells treated with IGF-1, veratridine-induced (22)Na(+) influx, and subsequent (45)Ca(2+) influx and catecholamine secretion were augmented by 35%, 33%, 31%, respectively. Pharmacological properties of Na(+) channels characterized by neurotoxins were similar between nontreated and IGF-1-treated cells. IGF-1-induced up-regulation of [(3)H]saxitoxin binding was prevented by phosphatydil inositol-3 kinase inhibitors (LY204002 or wortmannin), or Akt inhibitor (Akt inhibitor IV). Glycogen synthase kinase-3 (GSK-3) inhibitors (LiCl, valproic acid, SB216763 or SB415286) also increased cell surface [(3)H]saxitoxin binding by ∼ 33%, whereas simultaneous treatment of IGF-1 with GSK-3 inhibitors did not produce additive increasing effect on [(3)H]saxitoxin binding. IGF-1 (100 nM) increased Ser(437)-phosphorylated Akt and Ser(9)-phosphorylated GSK-3β, and inhibited GSK-3β activity. Treatment with IGF-1, LiCl or SB216763 increased protein level of Na(+) channel α-subunit; it was prevented by cycloheximide. Either treatment increased α-subunit mRNA level by ∼ 48% and accelerated α-subunit gene transcription by ∼ 30% without altering α-subunit mRNA stability. Thus, inhibition of GSK-3β caused by IGF-1 up-regulates cell surface expression of functional Na(+) channels via acceleration of α-subunit gene transcription.
  • 横山 徹, 南 浩一郎, 山田 賢治, 尾方 純一, 河合 誠義
    日本臨床救急医学会雑誌 (一社)日本臨床救急医学会 14 (4) 518 - 523 1345-0581 2011/08 [Not refereed][Not invited]
     
    目的:救急救命士による声門上気道デバイス(SAD)の使用実態を把握するとともに、新しいSADの使用に関する意識を調査する。方法:第19回全国救急隊員シンポジウムのライブセッションを聴講した救急救命士、および体験参加した救急救命士にアンケートを実施した。結果:体験参加した25名の救急救命士、聴講した293名の救急救命士からそれぞれ回答を得た。ふだん使用しているSADは、ラリンジアルチューブ(LT)が圧倒的に多かった。新しいSADでは、i-gelに関心が高く、今後の活動に有効であるという回答が多かった。結論:アンケートでは、通常LTを使用する救急救命士が多いことが確認された。新しいSADでは使用前の形状作成やカフ注入がいらないi-gelに関心が高かった。使用前準備に時間がかからず、確実に挿入しやすく手順も簡単なSADが現場では求められている。(著者抄録)
  • Toru Yokoyama, Kouichiro Minami, Yuka Sudo, Takafumi Horishita, Junichi Ogata, Toshihiko Yanagita, Yasuhito Uezono
    Journal of anesthesia 25 (4) 609 - 13 2011/08 [Refereed][Not invited]
     
    Sevoflurane is widely used as a volatile anesthetic in clinical practice. However, its mechanism is still unclear. Recently, it has been reported that voltage-gated sodium channels have important roles in anesthetic mechanisms. Much attention has been paid to the effects of sevoflurane on voltage-dependent sodium channels. To elucidate this, we examined the effects of sevoflurane on Na(v) 1.8, Na(v) 1.4, and Na(v) 1.7 expressed in Xenopus oocytes. The effects of sevoflurane on Na(v) 1.8, Na(v) 1.4, and Na(v) 1.7 sodium channels were studied by an electrophysiology method using whole-cell, two-electrode voltage-clamp techniques in Xenopus oocytes. Sevoflurane at 1.0 mM inhibited the voltage-gated sodium channels Na(v)1.8, Na(v)1.4, and Na(v)1.7, but sevoflurane (0.5 mM) had little effect. This inhibitory effect of 1 mM sevoflurane was completely abolished by pretreatment with protein kinase C (PKC) inhibitor, bisindolylmaleimide I. Sevoflurane appears to have inhibitory effects on Na(v)1.8, Na(v)1.4, and Na(v) 1.7 by PKC pathways. However, these sodium channels might not be related to the clinical anesthetic effects of sevoflurane.
  • 横山 徹, 南 浩一郎, 尾方 純一, 河合 誠義
    日本臨床救急医学会雑誌 (一社)日本臨床救急医学会 14 (3) 445 - 452 1345-0581 2011/06 [Not refereed][Not invited]
     
    目的:重症傷病者の救急搬送における気道管理は、生命予後を左右する最重要課題の1つである。ラリンジアルマスク(LMA)は気道確保のデバイスとして広く使用されてきたが、最近、LMAを改良したデバイスが臨床に使用されるようになった。本研究では、新型声門上デバイスの挿入時間や成功率などを従来のLMAと比較検討を行った。方法:新型声門上デバイス(sLMA、i-gel、air-Q)の使用経験のない救急救命士研修課程修了者10名に、cLMA、uLMAと同じ手順でモデル人形に挿入させ、初回挿入成功率、挿入時間を測定した。また、各デバイスの挿入しやすさをアンケートした。結果:挿入時間はair-Qが最も早く、i-gel、sLMA、cLMA、uLMAの順であった。air-Q、i-gel、sLMA、cLMAの初回挿入成功率は100%であった。アンケートではsLMA、air-Qが挿入しやすいという結果であった。結語:新型声門上デバイスのうちair-Qは挿入時間が短く、挿入もしやすかった。air-Qは救急搬送中の気道管理で有用性が期待できる。(著者抄録)
  • Toru Yokoyama, Toyoaki Ohbuchi, Takeshi Saito, Yuka Sudo, Hiroaki Fujihara, Kouichiro Minami, Toshihisa Nagatomo, Yasuhito Uezono, Yoichi Ueta
    European journal of pharmacology 655 (1-3) 31 - 7 2011/03 [Refereed][Not invited]
     
    Allyl isothiocyanates (AITC) and cinnamaldehyde are pungent compounds present in mustard oil and cinnamon oil, respectively. These compounds are well known as transient receptor potential ankyrin 1 (TRPA1) agonists. TRPA1 is activated by low temperature stimuli, mechanosensation and pungent irritants such as AITC and cinnamaldehyde. TRPA1 is often co-expressed in TRPV1. Recent study showed that hypertonic solution activated TRPA1 as well as TRPV1. TRPV1 is involved in excitatory synaptic inputs to the magnocellular neurosecretory cells (MNCs) that produce vasopressin in the supraoptic nucleus (SON). However, it remains unclear whether TRPA1 may be involved in this activation. In the present study, we examined the role of TRPA1 on the synaptic inputs to the MNCs in in vitro rat brain slice preparations, using whole-cell patch-clamp recordings. In the presence of tetrodotoxin, AITC (50μM) and cinnamaldehyde (30μM) increased the frequency of miniature excitatory postsynaptic currents without affecting the amplitude. This effect was significantly attenuated by previous exposure to ruthenium red (10μM), non-specific TRP channels blocker, high concentration of menthol (300μM) and HC-030031 (10μM), which are known to antagonize the effects of TRPA1 agonists. These results suggest that TRPA1 may exist at presynaptic terminals to the MNCs and enhance glutamate release in the SON.
  • Kouichiro Minami, Toru Yokoyama, Junichi Ogata, Yasuhito Uezono
    Journal of pharmacological sciences 115 (3) 421 - 4 2011 [Refereed][Not invited]
     
    Tramadol has been widely used as analgesic. O-Desmethyl tramadol (ODT) is one of the main metabolites of tramadol, having much greater analgesic potency than tramadol itself. Substance P receptors (SPR) are well known to modulate nociceptive transmission within the spinal cord. In this study, we investigated the effects of ODT on SPR expressed in Xenopus oocytes by examining SP-induced Ca(2+)-activated Cl(-) currents. ODT inhibited the SPR-induced Cl(-) currents at pharmacologically relevant concentrations. The protein kinase C (PKC) inhibitor bisindolylmaleimide I did not abolish the inhibitory effects of ODT on SP-induced Ca(2+)-activated Cl(-) currents. The results suggest that the tramadol metabolite ODT inhibits the SPR functions, which may be independent of activation of PKC-mediated pathways.
  • Kouichiro Minami, Yuka Sudo, Toru Yokoyama, Junichi Ogata, Mamoru Takeuchi, Yasuhito Uezono
    Pharmacology 88 (3-4) 127 - 32 2011 [Refereed][Not invited]
     
    Sevoflurane is widely used for anesthesia, and is commonly used together with opioids in clinical practice. However, the effects of sevoflurane on μ-opioid receptor (μOR) functions is still unclear. In this study, the effects of sevoflurane on μOR functions were analyzed by using Xenopus oocytes expressing a μOR fused to chimeric Gα protein G(qi5) (μOR-G(qi5)). Sevoflurane by itself did not elicit any currents in oocytes expressing μOR-G(qi5), whereas sevoflurane inhibited the [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO)-induced Cl(-) currents at clinically used concentrations. Sevoflurane did not affect the Cl(-) currents induced by AlF(4)(-), which directly led to activation of G proteins. The inhibitory effects of sevoflurane on the DAMGO-induced currents were not observed in oocytes pretreated with the protein kinase C (PKC) inhibitor GF109203X. These findings suggest that sevoflurane would inhibit μOR function. Further, the mechanism of inhibition by sevoflurane would be mediated by PKC.
  • Junichi Ogata, Tsuyoshi Udaka, Tsuyoshi Inaba, Yohei Kadokawa, Kouichiro Minami
    Masui. The Japanese journal of anesthesiology 克誠堂出版(株) 59 (1) 109 - 13 0021-4892 2010/01 [Refereed][Not invited]
     
    Polysomnography (PSG) has been the gold standard for the diagnosis of sleep apnea syndrome (SAS). However, PSG is not generally available since it is technically demanding, and cost and labour are necessary. Currently, there is growing demand for its diagnosis. Thus, simplified portable equipments have been increasingly utilized. Sleeprecorder SD-101 (Suzuken, Nagoya, Japan) is a pad-shaped and novel device for SAS analysis. A total of 162 sitting-sensor tips are 1.6 inch apart, embeded in the 55 x 22 inch pad, and capable of detecting load with precision of one gram. Sleeprecorder SD-101 placed beneath the chest can recognize respiratory pattern and record thoracic movement during sleep. SASLyzer (Suzuken, Nagoya, Japan), a software installed in a compatible PC, analyzes the data and indicates apnea-hypopnea index (AHI). We present a case of SAS in a 40-year-old man (181 cm, 98 kg) with peritonsillitis. We used Sleeprecorder SD-101 since he complained of severe snoring and excessive daytime sleepiness. He had severe SAS with AHI 50.7. Subsequently, conventional PSG also indicated AHI 77. In the present case with severe SAS, these two methods showed equivalent severity. Sleeprecorder SD-101 could be a useful device for screening of SAS patients.
  • Kouichiro Minami, Yuka Sudo, Seiji Shiraishi, Masanori Seo, Yasuhito Uezono
    Journal of pharmacological sciences 112 (4) 424 - 31 2010 [Refereed][Not invited]
     
    G protein-coupled receptors, in particular, Ca(2+)-mobilizing G(q)-coupled receptors have been reported to be targets for anesthetics. Opioids are commonly used analgesics in clinical practice, but the effects of anesthetics on the opioid mu-receptors (muOR) have not been systematically examined. We report here an electrophysiological assay to analyze the effects of anesthetics and ethanol on the functions of muOR in Xenopus oocytes expressing a muOR fused to chimeric Galpha protein G(qi5) (muOR-G(qi5)). Using this system, the effects of halothane, ketamine, propofol, and ethanol on the muOR functions were analyzed. In oocytes expressing muOR-G(qi5), the( )muOR agonist DAMGO ([D-Ala(2),N-MePhe(4),Gly-ol]-enkephalin) elicited Ca(2+)-activated Cl(-) currents in a concentration-dependent manner (EC(50) = 0.24 microM). Ketamine, propofol, halothane, and ethanol themselves did not elicit any currents in oocytes expressing muOR-G(qi5), whereas ketamine and ethanol inhibited the DAMGO-induced Cl(-) currents at clinically equivalent concentrations. Propofol and halothane inhibited the DAMGO-induced currents only at higher concentrations. These findings suggest that ketamine and ethanol may inhibit muOR functions in clinical practice. We propose that the electrophysiological assay in Xenopus oocytes expressing muOR-G(qi5) would be useful for analyzing the effects of anesthetics and analgesics on opioid receptor function.
  • Minoru Hojo, Yuka Sudo, Yuko Ando, Koichiro Minami, Masafumi Takada, Takehiro Matsubara, Masato Kanaide, Kohtaro Taniyama, Koji Sumikawa, Yasuhito Uezono
    JOURNAL OF PHARMACOLOGICAL SCIENCES 108 (3) 308 - 319 1347-8613 2008/11 [Refereed][Not invited]
     
    Interactions between mu-opioid receptor (mu OR) and cannabinoid CB(1) receptor (CB(1)R) were examined by morphological and electrophysiological methods. In baby hamster kidney (BHK) cells coexpressing mu OR fused to the yellow fluorescent protein Venus and CB(1)R fused to the cyan fluorescent protein Cerulean, both colors were detected on the cell surface; and fluorescence resonance energy transfer (FRET) analysis revealed that mu OR and CB(1)R formed a heterodimer. Coimmunoprecipitation and Western blotting analyses also confirmed the heterodimers of mu OR and CB(1)R. [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin (DAMGO) or CP55,940 elicited K(+) currents in Xenopus oocytes expressing mu OR or CB(1)R together with G protein activated-inwardly rectifying K(+) channels (GIRKs), respectively. In oocytes coexpressing both receptors, either of which was fused to the chimeric G alpha protein G(qi5) that activates the phospholipase C pathway, both DAMGO and CP55,940 elicited Ca(2+)-activated Cl(-) currents, indicating that each agonist can induce responses through Gqi5 fused to either its own receptor or the other. Experiments with endogenous G(i/o). protein inactivation by pertussis toxin (PTX) supported the functional heterodimerization of mu OR/CB(1)R through PTX-insensitive G(qi5(m)) fused to each receptor. Thus, mu OR and CB(1)R form a heterodimer and transmit a signal through a common G protein. Our electrophysiological method could be useful for determination of signals mediated through heterodimerized G protein-coupled receptors.
  • Junichi Ogata, Koji Tamura, Keita Miyanishi, Kouichiro Minami, Yasunori Haranishi, Takayuki Tsubaki
    Masui. The Japanese journal of anesthesiology 57 (4) 439 - 42 0021-4892 2008/04 [Refereed][Not invited]
     
    Alkaptonuric ochronosis, caused by a deficiency of homogentisate 1,2-dioxygenase, is a rare, autosomal recessive, metabolic disorder. Accumulation of homogentisate acid (HGA) at the connective tissue destructs the spine and large joints, and cardiac valvular disease is prominent. In this report, we describe a case of alkaptonuric ochronosis for anesthetic management. A 75-year-old female patient with the disease was scheduled for a total-hip arthroplasty. We avoided applying general anesthesia for her valvular regurgitations. Spinal anesthesia was achieved successfully, and resulted in a hypesthesia level at T12. Although a epidural catheter was indwelled with no leak of cerebrospinal fluid, an accidental dural puncture appeared later during the surgery, suggesting a subdural catheterization. She had an uneventful perioperative course without any symptoms. In the patient of alkaptonuric ochronosis, the dura and arachnoid membrane could be damaged made vulnerable by HGA. In addition, since the clinical findings resemble ankylosing spondylitis, degenerative changes such as a narrowing of the disk space and spine fusion would make the regional technique unsuccessful. In term of anesthesia, alkaptonuric ochronosis requires ingenuity since there are a number of factors associated with prevention of untoward complications. Each case is to be evaluated individually and managed carefully.
  • Junichi Ogata, Kayako Segawa, Kouichiro Minami
    Masui. The Japanese journal of anesthesiology 克誠堂出版 56 (8) 896 - 910 0021-4892 2007/08 [Not refereed][Not invited]
     
    In the failing heart, numerous changes occur in cardiac adrenergic receptors (ARs) and intracellular signal transduction pathways. The most striking of these alterations appears at beta1 ARs, and the desensitization is the most prominent. Since malfunctions of beta1 ARs prevent intracellular signal transduction, the desensitization plays an important role in the onset and progression of the heart failure. Currently, several lines of evidence show the efficacy of inotropic agents, such as adenylate cyclase activator, that depend not on the ARs. Thus, it is essential to understand the pathway for the etiologic/pathologic evaluation for appropriate usage of these drugs for an adequate period. A novel water-soluble forskolin derivative, colforsin daropate hydrochloride (CDH) is a positive inotropic agent for treatment of the heart failure, especially in the severe stage with the beta1 AR desensitization. CDH potentiates cAMP activity via its direct action on adenylate cyclase, resulting in cardiotonic action. On the other hand, CDH relaxes vascular smooth muscle, while it antagonizes antidiuretic effects of angiotensin II and noradrenaline, involved in renal protection. In addition, CDH attenuates the mesangial cell proliferation and the inflammatory reaction, related with antiproliferative property of adrenomedullin and ketamine. To gain insights into the CDH action, we should take into account that intracellular signal transduction pathways in myocardium, smooth muscle and mesangial cell are controlled in a distinct manner.
  • Atsushi Takizuka, Kouichiro Minami, Yasuhito Uezono, Takafumi Horishita, Toru Yokoyama, Munehiro Shiraishi, Takeshi Sakurai, Akio Shigematsu, Yoichi Ueta
    Naunyn-Schmiedeberg's archives of pharmacology 375 (5) 293 - 301 0028-1298 2007/07 [Refereed][Not invited]
     
    Dexmedetomidine, an alpha(2)-adrenoceptor agonist, has been approved for clinical use, although the mechanism of dexmedetomidine action has not been fully elucidated. Several studies have shown that G protein-coupled receptors (GPCRs) are recognized as targets for anesthetics and analgesics. Therefore, it is of interest to determine whether dexmedetomidine affects the function of GPCRs other than the alpha(2)-adrenoceptor. We examined the effects of dexmedetomidine on M(1), M(3), 5-HT(2C), substance P, and orexin 1 receptors in Xenopus oocytes expressing individual receptors. In addition, we investigated the effects of dexmedetomidine on muscarinic receptor-mediated changes in [Ca(2+)](i) in the dorsal root ganglia (DRG) of 3-week-old Wister rats. Dexmedetomidine did not affect the 5-HT(2C)-, or substance P-induced Cl(-) currents and had little inhibition on the orexin A-induced current in oocytes expressing the respective receptors. The compound also had little effect on the acetylcholine (ACh, 1 microM)-induced Ca(2+)-activated Cl(-) currents in Xenopus oocytes expressing M(1) receptors. In contrast, dexmedetomidine inhibited the ACh-induced currents in Xenopus oocytes expressing M(3) receptors; 1 nM, 10 nM, 100 nM, and 1 microM dexmedetomidine reduced the current to 66.5 +/- 4.8, 51.3 +/- 12, 34.6 +/- 11, and 26.8 +/- 6.4% of the control value, respectively (EC(50) = 3.5 +/- 0.7 nM). Dexmedetomidine reduced the ACh-induced Cl(-) currents after treatment with the selective protein kinase C inhibitor GF109203X. Moreover, the compound inhibited the muscarinic receptor-mediated increases in [Ca(2+)](i) in cultured DRG cells in a concentration-dependent manner. Dexmedetomidine inhibits the function of M(3) receptors, in addition to its agonistic effects on alpha(2)-adrenoceptors, which provides further insight into the pharmacological properties of dexmedetomidine.
  • Synthetic oxytocin and latex allergy
    J. Ogata, K. Minami
    BRITISH JOURNAL OF ANAESTHESIA 98 (6) 845 - 846 2007/06 [Refereed][Not invited]
  • Kouichiro Minami, Yasuhito Uezono, Yoichi Ueta
    Journal of pharmacological sciences 103 (3) 253 - 60 1347-8613 2007/03 [Refereed][Not invited]
     
    Tramadol is an analgesic that is used worldwide, but its mechanisms of action have not been elucidated. It has been speculated that tramadol acts primarily through the activation of micro-opioid receptors and the inhibition of monoamine reuptake. The majority of studies to date have focused on ion channels in the central nervous system as targets of anesthetics and analgesics. During the past decade, major advances have been made in our understanding of the physiology and pharmacology of G-protein coupled receptor (GPCR) signaling. Several studies have shown that GPCRs and ion channels are targets for analgesics and anesthetics. In particular, tramadol has been shown to affect GPCRs, including muscarinic acetylcholine receptors and 5-hydroxytryptamine receptors. Here, the effects of tramadol on monoamine transporters, GPCRs, and ion channels are presented, and recent research on the pharmacology of tramadol is discussed.
  • Junichi Ogata, Takafumi Horishita, Munehiro Shiraishi, Kouichiro Minami
    Journal of anesthesia 21 (4) 525 - 6 0913-8668 2007 [Refereed][Not invited]
  • Kouichiro Minami, Yasuhito Uezono, Takeshi Sakurai, Takafumi Horishita, Munehiro Shiraishi, Yoichi Ueta
    Pharmacology 79 (4) 236 - 42 0031-7012 2007 [Refereed][Not invited]
     
    Neurons in the hypothalamus containing the neuropeptide orexin have been implicated in the control of sleep and wakefulness and in the pathology of narcolepsy. In this study, we investigated the effects of volatile anesthetics, ethanol and intravenous anesthetics on orexin-A-induced Ca2+-activated Cl- currents using Xenopus oocytes expressing orexin-1 receptors (OX1Rs). The volatile anesthetics isoflurane, enflurane and halothane inhibited Cl- currents elicited by 1-micromol/l orexin-A. Ethanol and the intravenous anesthetics pentobarbital and ketamine also inhibited the action of orexin-A. The inhibitory effects of all of the compounds tested were shown to be caused by the inhibition of OX1R function. These results may, at least in part, explain their hypnotic effects.
  • Tadanori Terada, Kouichiro Minami, Munehiro Shiraishi, Takafumi Horishita, Takeyoshi Sata
    Masui. The Japanese journal of anesthesiology 55 (12) 1484 - 6 0021-4892 2006/12 [Refereed][Not invited]
     
    There has been little information about anesthesia for a patient with a history of multiple drug allergies. We gave anesthesia for a 32-year-old woman with polyarteritis nodosa and history of multiple drug allergies. She was scheduled to undergo bilateral tonsilectomy. We could not perform the preoperative screening of the drugs using a dermal test because of a high risk of anaphylactic shock. Anesthesia was induced with sevoflurane and nitrous oxide and maintained with sevoflurane, nitrous oxide, and fentanyl. The intra- and postoperative course was uneventful. It is important to inquire history of allergies adequately for preoperative recognition of allergens. General anesthesia with sevoflurane would be useful for a patient with history of multiple drug allergies.
  • Takafumi Horishita, Kouichiro Minami, Yasuhito Uezono, Munehiro Shiraishi, Junichi Ogata, Takashi Okamoto, Akio Shigematsu
    Pharmacology 77 (2) 93 - 9 0031-7012 2006 [Refereed][Not invited]
     
    PURPOSE: Tramadol is widely used clinically as an analgesic, yet the mechanism by which it produces antinociception remains unclear. O-Desmethyl tramadol, the main metabolite of tramadol, is a more potent analgesic than tramadol. We reported previously that tramadol inhibits the 5-hydroxytryptamine (5-HT) type 2C receptor (5-HT(2C)R), a G-protein-coupled receptor that is expressed widely within brain and that mediates several effects of 5-HT, including nociception, feeding, and locomotion. The effects of O-desmethyl tramadol on 5-HT(2C)R have not been studied. In this study, we investigated the effect of O-desmethyl tramadol on 5-HT(2C)R expressed in Xenopus oocytes. METHODS: We examined the effect of O-desmethyl tramadol on 5-HT(2C)R using the Xenopus oocyte expression system. Furthermore, we investigated the effects of O-desmethyl tramadol on the binding of [(3)H]5-HT by 5-HT(2C)R. RESULTS: O-Desmethyl tramadol, at pharmacologically relevant concentrations, inhibited 5-HT-evoked Ca(2+)-activated Cl(-) currents in oocytes that expressed 5-HT(2C)R. The inhibitory effect of O-desmethyl tramadol on 5-HT(2C)R was overcome at higher concentrations of 5-HT. Bisindolylmaleimide I (GF109203X), a protein kinase C inhibitor, increased 5-HT-evoked currents but had little effect on the inhibition of 5-HT-evoked currents by O-desmethyl tramadol. O-Desmethyl tramadol inhibited the specific binding of [(3)H]5-HT by 5-HT(2C)R expressed in oocytes. O-Desmethyl tramadol altered the apparent dissociation constant for binding of [(3)H]5-HT by 5-HT(2C)R without changing maximum binding, which indicated competitive inhibition. CONCLUSION: These results suggest that O-desmethyl tramadol inhibits 5-HT(2C)R, which provides further insight into the pharmacological properties of tramadol and O-desmethyl tramadol.
  • Kouichiro Minami, Yasuhito Uezono
    Current pharmaceutical design 12 (15) 1931 - 7 1381-6128 2006 [Refereed][Not invited]
     
    The mechanisms of action of anesthetics are unclear. Much attention has been focused on ion channels in the central nervous system as targets for anesthetics. During the last decade, major advances have been made in our understanding of the physiology and pharmacology of G-protein-coupled receptor (GPCR) signaling. Several lines of studies have shown that GPCRs are targets for anesthetics and that some anesthetics inhibit the functions of Gq-coupled receptors, including muscarinic acetylcholine (ACh) M(1), metabotropic type 5 glutamate, 5-hydroxytryptamine (5-HT) type 2A, and substance P receptors. Nearly 160 GPCRs have been identified, based on their gene sequence and ability to interact with known endogenous ligands. However, an estimated 500-800 additional GPCRs have been classified as "orphan" receptors (oGPCRs) because their endogenous ligands have not yet been identified. Given that known GPCRs are targets for anesthetics, these oGPCRs represent a rich group of receptor targets for anesthetics. This article highlights the effects of anesthetics on Gq-coupled receptors, and discusses whether GPCRs other than Gq-coupled receptors are targets for anesthetics.
  • Takafumi Horishita, Munehiro Shiraishi, Kouichiro Minami
    International Congress Series 1283 277 - 278 0531-5131 2005/11 [Refereed][Not invited]
     
    We investigated the effect of volatile anesthetics, enflurane, isoflurane on 5-HT2CR expressed in Xenopus oocytes. Enflurane, and isoflurane inhibited 5-HT-evoked Ca2+-activated Cl- currents in oocytes that expressed 5-HT2CR in dose-dependent manner. Bisindolylmaleimide I (GF109203X), a protein kinase C inhibitor, increased 5-HT-evoked currents but had little effect on the inhibition of 5-HT-evoked currents by enflurane and isoflurane. These results suggest that O-desmethyl tramadol inhibits the function of 5-HT2CR, which may explain the antinociceptive effects of this substance. © 2005.
  • Kouichiro Minami, Yasuhito Uezono
    International Congress Series 1283 108 - 112 0531-5131 2005/11 [Refereed][Not invited]
     
    During the last decade, major advances have been made in our understanding of the physiology and pharmacology of G-protein-coupled receptor (GPCR) signaling. Several lines of studies have shown that GPCRs are targets for anesthetics and that some anesthetics inhibit the functions of Gq-coupled receptors. Nearly 160 GPCRs have been identified based on their gene sequence and ability to interact with known endogenous ligands. However, an estimated 500-800 additional GPCRs have been classified as "orphan" receptors (oGPCRs) because their endogenous ligands have not yet been identified. Given that known GPCRs are targets for anesthetics, these oGPCRs represent a rich group of receptor targets for anesthetics. This article highlights the effects of anesthetics on Gq-coupled receptors, and discusses whether GPCRs other than Gq-coupled receptors are targets for anesthetics. © 2005 Elsevier B.V. All rights reserved.
  • 南 浩一郎
    麻酔 克誠堂出版 54 (11) 1224 - 1233 0021-4892 2005/11 [Not refereed][Not invited]
  • 堀下 貴文, 南 浩一郎, 白石 宗大
    麻酔 克誠堂出版 54 (9) 1037 - 1039 0021-4892 2005/09 [Not refereed][Not invited]
     
    56歳男.甲状腺腫瘍で,甲状腺左葉切除術,放射線療法が施行された.以後,腫瘍の気管浸潤により,気道狭窄を起こし,呼吸困難となった.1ヵ月前に全身麻酔下で気管内から腫瘍のレーザー焼却術を行い,気管狭窄部にステントが挿入された.再度,腫瘍増大による気管狭窄を起こし,トラヘルパーが挿入された.CTによりステント直下に腫瘍増大による気管狭窄を認めた.内視鏡下に狭窄部位への新たなステント留置を試みたが,誤って左主気管支まで挿入された.急遽,全身麻酔下でのステント抜去術を予定した.麻酔導入は気管支ファイバーを用いて,プロポフォール,フェンタニル,ドロペリドールによる半覚醒下気管挿管を行った.輪状軟骨下部を切開し,切開部位からステントを抜去する方法に変更した.手術操作時は気管チューブからの換気が不能になり,自発呼吸を残したまま,麻酔深度を深くすることが安全な麻酔法と考えた.手術は,気管切開部位に気管チューブを挿入して終了した
  • Takafumi Horishita, Kouichiro Minami, Kazunori Koga, Junichi Ogata, Takeyoshi Sata
    Anesthesia and analgesia 101 (2) 608 - 608 0003-2999 2005/08 [Refereed][Not invited]
  • Kouichiro Minami, Motohiro Nakamura, Takafumi Horishita, Junichi Ogata, Takeyoshi Sata
    Masui. The Japanese journal of anesthesiology 54 (8) 929 - 33 0021-4892 2005/08 [Refereed][Not invited]
     
    BACKGROUND: Complications related to anesthesia remain a problem. We studied the incidence of complications during anesthesia in 2688 patients who had undergone anesthesia in the University of Occupational and Environmental Health Hospital. METHODS: We checked the anesthesia records retrospectively and analyzed the collected data for the incidence of complications during anesthesia. RESULTS: The total incidence of complications during anesthesia was 8.7%:5.5% related to circulation and 1.9% to respiration. CONCLUSIONS: Complications related to anesthesia should be prevented as much as possible through anesthesiologists' efforts in protocol development and skilled assistance.
  • 南 浩一郎, 中村 元洋, 堀下 貴文
    麻酔 克誠堂出版 54 (8) 929 - 933 0021-4892 2005/08 [Not refereed][Not invited]
     
    麻酔中に発生した合併症の現状を把握するため,2002年1月1日から12月31日の間に行われた麻酔科管理症例において発生した合併症を検討した.麻酔科管理2688症例を対象とし,麻酔導入時から手術室搬出までに処置を必要としたものを合併症とした.合併症を起こしていたのは2688例中236例で,全体の8.7%であった.発生する時間帯は,麻酔導入時89例,麻酔中92例,術後から手術室搬出時までの時間帯64例であった.合併症は,年齢が高齢になるに従って増える傾向を示した.ASA physical status別分類による頻度では,ASAリスク分類が上がるに従って合併症の頻度も高かった.合併症の種類では,循環器系合併症(5.5%)がもっとも多く,呼吸器系合併症(1.9%)の順であった.術前に予測できなかった挿管困難や心筋虚血の所見も認めた
  • Motohiro Nakamura, Kouichiro Minami, Yasuhito Uezono, Takafumi Horishita, Junichi Ogata, Munehiro Shiraishi, Takashi Okamoto, Tadanori Terada, Takeyoshi Sata
    Anesthesia and analgesia 101 (1) 180 - 6 0003-2999 2005/07 [Refereed][Not invited]
     
    O-desmethyl tramadol is one of the main metabolites of tramadol. It has been widely used clinically and has analgesic activity. Muscarinic receptors are involved in neuronal functions in the brain and autonomic nervous system, and much attention has been paid to these receptors as targets for analgesic drugs in the central nervous system. We have reported that tramadol inhibits the function of type-1 muscarinic (M(1)) receptors and type-3 muscarinic (M(3)) receptors, suggesting that muscarinic receptors are sites of action of tramadol. However, the effects of O-desmethyl tramadol on muscarinic receptor functions have not been studied in detail. In this study, we investigated the effects of O-desmethyl tramadol on M(1) and M(3) receptors, using the Xenopus oocyte expression system. O-desmethyl tramadol (0.1-100 microM) inhibited acetylcholine (ACh)-induced currents in oocytes expressing the M(1) receptors (half-maximal inhibitory concentration [IC(50)] = 2 +/- 0.6 microM), whereas it did not suppress ACh-induced currents in oocytes expressing the M(3) receptor. Although GF109203X, a protein kinase C inhibitor, increased the ACh-induced current, it had little effect on the inhibition of ACh-induced currents by O-desmethyl tramadol in oocytes expressing M(1) receptors. The inhibitory effect of O-desmethyl tramadol on M(1) receptor was overcome when the concentration of ACh was increased (K(D) with O-desmethyl tramadol = 0.3 microM). O-desmethyl tramadol inhibited the specific binding of [(3)H]quinuclidinyl benzilate ([(3)H]QNB) to the oocytes expressed M(1) receptors (IC(50) = 10.1 +/- 0.1 microM), whereas it did not suppress the specific binding of [(3)H]QNB to the oocytes expressed M(3) receptors. Based on these results, O-desmethyl tramadol inhibits functions of M(1) receptors but has little effect on those of M(3) receptors. This study demonstrates the molecular action of O-desmethyl tramadol on the receptors and may help to explain its neural function.
  • Junchi Ogata, Kouichiro Minami, Takafumi Horishita, Munehiro Shiraishi, Takashi Okamoto, Tadanori Terada, Takeyoshi Sata
    Anesthesia and analgesia 101 (1) 290 - 3 0003-2999 2005/07 [Refereed][Not invited]
     
    Postoperative sore throat (POST) is a complication that remains to be resolved in patients undergoing endotracheal intubation. In this study, we investigated whether preoperative gargling with sodium 1,4-dimethyl-7-isopropylazulene-3-sulfonate monohydrate (sodium azulene sulfonate, Azunol) reduces POST after endotracheal intubation. Forty patients scheduled for elective surgery under general anesthesia were randomized into Azunol and control groups. In the Azunol group, patients gargled with 4 mg Azunol diluted with 100 mL tap water (40 microg/mL). In the control group, patients gargled with 100 mL of tap water. After emergence from general anesthesia, the patients with POST were counted and POST was evaluated using a verbal analog pain scale. There were no significant differences between the two groups by age, height, body weight, gender distribution, or duration of anesthesia and surgery. In the control group, 13 patients (65%) complained of POST, which remained 24 h later in nine patients (45%). In the Azunol group, five patients (25%) also complained of POST, which completely disappeared by 24 h later. The incidence of POST and verbal analog pain scale scores in the Azunol group decreased significantly compared with the control group. We demonstrated that gargling with Azunol effectively attenuated POST with no adverse reactions.
  • Koji Hara, Kouichiro Minami, Takeyoshi Sata
    Anesthesia and analgesia 100 (5) 1400 - 5 0003-2999 2005/05 [Refereed][Not invited]
     
    We assessed the effects of tramadol, a centrally acting analgesic, and its major metabolite, on neurotransmitter-gated ion channels. Tramadol binds to mu-opioid receptors with low affinity and inhibits reuptake of monoamines in the central nervous system. These actions are believed to primarily contribute to its antinociceptive effects. However, little is known about other sites of tramadol's action. We tested the effects of tramadol and its M1 metabolite (0.1-100 microM) on human recombinant neurotransmitter-gated ion channels, including glycine, gamma-aminobutyric acid(A) (GABA(A)), and N-methyl-D-aspartate (NMDA) receptors, expressed in Xenopus oocytes. Tramadol and M1 metabolite did not have any effects on glycine receptors. GABA(A) receptors were significantly inhibited only at large concentrations (100 microM). NMDA receptors were inhibited in a concentration-dependent manner. Tramadol and M1 metabolite inhibited the glutamate-concentration response curve without changing the half-maximal effective concentration or the Hill coefficient, indicating a noncompetitive inhibition. This study suggests that glycine receptors do not provide the antinociceptive effect of tramadol and that the inhibition of GABA(A) receptors at large concentration might correlate with convulsions. The inhibitory effect on NMDA receptors may contribute to the antinociceptive effect of tramadol at relatively large concentrations.
  • Kouichiro Minami, Junichi Ogata, Takafumi Horishita, Munehiro Shiraishi, Takeyoshi Sata
    Masui. The Japanese journal of anesthesiology 54 (3) 320 - 6 0021-4892 2005/03 [Refereed][Not invited]
     
    BACKGROUND: Complications related to anesthesia remain a problem. We studied the incidence of complications during anesthesia in 2758 patients who had undergone anesthesia in the University of Occupational and Environmental Health Hospital. METHODS: We checked the anesthesia records retrospectively and analyzed the collected data for the incidence of complications during anesthesia. RESULTS: The total incidence of complications during anesthesia was 12.2%. The incidences of complication are estimated to be 13.4% in inhalation anesthesia, 11.9% in inhalation anesthesia plus epidural, spinal or conduction block, 8.9% in CSEA, zero % in epidural anesthesia and 7.5% in spinal anesthesia. CONCLUSIONS: The incidence of complications in inhalation anesthesia was almost as same as that in inhalation anesthesia plus epidural, spinal or conduction block. More study should be necessary to prevent complications related to anesthesia.
  • Takafumi Horishita, Kouichiro Minami, Yasuhito Uezono, Munehiro Shiraishi, Junichi Ogata, Takashi Okamoto, Tadanori Terada, Takeyoshi Sata
    Naunyn-Schmiedeberg's archives of pharmacology 371 (3) 221 - 8 0028-1298 2005/03 [Refereed][Not invited]
     
    The neurosteroids pregnenolone, progesterone, and dehydroepiandrosterone (DHEA) occur naturally in the nervous system. They act on neural tissues, participate in neuronal signaling, and are reported to alter neuronal excitability via nongenomic mechanisms. Muscarinic receptors have important roles in neuronal functions in the brain and autonomic nervous system. In this study, we investigated the effects of pregnenolone, progesterone, and DHEA on M(1) and M(3) muscarinic receptors using the Xenopus oocyte expression system. Pregnenolone and progesterone inhibited the acetylcholine (ACh)-mediated responses of M(1) and M(3) receptors expressed in Xenopus oocytes, whereas DHEA did not. The half-maximal inhibitory concentrations (IC(50)) for pregnenolone inhibition of M(1) receptor- and M(3) receptor-mediated currents were 11.4 and 6.0 microM respectively; the IC(50) values for progesterone inhibition of M(1) receptor- and M(3) receptor-mediated currents were 2.5 and 3.0 microM respectively. The selective protein kinase C (PKC) inhibitor GF109203X had little effect on the pregnenolone or progesterone inhibition of the ACh-induced currents in Xenopus oocytes expressing M(1) or M(3) receptors. The inhibitory effects of pregnenolone and progesterone were overcome at higher concentrations of ACh. Pregnenolone and progesterone inhibited the [(3)H]quinuclidinyl benzilate (QNB) binding to M(1) and M(3) receptor expressed in Xenopus oocytes, and Scatchard plot analysis of [(3)H]QNB binding revealed that pregnenolone and progesterone altered the K(d) value and the B(max), indicating noncompetitive inhibition. In conclusion, pregnenolone and progesterone inhibited M(1) and M(3) receptor functions noncompetitively by the mechanism independent of PKC and by interfering with ACh binding to the receptors.
  • Kouichiro Minami, Yasuhito Uezono
    Masui. The Japanese journal of anesthesiology 54 (2) 118 - 25 0021-4892 2005/02 [Refereed][Not invited]
     
    Although anesthetics have been often used clinically, the mechanisms of action of anesthetics have not yet been clarified. Recently, major advances have been made in our understanding of the physiology and pharmacology of G-protein-coupled receptor (GPCR)-mediated signaling. Several lines of studies have shown that GPCRs are targets for anesthetics and that some anesthetics inhibit the functions of Gq-coupled receptors, including muscarinic acetylcholine (ACh) M1, metabotropic type 5 glutamate, 5-hydroxytryptamine (5-HT) type 2 A, and substance P receptors. Many additional GPCRs have been classified as "orphan" receptors (oGPCRs) because their endogenous ligands have not been identified yet. Given that known GPCRs are targets for anesthetics, these oGPCRs may represent a rich group of receptor targets for anesthetics. This review highlights the effects of anesthetics on Gq-coupled receptors, and discusses whether GPCRs other than Gq-coupled receptors, and proteins that convey GPCR signals are also targets for anesthetics.
  • Junichi Ogata, Kouichiro Minami, Hiroshi Miyamoto, Takafumi Horishita, Midori Ogawa, Takeyoshi Sata, Hatsumi Taniguchi
    Canadian journal of anaesthesia = Journal canadien d'anesthesie 51 (9) 932 - 6 0832-610X 2004/11 [Refereed][Not invited]
     
    PURPOSE: Nosocomial pneumonia remains a common complication in patients undergoing endotracheal intubation. This study examined the transport of bacteria into the trachea during endotracheal intubation, and evaluated the effects of gargling with povidone-iodine on bacterial contamination of the tip of the intubation tube. METHODS: In the gargling group, patients gargled with 25 mL of povidone-iodine (2.5 mg.mL(-1)). In the control group, patients gargled with 25 mL of tap water. Before tracheal intubation, microorganisms were obtained from the posterior wall of the patient's pharynx using sterile cotton swabs. After anesthesia, all patients were extubated and bacteria contaminating the tip of the tracheal tube were sampled and cultured. RESULTS: Before orotracheal intubation, all 19 patients who gargled with tap water (control group) had bacterial colonization on the posterior walls of the pharynx. This group included five patients who had methicillin-resistant staphylococcus aureus (MRSA) in their nasal cavity preoperatively and MRSA was also detected in the pharynx of four patients. Bacterial colonization was observed in all 19 patients who gargled with povidone-iodine (gargling group) and four patients carried MRSA in their nasal cavity, although no MRSA was detected in the pharynx. In the control group, all the patients had bacterial colonization at the tip of the tube after extubation. Additionally, MRSA was detected in two of the four patients. In the gargling group, povidone-iodine eradicated general bacteria and MRSA colonies in the pharynx before intubation and at the tip of the tube after extubation. CONCLUSION: Gargling with povidone-iodine before oral intubation reduces the transport of bacteria into the trachea.
  • Junichi Ogata, Takafumi Horishita, Kouichiro Minami
    Masui. The Japanese journal of anesthesiology 53 (11) 1282 - 5 0021-4892 2004/11 [Refereed][Not invited]
     
    A 9-year-old boy was scheduled for excision of tracheal granuloma which had developed at the tip of a tracheostomy tube. Instead of a tracheostomy tube, a 4 mm ID tracheal tube was inserted via the tracheostomy beyond the tracheal constriction because of rapid development of respiratory failure. General anesthesia was induced and maintained with sevoflurane and oxygen via the tube, and a size 2.5 laryngeal mask airway (LMA) was inserted without muscle relaxant. Spontaneous respiration remained. Under monitoring by fiberoptic tracheoscopy via the LMA, the tracheal tube was extubated carefully. An 8 Fr. suction tube was indwelled via the tracheostomy beyond the stenosis for oxygen supply. After sealing the tracheostomy, he could breath spontaneously through the LMA. During the excision of tracheal granuloma by holmium:YAG laser, fiberoptic observation was continued via the LMA, and the procedure was performed without any complication. We conclude that the tracheal stenosis can be managed using the LMA, continuous fiberoptic monitoring and additional option of keeping spontaneous ventilation.
  • Junichi Ogata, Kouichiro Minami, Motohiro Nakamura, Takafumi Horishita, Takeyoshi Sata
    Masui. The Japanese journal of anesthesiology 53 (11) 1286 - 9 0021-4892 2004/11 [Refereed][Not invited]
     
    A 71-year-old man was scheduled for an extirpation of chronic expanding hematoma (CEH) of his right thorax. He had a history of right thoracoplasty for tuberculosis 37 years previously. He complained of dyspnea that had deteriorated over three months. His inflammatory responses including general fatigue and fever due to chronic empyema remained to be resolved. The chest computed tomography revealed that the CEH remarkably compressed the trachea and the heart resulting in the cause of left mediastinal deviation. General anesthesia was induced with fentanyl and propofol, and maintained with sevoflurane. During general anesthesia, mean central venous pressure (CVP) via the right femoral vein and arterial blood pressure (ABP) via the left radial artery were monitored. Bilateral peripheral vein catheters with 16 G could effectively provide huge amount of transfusion. Although his blood loss was 10,000 ml because of superior vena caval rupture and oozing from pleura, prompt and adequate management of hemodynamics could be maintained using CVP and ABP monitoring. The CEH is known as a specific type of chronic empyema and its extraction would require ingenuity since there are number of factors associated with diagnosis, indication and prevention. Each case is to be evaluated individually and managed carefully.
  • Kouichiro Minami, Yasuhito Uezono, Munehiro Shiraishi, Takashi Okamoto, Jun-ichi Ogata, Takafumi Horishita, Kohtaro Taniyama, Akio Shigematsu
    Pharmacology 72 (3) 205 - 12 0031-7012 2004/11 [Refereed][Not invited]
     
    Metabotropic G protein-coupled receptors have recently been recognized as targets for anesthetics and analgesics. In particular, G(q)-coupled receptors such as muscarinic M(1) receptors (M(1)R) and 5-hydroxytryptamine (5-HT) type 2A receptors have been reported to be targets for anesthetics. Much less is known, however, about the effects of anesthetics on G(i)-coupled receptors. Here we report a method to analyze functions of G(i)-coupled receptors in Xenopus oocytes expressing a chimeric G alpha protein. A chimeric G alpha(q) protein G alpha(qi5), which contains carboxy-terminus five amino acids of G alpha(i), enables G(i)-coupled receptors to couple to Gq-coupled receptor-mediated downstream pathways such as activation of phospholipase C. We determined acetylcholine (ACh)-induced Ca(2+)-activated Cl(-) currents in Xenopus oocytes coexpressing G(i)-coupled muscarinic M(2)receptors (M(2)R) with the chimeric G alpha(qi5). Although ACh did not induce any currents in oocytes expressing M(2)R alone, it caused robust Cl(-) currents in oocytes coexpressing M(2)R with G alpha(qi5). The EC(50) of the ACh-induced Cl(-) current mediated through G alpha(qi5) was 0.2 micromol/l, which was 2.2 times higher than that of the ACh-induced G protein-activated inwardly rectifying K(+) currents activated by G beta gamma subunits liberated from endogenously expressed G alpha(i) in Xenopus oocytes. Other G(i)-coupled somatostatin type 2, 5-HT(1A) and delta-opioid receptors, when coexpressed with G alpha(qi5) in oocytes, also caused robust Ca(2+)-activated Cl(-) currents. In oocytes coexpressing M(2)R and G alpha(qi5), a volatile anesthetic halothane inhibited M(2)R-induced Cl(-) currents in a concentration-dependent manner with the IC(50) of 1.1 mmol/l, suggesting that halothane inhibits M(2)R-induced cellular responses at clinically relevant concentrations. Treatment with the protein kinase C inhibitor GF109203X produced a 3.5-fold enhancement of the initial Cl(-) currents induced by 1 micromol/l ACh in oocytes expressing M(2)R and G(qi5). The rate of halothane-induced inhibition of Cl(-) currents elicited by ACh, however, was not changed in such oocytes pretreated with GF109203X. These findings suggest that halothane inhibits the M(2)R-induced signaling by acting at sites other than PKC activity. Collectively these findings suggest that the use of oocyte expressing G alpha(qi5) would be helpful to examine the effects of anesthetics or analgesics on the function of G(i)-coupled receptors in the Xenopus oocyte expression system.
  • Yousuke Shiga, Kouichiro Minami, Kayoko Segawa, Yasuhito Uezono, Munehiro Shiraishi, Takeyoshi Sata, Chieko Yamamoto, Kim Sung-Teh
    Anesthesia and analgesia 99 (5) 1408 - 12 0003-2999 2004/11 [Refereed][Not invited]
     
    Smooth muscle cell (SMC) proliferation has been recognized as central to the pathology of both major forms of vascular disease, atherosclerosis and hypertension. Recently, we reported that ketamine inhibits rat mesangial cell proliferation, suggesting that ketamine inhibits cell growth. Although the IV anesthetic ketamine has been widely used clinically, the exact effects of ketamine on vascular SMC proliferation have not been studied. In this study, we investigated the effects of ketamine on vascular SMC proliferation. Ketamine inhibited [(3)H]thymidine incorporation and decreased the number of SMCs in a concentration-dependent manner (10-200 microM); neither propofol nor fentanyl inhibited [(3)H]thymidine incorporation into human aortic SMCs. The protein kinase C (PKC) inhibitor GF109203x abolished the ketamine-induced inhibition of [(3)H]thymidine incorporation into SMC, but the inhibition was not affected by either the protein kinase A inhibitor H-89 or the protein kinase G inhibitor KT5823. A histological analysis demonstrated the inhibitory effect of ketamine on the intimal thickening of the balloon-injured rat aorta. Based on these results, ketamine inhibits SMCs at clinical concentrations via the PKC pathway. Our results indicate that ketamine might prevent the proliferation of SMCs clinically.
  • Motohiro Nakamura, Kouichiro Minami, Koji Hara, Takeyoshi Sata
    Masui. The Japanese journal of anesthesiology 53 (9) 1025 - 8 0021-4892 2004/09 [Refereed][Not invited]
     
    There have been several reports on anesthesia for a patient with a history of multiple drug allergies. We present here anesthesia for a 33-year-old woman with histories of multiple drug allergies. She was scheduled to undergo total abdominal hysterectomy. We could not perform preoperative screening of the drugs using a dermal test because of a high risk of anaphylactic shock. Anesthesia was induced and maintained with sevoflurane and nitric oxide. The operation was finished without complications and her postoperative course was uneventful. It is important preoperatively to obtain histories of allergies adequately for recognition of allergens.
  • Takafumi Horishita, Kouichiro Minami, Junichi Ogata, Takeyoshi Sata
    Anesthesia and analgesia 99 (2) 438 - 9 0003-2999 2004/08 [Refereed][Not invited]
     
    Calciphylaxis is a small-vessel disease associated with renal failure. Here, we report the management of a 43-yr-old man with calciphylaxis who received left lower leg amputation with prostaglandin E(1) (PGE(1)) under monitoring by laser Doppler blood flowmetry in the left second and third fingers. Anesthesia was induced with midazolam, fentanyl, and vecuronium and was maintained with oxygen, nitrous oxide, and sevoflurane. The peripheral blood flow varied and decreased gradually; therefore, we added PGE(1) 20 ng. kg(-1). min(-1), which increased blood flow of the tissues. Three weeks after the operation, we again anesthetized the patient. We maintained the blood flow with PGE(1) throughout anesthesia. Monitoring by laser Doppler blood flowmetry and PGE(1) 20 ng. kg(-1). min(-1) could be useful for patients with impaired peripheral circulation, as in calciphylaxis.
  • K Minami, J Ogata, T Horishita, M Shiraishi, T Okamoto, T Sata, A Shigematsu
    CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE 51 (6) 545 - 548 0832-610X 2004/06 [Refereed][Not invited]
     
    Purpose: Tramadol, [(IRS, 2RS)-2-dimethylamino) methyl-1-(3-methoxyphenyl)-cyclohexanol hydrochloride], is an analgesic in clinical use. It has been reported that tramadol inhibits muscarinic type 3 receptor function, which primarily mediates smooth muscle contraction and glandular secretion. We investigated the effects of tramadol on the pH of gastric juices during anesthesia to determine whether tramadol inhibits secretion from the gastric glands. Methods: ASA physical status I or II adult patients (n = 30) presenting for major elective orthopedic surgery of the upper extremities or mastectomy were enrolled. Patients were randomly assigned to receive treatment with tramadol (n = 10), famotidine (n = 10), or saline (n = 10). General anesthesia was then induced using propofol, vecuronium bromide, and fentanyl. After inducing anesthesia, the gastric pH was measured using pH test paper and, then, 100 mg tramadol, 20 mg famotidine, or saline were injected into the deltoid muscle. Three hours after starting the operation, gastric juice was again aspirated and its gastric pH measured. Results: There were no differences in the pH before anesthesia between the three groups. By contrast, gastric pH was increased in the tramadol group by the same amount as it was in the famotidine group three hours after administering the drugs. Gastric pH of the saline, famotidine, and tramadol groups was 2.6 +/-2.5, 6.3 +/- 2.0, and 6.4 +/- 0.8, respectively. Conclusion: These results suggest that tramadol inhibits the secretion of gastric acid.
  • Susumu Ueno, Masato Tsutsui, Yumiko Toyohira, Kouichiro Minami, Nobuyuki Yanagihara
    FEBS letters 566 (1-3) 213 - 7 0014-5793 2004/05 [Refereed][Not invited]
     
    Neurosteroids are known as allosteric modulators of ionotropic gamma-aminobutyric acid (GABA) receptors. Here, we investigated sites of positive allosteric modulation by allotetrahydrodeoxycorticosterone (5alpha-THDOC) at GABA receptors using the technique of chimeragenesis and the Xenopus oocyte expression system. Our findings have demonstrated that the region from transmembrane segment (TM) 4 to the C-terminus of the GABA(A) receptor alpha1 subunit is crucial for the action of 5alpha-THDOC, but insufficient for the action of another neurosteroid allopregnanolone, suggesting that a specific region critical for neurosteroid action at GABA receptors exists in the domain between TM4 and the C-terminus of GABA receptor subunits.
  • Junichi Ogata, Kouichiro Minami, Yasuhito Uezono, Takashi Okamoto, Munehiro Shiraishi, Akio Shigematsu, Yoichi Ueta
    Anesthesia and analgesia 98 (5) 1401 - 6 0003-2999 2004/05 [Refereed][Not invited]
     
    UNLABELLED: Although tramadol is widely available as an analgesic, its mechanism of antinociception remains unresolved. Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that modulates numerous sensory, motor, and behavioral processes. The 5-HT type 2C receptor (5-HT(2C)R) is one of the major 5-HT receptor subtypes and is implicated in many important effects of 5-HT, including pain, feeding, and locomotion. In this study, we used a whole-cell voltage clamp to examine the effects of tramadol on 5-HT-induced Ca(2+)-activated Cl(-) currents mediated by 5-HT(2C)R expressed in Xenopus oocytes. Tramadol inhibited 5-HT-induced Cl(-) currents at pharmacologically relevant concentrations. The protein kinase C (PKC) inhibitor, bisindolylmaleimide I (GF109203x), did not abolish the inhibitory effects of tramadol on the 5-HT(2C)R-mediated events. We also studied the effects of tramadol on [(3)H]5-HT binding to 5-HT(2C)R expressed in Xenopus oocytes, and found that it inhibited the specific binding of [(3)H]5-HT to 5-HT(2C)R. Scatchard analysis of [(3)H]5-HT binding revealed that tramadol altered the apparent dissociation constant for binding without changing maximal binding, indicating competitive inhibition. The results suggest that tramadol inhibits 5-HT(2C)R function, and the mechanism of this inhibitory effect seems to involve competitive displacement of the 5-HT binding to the 5-HT(2C)R, rather than via activation of the PKC pathway. IMPLICATIONS: We examined the effects of tramadol on 5-hydroxytryptamine type 2C receptor (5-HT(2C)R) expressed in Xenopus oocytes. Tramadol inhibited 5-HT(2C)R function and the specific binding of [(3)H]5-HT to 5-HT(2C)R in a competitive manner. From these data, the mechanism of the inhibitory effect on 5-HT(2C)R might involve the competitive displacement of 5-HT binding to the 5-HT(2C)R.
  • Kouichiro Minami, Nobuyuki Yanagihara, Yumiko Toyohira, Masato Tsutsui, Akio Shigematsu, Akihiko Wada, Futoshi Izumi
    Naunyn-Schmiedeberg's Archives of Pharmacology 349 (3) 223 - 229 0028-1298 2004 [Refereed][Not invited]
     
    The effects of isoflurane on 22Na+ influx, 45Ca2+ influx, catecholamine secretion and cyclic GMP production induced by three kinds of secretagogue (nicotinic agonists, veratridine and a high concentration of K+) have been investigated using cultured bovine adrenal medullary cells. (1) Isoflurane (1-6%) inhibited catecholamine secretion stimulated by carbachol, nicotine and dimethyl-4-phenylpiperazinium in a concentration-dependent manner. Isoflurane suppressed carbachol-evoked 22Na+ influx and 45Ca2+ influx at concentrations similar to those which suppressed catecholamine secretion. The inhibition of catecholamine secretion by isoflurane was not overcome by increasing the concentration of carbachol. (2) The inhibitory effects of isoflurane on veratridine-induced 22Na+ influx, 45Ca2+ influx and catecholamine secretion became evident when the concentration of isoflurane was raised to 4-6%, i.e. 2-3 fold higher than the concentrations (1-2%) employed clinically. (3) High K+-evoked 45Ca2+ influx and catecholamine secretion were not affected by isoflurane (1-6%). (4) Isoflurane (1-6%) attenuated the production of cyclic GMP caused by muscarine, but not that caused by atrial natriuretic peptide or by sodium nitroprusside. These results suggest that isoflurane, at clinical anesthetic concentrations, inhibits nicotinic acetylcholine receptor-mediated cell responses as well as muscarinic receptor-mediated cyclic GMP production in adrenal medullary cells. © 1994 Springer-Verlag.
  • OGATA Junichi, MARUTANI Keiko, HORISHITA Takafumi, MINAMI Kouichiro
    Japanese journal of occupational medicine and traumatology 日本職業・災害医学会 52 (1) 62 - 64 1345-2592 2004/01 [Not refereed][Not invited]
     
    53歳男.性交渉中に性的嗜好からスリコギを経肛門的に直腸内へ挿入し,抜去不能となった.以降排便不能となり,挿入4日後より腹満感と会陰部痛が増悪した.直腸内視鏡を挿入して確認したところ,スリコギが直腸・S状結腸移行部に嵌入していた.内視鏡下に摘出を試みたが,疼痛による大腿,会陰部の筋緊張が強く摘出不能であった.筋緊張を除いて用手摘出する必要があると判断されたため,脊椎麻酔の適応となった.腰椎麻酔下では肛門から術者の右手関節まで挿入が可能となったため,開創器など機器を使用しなくても恥骨上部の用手圧迫と直腸内スリコギの直接把特によって摘出は極めて容易であった.術中の循環動態に変化はなく,特に合併症なく帰棟した.腹満,会陰部痛は術後消失し,自然排便を得た.術後の経過観察でも消化管穿孔や腸閉塞,感染症を疑う所見はみられなかった
  • Junichi Ogata, Kouichiro Minami, Kayoko Segawa, Yasuhito Uezono, Munehiro Shiraishi, Chikako Yamamoto, Takeyoshi Sata, Kim Sung-Teh, Akio Shigematsu
    Nephron. Physiology 96 (2) p59-64  2004 [Refereed][Not invited]
     
    A forskolin derivative, colforsin daropate hydrochloride (CDH), acts directly on adenylate cyclase to increase the intracellular cyclic adenosine monophosphate levels which produce a positive inotropic effect and a lower blood pressure. However, little is known about the effects of CDH on the renal function. We used laser Doppler flowmetry to measure the cortical renal blood flow (RBF) in male Wistar rats given a continuous intravenous infusion of CDH and evaluated the effects of CDH on the noradrenaline (NA) and angiotensin II (AngII) induced increases in blood pressure and reductions in RBF. Continuous intravenous administration of CDH at 0.25 microg/kg/min did not affect the mean arterial pressure (MAP), but increased heart rate and RBF. Continuous intravenous administration of CDH at high doses (0.5-0.75 microg/kg/min) decreased the MAP, with little effect on the RBF. The administration of exogenous NA (1.7 microg/kg) increased the MAP and decreased the RBF. However, a bolus injection of NA did not decrease the RBF during continuous intravenous administration of CDH, and CDH did not affect the NA-induced increase in MAP. The administration of exogenous AngII (100 ng/kg) increased MAP and decreased RBF and heart rate, but a bolus injection of AngII did not decrease RBF during continuous intravenous administration of CDH. These results suggest that CDH plays a protective role against the pressor effects and the decrease in RBF induced by NA or AngII.
  • Takafumi Horishita, Junichi Ogata, Kouichiro Minami
    Anesthesia and analgesia 97 (6) 1856 - 1856 0003-2999 2003/12 [Refereed][Not invited]
  • Junichi Ogata, Kouichiro Minami, Kayoko Segawa, Chieko Yamamoto, Sung-Teh Kim, Akio Shigematsu
    Pharmacology 69 (3) 127 - 31 0031-7012 2003/11 [Refereed][Not invited]
     
    A forskolin derivative, colforsin daropate hydrochloride (CDH), has been introduced as an inotropic agent that acts directly on adenylate cyclase to increase intracellular cyclic AMP (cAMP) levels and ventricular contractility, resulting in positive inotropic activity. We investigated the effects of CDH on rat mesangial cell (MC) proliferation. CDH (10(-7)-10(-5) mol/l) inhibited [(3)H]thymidine incorporation into cultured rat MCs in a concentration-dependent manner. CDH (10(-7)-10(-5) mol/l) also decreased cell numbers in a similar manner, and stimulated cAMP accumulation in MCs in a concentration-dependent manner. A protein kinase A inhibitor, H-89, abolished the inhibitory effects of CDH on MC mitogenesis. These findings suggest that CDH would inhibit the proliferation of rat MCs via the cAMP pathway.
  • T. Okamoto, K. Minami
    Anaesthesia and Intensive Care 31 (5) 596  0310-057X 2003/10 [Refereed][Not invited]
  • T Okamoto, K Minami, M Shiraishi, J Ogata, A Shigematsu
    CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE 50 (7) 752 - 753 0832-610X 2003/08 [Refereed][Not invited]
  • Munehiro Shiraishi, Kouichiro Minami, Izumi Shibuya, Yasuhito Uezono, Junichi Ogata, Takashi Okamoto, Osamu Murasaki, Muneshige Kaibara, Yoichi Ueta, Akio Shigematsu
    Anesthesia and analgesia 97 (2) 449 - 55 0003-2999 2003/08 [Refereed][Not invited]
     
    UNLABELLED: Alphaxalone is a neurosteroid anesthetic, but its mechanisms of action are not completely understood. Muscarinic receptors are involved in a variety of neuronal functions in the brain and autonomic nervous system, and much attention has been paid to them as targets of anesthetics. In this study, we investigated the effects of alphaxalone on M(1) and M(3) muscarinic receptors using the Xenopus oocyte expression system. Alphaxalone inhibited acetylcholine-induced currents in oocytes expressing M(1) receptors at clinically relevant concentrations. Alphaxalone also suppressed acetylcholine-induced currents in oocytes expressing M(3) receptors. The half-maximal inhibitory concentration values for the inhibition of M(1)- and M(3)-mediated currents were 1.8 +/- 0.6 micro M and 5.3 +/- 1.0 micro M, respectively. GF109203X, a selective protein kinase C inhibitor, had little effect on the inhibition of acetylcholine-induced currents by alphaxalone in oocytes expressing these receptors. Alphaxalone inhibited the specific binding of [(3)H]quinuclidinyl benzilate to oocytes expressing M(1) or M(3) receptors. These findings suggest that alphaxalone at clinically relevant concentrations inhibits the function of M(1) and M(3) receptors through a protein kinase C-independent mechanism by interfering with the [(3)H]quinuclidinyl benzilate binding sites on the receptors. IMPLICATIONS: Alphaxalone, a neurosteroid anesthetic, inhibited the function of muscarinic M(1) and M(3) receptors and the specific binding of [(3)H]quinuclidinyl benzilate ([(3)H]QNB) to oocytes expressing these receptors. These findings suggest that alphaxalone inhibits these receptors by interfering with the QNB binding sites.
  • Landiolol for the treatment of tachyarrhythmia associated with atrial fibrillation
    Junichi Ogata, Takashi Okamoto, Kouichiro MInami
    Can J Anesth 50(7) 753  2003/08 [Refereed][Not invited]
  • Satoshi Takahashi, Kouichiro Minami, Midori Ogawa, Hiroshi Miyamoto, Kunio Ikemura, Akio Shigematsu, Hatsumi Taniguchi
    Anesthesia and analgesia 97 (1) 222 - 5 0003-2999 2003/07 [Refereed][Not invited]
     
    UNLABELLED: Nasotracheal intubation is often required during dental and maxillofacial surgery. The complications of nasotracheal intubation are well documented, but there have been few systematic attempts to find methods for their prevention. We examined intubation-related carriage of bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), into the trachea and evaluated the effects of topical nasal treatment with mupirocin on intubation-related bacterial colonization. Of 38 patients without mupirocin treatment (nontreatment group), 27 (71.1%) showed general bacterial colonization in the nasal cavities before intubation. MRSA was isolated from 13.2% of the patients in this group. However, 10 of 22 patients (45%) treated with mupirocin (treatment group) showed colonization by general bacteria, and 2 (9%) were MRSA carriers before intubation. After nasal intubation, general bacteria and MRSA were isolated from the endotracheal tube tip in 66.2% and 16.7% of these patients in the nontreatment group, respectively. In contrast, general bacteria were isolated from the endotracheal tube tip in 19.2% of these patients after oral intubation, but no MRSA was detected. However, after nasal intubation, general bacteria were isolated from the endotracheal tube tip in 3 of the patients in the treatment group (23.1%), and no MRSA was detected, whereas no bacteria were isolated from oral intubation tubes. These results indicate that bacteria were carried into the trachea at a more frequent rate by nasal intubation as compared with oral intubation, and nasal treatment with mupirocin eliminated the nasal carriage of S. aureus. Topical nasal treatment with mupirocin before nasal intubation is thus suggested to be effective for preventing carriage of bacteria into the trachea. IMPLICATIONS: We studied the carriage rate of bacteria into the trachea caused by nasal intubation. The bacterial carriage by nasal intubation was more frequent than that by oral intubation, and intranasal administration of mupirocin eliminated the carriage of S. aureus. These results indicate that topical nasal treatment with mupirocin is effective to prevent carriage of bacteria into the trachea.
  • Junichi Ogata, Toru Yokoyama, Takashi Okamoto, Kouichiro Minami
    Anesthesia and analgesia 97 (1) 294 - 5 0003-2999 2003/07 [Refereed][Not invited]
  • Takashi Okamoto, Kouichiro Minami, Yasuhito Uezono, Junichi Ogata, Munehiro Shiraishi, Akio Shigematsu, Yoichi Ueta
    Anesthesia and analgesia 97 (1) 104 - 10 0003-2999 2003/07 [Refereed][Not invited]
     
    UNLABELLED: Substance P receptors (SPR) modulate nociceptive transmission within the spinal cord. The effects of IV anesthetics on SPR are not clear. In this study, we investigated the effects of IV anesthetics on SPR expressed in Xenopus oocytes. We examined the effects of ketamine, pentobarbital, propofol, and tramadol on SP-induced Ca(2+)-activated Cl(-) currents mediated by SPR expressed in Xenopus oocytes using a whole-cell voltage clamp. Ketamine and pentobarbital inhibited the SPR-induced currents at pharmacologically relevant concentrations, but propofol and tramadol had little effect on the currents. We also studied the effects of ketamine and pentobarbital on [(3)H]-SP to SPR. Ketamine and pentobarbital inhibited the specific binding of [(3)H]-SP to SPR expressed in Xenopus oocytes. Scatchard analysis of [(3)H]-SP binding revealed that ketamine and pentobarbital decreased the apparent dissociation constant for binding and maximal binding, indicating noncompetitive inhibition. The protein kinase C (PKC) inhibitor bisindolylmaleimide I did not abolish the inhibitory effects of ketamine and pentobarbital on SP-induced Ca(2+)-activated Cl(-) currents. The results suggest that ketamine and pentobarbital inhibit SPR function. The mechanism of their inhibition on SPR function could not be through activation of the PKC pathway and may be due to noncompetitive displacing the SP binding. IMPLICATIONS: We investigated the effects of IV anesthetics on substance P receptors (SPR) expressed in Xenopus oocytes. Ketamine and pentobarbital inhibit SPR function via noncompetitive displacing SP binding. The findings imply that the inhibition of SPR function by these compounds may play a role in the analgesic effects of these IV anesthetics.
  • Takashi Okamoto, Junichi Ogata, Kouichiro Minami
    Anesthesia and analgesia 97 (1) 19 - 20 0003-2999 2003/07 [Refereed][Not invited]
     
    IMPLICATIONS: Epirubicin, an anticancer drug, causes cardiotoxicity. We reported a case of sino-atrial block during general anesthesia in a woman with breast cancer who had received epirubicin. Anesthesiologists should be aware of the possible occurrence of sino-atrial block with epirubicin, and planting a pacemaker might be considered even in asymptomatic patients.
  • Yumiko Toyohira, Kensuke Utsunomiya, Susumu Ueno, Kouichiro Minami, Yasuhito Uezono, Reiji Yoshimura, Masato Tsutsui, Futoshi Izumi, Nobuyuki Yanagihara
    Biochemical pharmacology 65 (12) 2049 - 54 0006-2952 2003/06 [Refereed][Not invited]
     
    We report here the effects of an environmental estrogen, bisphenol A, on norepinephrine (NE) transporter function in cultured bovine adrenal medullary cells. The effects of bisphenol A were compared to those of 17beta-estradiol. Bisphenol A significantly inhibited [3H]NE uptake by the cells in a concentration-dependent manner (1-100 microM). Kinetic analysis revealed that bisphenol A, as well as 17beta-estradiol, noncompetitively inhibited [3H]NE uptake. Bisphenol A and 17beta-estradiol inhibited the specific binding of [3H]desipramine to plasma membranes isolated from bovine adrenal medulla. As shown by Scatchard analysis of [3H]desipramine binding, bisphenol A increased the dissociation constant (K(d)) and decreased the maximal binding (B(max)), indicating a mixed type of inhibition. 17beta-Estradiol increased the K(d) without altering the B(max), thereby indicating competitive inhibition. The present findings suggest that bisphenol A inhibits the function of the NE transporter by acting on a site different from that of 17beta-estradiol in the adrenal medulla and probably in the brain noradrenergic neurons.
  • J Ogata, T Yokoyama, K Minami
    CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE 50 (6) 623 - 623 0832-610X 2003/06 [Refereed][Not invited]
  • Multiple injections with the same syringe increase the risk of contamination [11] (multiple letters)
    Scott Groudine, Elliot Greene, Masayuki Ozaki, Kouichiro Minami, Akio Shigematsu
    Anesthesia and Analgesia 96 (5) 1532 - 1533 2003/05 [Refereed][Not invited]
  • M Ozaki, K Minami, A Shigematsu
    ANESTHESIA AND ANALGESIA 96 (5) 1533 - 1533 0003-2999 2003/05 [Refereed][Not invited]
  • Yousuke Shiga, Kouichiro Minami, Yasuhito Uezono, Kayoko Segawa, Etsuko Nagaoka, Munehiro Shiraishi, Takashi Noguchi, Akio Shigematsu
    Pharmacology 68 (1) 17 - 23 0031-7012 2003/05 [Refereed][Not invited]
     
    Intravenous anaesthetics such as ketamine, propofol, and thiamylal are widely used, although the direct effects of these anaesthetics on the renal blood flow (RBF) have not been well elucidated. In this study, we examined the effects of bolus and continuous administrations of ketamine, propofol, and thiamylal on cortical RBF and the effects of noradrenaline (NA) on RBF under continuous administration of these anaesthetics. We used laser Doppler flowmetry to measure the effects of bolus injection and continuous infusion of ketamine, propofol, and thiamylal on cortical RBF in male Wistar rats. We also examined the effects of the anaesthetics on mean arterial blood pressure (MAP) and heart rate (HR). Bolus injections of ketamine, propofol, or thiamylal (1-8 mg/kg each, n = 10) at clinically relevant concentrations did not affect MAP, HR, or RBF. Continuous administration of ketamine, propofol, or thiamylal (1-8 mg/kg/h each, n = 10) did not affect MAP, HR or RBF. Exogenous NA (2 microg/kg) caused an increase in MAP and a decrease in RBF and HR. In experiments with continuous infusions of propofol or thiamylal (1-8 mg/kg/h each, n = 10), similar results were observed without infusion of any anaesthetics. However, bolus injection of NA did not result in a decrease in RBF during continuous ketamine infusion (98.8 +/- 6.7% of control, n = 6, p < 0.05), while ketamine did not affect the NA-induced increase in MAP. In conclusion, bolus and continuous administrations of ketamine, propofol, and thiamylal did not affect the RBF. From our present findings, ketamine would be useful for maintaining the RBF.
  • 先天性アンチトロンビンIII(AT III)欠乏症男児の麻酔経験
    岡本 隆史, 南 浩一郎, 佐多 竹良, 重松 昭生
    麻酔 克誠堂出版(株) 52 (4) 449 - 450 0021-4892 2003/04 [Not refereed][Not invited]
  • Takashi Okamoto, Kouichiro Minami
    Canadian journal of anaesthesia = Journal canadien d'anesthesie 50 (3) 311 - 311 0832-610X 2003/03 [Refereed][Not invited]
  • Takafumi Horishita, Kouichiro Minami, Nobuyuki Yanagihara, Munehiro Shiraishi, Takashi Okamoto, Yousuke Shiga, Susumu Ueno, Akio Shigematsu
    Anesthesia and analgesia 95 (6) 1661 - 6 0003-2999 2002/12 [Refereed][Not invited]
     
    UNLABELLED: We studied the effects of alphaxalone, a neurosteroid anesthetic, on norepinephrine transporter (NET) function in cultured bovine adrenal medullary cells and the effect of a bolus injection of alphaxalone on blood pressure and serum norepinephrine (NE) levels in anesthetized rats. Alphaxalone (10-100 micro M) inhibited the desipramine-sensitive uptake of [(3)H]-NE by bovine adrenal medullary cells in a concentration-dependent manner. Eadie-Hofstee analysis of [(3)H]-NE uptake showed that alphaxalone increased the apparent Michaelis constant without altering the maximal velocity, indicating that inhibition occurred via competition for the NET. Alphaxalone inhibited the specific binding of [(3)H]-desipramine to plasma membranes isolated from bovine adrenal medulla. Scatchard analysis of [(3)H]-desipramine binding revealed that alphaxalone increased the apparent dissociation constant for binding without altering maximal binding, indicating competitive inhibition. Bolus IV administration of alphaxalone had little effect on blood pressure but slightly, and significantly, increased the serum NE levels in anesthetized rats. These findings suggest that alphaxalone competitively inhibits NET function by interfering with both desipramine binding and NE recognition on the NET in adrenal medullary cells and probably in sympathetic neurons. IMPLICATIONS: Alphaxalone inhibited the desipramine-sensitive uptake of [(3)H]-norepinephrine (NE) by interfering with desipramine binding in bovine adrenal medullary cells. A bolus IV administration of alphaxalone slightly and significantly increased the serum NE levels in anesthetized rats. These findings suggest that alphaxalone competitively inhibits NE transporter function probably in sympathetic neurons.
  • Yumiko Toyohira, Nobuyuki Yanagihara, Kouichiro Minami, Susumu Ueno, Yasuhito Uezono, Eiichi Tachikawa, Yukiko Kondo, Takeshi Kashimoto, Futoshi Izumi
    Journal of Neurochemistry 70 (4) 1441 - 1447 0022-3042 2002/11
  • Masayuki Ozaki, Kouichiro Minami, Akio Shigematsu
    Anesthesia and analgesia 95 (5) 1461 - 1461 0003-2999 2002/11 [Refereed][Not invited]
  • Yousuke Shiga, Kouichiro Minami, Munehiro Shiraishi, Yasuhito Uezono, Osamu Murasaki, Muneshige Kaibara, Akio Shigematsu
    Anesthesia and analgesia 95 (5) 1269 - 73 0003-2999 2002/11 [Refereed][Not invited]
     
    UNLABELLED: Tramadol is a widely used analgesic, but its mechanism of action is not completely understood. Muscarinic receptors are involved in neuronal function in the brain and autonomic nervous system, and much attention has been paid to these receptors as targets of analgesic drugs in the central nervous system. In this study, we investigated the effects of tramadol on type-3 muscarinic (M(3)) receptors using the Xenopus oocyte expression system. Tramadol (10 nM-100 micro M) inhibited acetylcholine-induced currents in oocytes expressing M(3) receptor. Although GF109203X, a protein kinase C inhibitor, increased the basal current, it had little effect on the inhibition of acetylcholine-induced currents by tramadol. Moreover, tramadol inhibited the specific binding sites of [(3)H]quinuclidinyl benzilate. These findings suggest that tramadol at clinically relevant concentrations inhibits M(3) function via quinuclidinyl benzilate-binding sites. This may explain the modulation of neuronal function and the anticholinergic effects of tramadol. IMPLICATIONS: Muscarinic receptors are involved in neuronal function and are targets of analgesic drugs. We here report that tramadol inhibits type-3 muscarinic receptors function via quinuclidinyl benzilate-binding sites at clinically relevant concentrations. These findings may explain the modulation of neuronal function and the anticholinergic effects of tramadol.
  • Munehiro Shiraishi, Izumi Shibuya, Kouichiro Minami, Yasuhito Uezono, Takashi Okamoto, Nobuyuki Yanagihara, Susumu Ueno, Yoichi Ueta, Akio Shigematsu
    Anesthesia and analgesia 95 (4) 900 - 6 0003-2999 2002/10 [Refereed][Not invited]
     
    UNLABELLED: Several lines of evidence suggest that nicotinic acetylcholine receptors (nAChRs) are a target of general anesthetics. Alphaxalone (5alpha-pregnan-3alpha-ol-11, 20-dion) is a neurosteroid, which was used clinically for anesthesia, but its effects on the function of nAChRs have not been well investigated. We examined the effects of alphaxalone on nAChRs in cultured bovine adrenal chromaffin cells. We studied the effects of alphaxalone on nicotine-induced increases in the cytosolic Ca(2+) concentration ([Ca(2+)](i)) and on membrane currents using Ca(2+)-imaging and whole-cell patch-clamp techniques, respectively, in these cells. We also examined the effects of alphaxalone on gamma-aminobutyric acid A receptors in the same cells and compared them with the effects on nAChRs. Alphaxalone (0.1-100 micro M) inhibited nicotine-induced [Ca(2+)](i) increases in a concentration-dependent manner. Alphaxalone inhibited high K(+)-induced [Ca(2+)](i) increases, but the inhibition was observed only at 100 micro M. In voltage-clamp experiments using negative holding potentials, alphaxalone (0.1-100 micro M) itself induced inward currents, which were abolished by the gamma-aminobutyric acid A receptor antagonist picrotoxin. Alphaxalone also inhibited nicotine-induced inward currents, and the inhibition was unaffected by picrotoxin. We conclude that alphaxalone, at anesthetic concentrations, inhibits nAChRs in adrenal chromaffin cells. Alphaxalone may affect the sympathetic and other nervous systems via inhibition of nAChRs. IMPLICATIONS: Alphaxalone inhibits the function of nAChRs at clinically relevant concentrations in adrenal chromaffin cells. Thus, the present findings may provide some information for understanding the anesthetic mechanism of alphaxalone.
  • Masayuki Ozaki, Kouichiro Minami, Akio Shigematsu
    Anesthesia and analgesia 95 (1) 255 - 255 0003-2999 2002/07 [Refereed][Not invited]
  • Munehiro Shiraishi, Kouichiro Minami, Yasuhito Uezono, Nobuyuki Yanagihara, Akio Shigematsu, Izumi Shibuya
    British journal of pharmacology 136 (2) 207 - 16 0007-1188 2002/05 [Refereed][Not invited]
     
    1. Tramadol has been used clinically as an analgesic; however, the mechanism of its analgesic effects is still unknown. 2. We used bovine adrenal chromaffin cells to investigate effects of tramadol on catecholamine secretion, nicotine-induced cytosolic Ca(2+) concentration ([Ca(2+)](i)) increases and membrane current changes. We also investigated effects of tramadol on alpha7 nicotinic acetylcholine receptors (AChRs) expressed in Xenopus oocytes. 3. Tramadol concentration-dependently suppressed carbachol-induced catecholamine secretion to 60% and 27% of the control at the concentration of 10 and 100 microM, respectively, whereas it had little effect on veratridine- or high K(+)-induced catecholamine secretion. 4. Tramadol also suppressed nicotine-induced ([Ca(2+)](i)) increases in a concentration-dependent manner. Tramadol inhibited nicotine-induced inward currents, and the inhibition was unaffected by the opioid receptor antagonist naloxone. 5. Tramadol inhibited nicotinic currents carried by alpha7 receptors expressed in Xenopus oocytes. 6. Tramadol inhibited both alpha-bungarotoxin-sensitive and -insensitive nicotinic currents in bovine adrenal chromaffin cells. 7. In conclusion, tramadol inhibits catecholamine secretion partly by inhibiting nicotinic AChR functions in a naloxone-insensitive manner and alpha7 receptors are one of those inhibited by tramadol.
  • Koji Hara, Kouichiro Minami, Susumu Ueno, Yumiko Toyohira, Masato Tsutsui, Akio Shigematsu, Nobuyuki Yanagihara
    Naunyn-Schmiedeberg's archives of pharmacology 365 (5) 406 - 12 0028-1298 2002/05 [Refereed][Not invited]
     
    We previously reported that the intravenous anaesthetic ketamine acutely inhibits the activity of the noradrenaline transporter (NAT) by acting on a site partly overlapping the desipramine binding site. Here we report the effects of a prolonged exposure to ketamine on the functional activity and number of NAT and its mRNA in cultured bovine adrenal medullary cells. Treatment of cells with ketamine (10-1000 microM) for 1-24 h resulted in a transient decrease and subsequent increase in [(3)H]noradrenaline (NA) uptake by the cells. Saturation analysis showed that ketamine (100 microM, 12 h) increased the V(max) value of [(3)H]NA uptake without any change in the K(m) value. Ketamine also increased the specific binding of [(3)H]nisoxetine to plasma membranes isolated from the cells. Scatchard analysis of [(3)H]nisoxetine binding revealed that ketamine increased the B(max) value without altering the K(d) value, suggesting an increase in the number of NAT in the plasma membrane. The stimulatory effect of ketamine on [(3)H]NA uptake was blocked by cycloheximide, an inhibitor of protein synthesis. Treatment of cells with ketamine for 12-24 h enhanced the expression of NAT mRNA. The present findings demonstrated that prolonged exposure to ketamine increases the functional activity of NAT and its mRNA. This may imply that ketamine negatively modulates sympathetic nervous activity through an up-regulation of NAT during long anaesthesia.
  • Kenichiro Sagata, Kouichiro Minami, Nobuyuki Yanagihara, Munehiro Shiraishi, Yumiko Toyohira, Susumu Ueno, Akio Shigematsu
    Anesthesia and analgesia 94 (4) 901 - 6 0003-2999 2002/04 [Refereed][Not invited]
     
    UNLABELLED: Tramadol is a widely used analgesic, but its mode of action is not well understood. To study the effects of tramadol on norepinephrine transporter (NET) function, we assayed the effect of tramadol on [3H]-norepinephrine ([3H]-NE) uptake and [3H]-desipramine binding to plasma membranes isolated from bovine adrenal medulla. We then characterized [14C]-tramadol binding in cultured bovine adrenal medullary cells. Tramadol inhibited the desipramine-sensitive uptake of [3H]-NE by the cells in a concentration-dependent manner (50% inhibitory concentration = 21.5 +/- 6.0 microM). Saturation analysis revealed that tramadol increased the apparent Michaelis constant of [3H]-NE uptake without changing the maximal velocity, indicating that inhibition occurred via competition for the NET (inhibition constant, K(i) = 13.7 microM). Tramadol inhibited the specific binding of [3H]-desipramine to plasma membranes. Scatchard analysis of [3H]-desipramine binding revealed that tramadol increased the apparent dissociation constant (K(d)) for binding without altering maximal binding, indicating competitive inhibition (K(i) = 11.2 microM). The binding of [14C]-tramadol to the cells was specific and saturable, with a K(d) of 18.1 +/- 2.4 microM. These findings indicate that tramadol competitively inhibits NET function at desipramine-binding sites. IMPLICATIONS: Tramadol competitively inhibits norepinephrine transporter function at desipramine-binding sites in the adrenal medullary cells and probably the noradrenergic neurons of the descending inhibitory system.
  • Kayoko Segawa, Kouichiro Minami, Yasuhito Uezono, Munehiro Shiraishi, Akio Shigematsu
    Alcoholism, clinical and experimental research 26 (3) 358 - 62 0145-6008 2002/03 [Refereed][Not invited]
     
    A large body of evidence has shown that ethanol inhibits the cell growth and cell proliferation in a variety of cell types. However, it has not been studied whether ethanol inhibits the proliferation of mesangial cells (MC) in the kidney. We examined the effects of ethanol on cell proliferation in cultured rat MC. Treatment with ethanol (10-200 mM) for 48 hr inhibited [(3)H]thymidine incorporation into MC in a concentration-dependent manner. The same concentrations of ethanol also inhibited the increase in cell number of MC. GF109203X and chelerythrine chloride, inhibitors for protein kinase C, eliminated the inhibitory effects of ethanol; and protein kinase C activator, PMA, mimicked the effects of ethanol. In contrast, neither the protein kinase A inhibitor H-89 nor the protein kinase G inhibitor KT5823 had any effect. These findings suggest that ethanol has inhibitory effects on the proliferation of MC, probably via activation of the protein kinase C pathway.
  • Etsuko Nagaoka, Kouichiro Minami, Yohsuke Shiga, Yasuhito Uezono, Munehiro Shiraishi, Kazuyoshi Aoyama, Akio Shigematsu
    Anesthesia and analgesia 94 (3) 619 - 25 0003-2999 2002/03 [Refereed][Not invited]
     
    UNLABELLED: Tramadol is an analgesic that inhibits norepinephrine (NE) reuptake. Although NE released from renal sympathetic nerves causes renal hypoperfusion, the effects of tramadol on renal hemodynamics have not been well characterized. We investigated the effects of tramadol on renal blood flow (RBF), mean arterial blood pressure (MAP), and heart rate (HR) by using a laser Doppler flowmeter, both in normal anesthetized rats and in rats with experimentally-induced nephritis secondary to anti-Thy 1.1 antibody administration. We also studied the effects of tramadol on serum NE levels. Tramadol increased MAP and decreased HR without changing RBF in normal rats at clinical doses. Serum NE levels increased up to 176% of control after a 2 mg/kg bolus injection of tramadol. Continuously infused, increasing doses of tramadol (0.5-4 mg.kg(-1).h(-1)) did not affect MAP, HR, or RBF. Tramadol also increased MAP and decreased HR without changing RBF in rats with experimentally induced renal insufficiency. These findings suggest that a bolus injection of tramadol does not alter RBF, although it causes a decrease in HR and an increase in MAP and serum NE in both normal rats and in rats with renal insufficiency. These results suggest that tramadol may have little effect on RBF during the postoperative period. IMPLICATIONS: A bolus and continuous injection of tramadol does not alter renal blood flow (RBF) in normal rats. A bolus injection of tramadol has little effect on RBF in rats with experimentally induced renal insufficiency. These results suggest that tramadol would be a safe analgesic for maintaining RBF during the postoperative period.
  • 最近の研究からみた全身麻酔薬の作用メカニズム
    池本清海, 真下節, 難波恒久, 南浩一郎, 内田一郎
    麻酔 51 5164 - 5171 2002 [Refereed][Not invited]
  • Kouichiro Minami, Munehiro Shiraishi, Yasuhito Uezono, Susumu Ueno, Akio Shigematsu
    Anesthesia and analgesia 94 (1) 79 - 83 0003-2999 2002/01 [Refereed][Not invited]
     
    UNLABELLED: The neuropeptide substance P (SP) modulates nociceptive transmission within the spinal cord. SP is unique to a subpopulation of C fibers found within primary afferent nerves. However, the effects of anesthetics on the SP receptor (SPR) are not clear. In this study, we investigated the effects of volatile anesthetics and ethanol on SPR expressed in Xenopus oocytes. We examined the effects of halothane, isoflurane, enflurane, diethyl ether, and ethanol on SP-induced currents mediated by SPR expressed in Xenopus oocytes, by using a whole-cell voltage clamp. All the volatile anesthetics tested, and ethanol, inhibited SPR-induced Ca(2+)-activated Cl(-) currents at pharmacologically relevant concentrations. The protein kinase C inhibitor bisindolylmaleimide I (bisindolylmaleimide) enhanced the SP-induced Cl(-) currents. However, bisindolylmaleimide abolished the inhibitory effects on SPR of the volatile anesthetics examined and of ethanol. These results demonstrate that halothane, isoflurane, enflurane, diethyl ether, and ethanol inhibit the function of SPR and suggest that activation of protein kinase C is involved in the mechanism of action of anesthetics and ethanol on the inhibitory effects of SPR. IMPLICATIONS: We examined the effects of halothane, isoflurane, enflurane, diethyl ether, and ethanol on substance P receptor (SPR) expressed in Xenopus oocytes, by using a whole-cell voltage clamp. All the anesthetics and ethanol inhibited SPR function, and the protein kinase C (PKC) inhibitor abolished these inhibitions. These results suggest that anesthetics and ethanol inhibit SPR function via PKC.
  • Munehiro Shiraishi, Kouichiro Minami, Tatsuo Kadaya
    Anesthesia and analgesia 94 (1) 233 - 233 0003-2999 2002/01 [Refereed][Not invited]
  • M Ozaki, K Minami, T Sata, A Shigematsu
    CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE 48 (11) 1080 - 1083 0832-610X 2001/12 [Refereed][Not invited]
     
    Purpose: To evaluate prospectively the incidence and severity of postoperative sore throat in 63 orotracheally intubated patients undergoing general anesthesia for various surgical procedures and to determine whether postoperative sore throat could be attenuated by treatment with the transdermal nonsteroidal anti-inflammatory drug ketoprofen applied on the anterior skin of the neck during operation, Method: Patients were randomly assigned to have treatment with ketoprofen (ketoprofen group) or to have placebo tape treatment (control group). Postoperative analgesia was obtained by continuous epidural infusion of local anesthetics, and no narcotics were administered intraoperatively or postoperatively. Al patients were interviewed postoperatively after 12-20 hr using a scoring scale questionnaire, Sore throat was scored as 0=no sore throat, 1=minimal, 2=mild, 3=moderate, 4=severe. Results: In the control group, 16 of 32 patients had a sore throat. In the ketoprofen group, less patients (ten of 31 patients) had a sore throat (not significant). The severity of sore throat was alleviated significantly in the ketoprofen group (P <0.05). Conclusion: This study suggests the pain caused by tracheal intubation is relieved by intraoperative topical use of transdermal ketoprofen.
  • J Ogata, K Minami, M Oishi, H Tamura, A Shigematsu
    ANESTHESIA AND ANALGESIA 93 (4) 1069 - 1072 0003-2999 2001/10 [Refereed][Not invited]
     
    Although transient sialadenopathy of the submandibular gland associated with insertion of the laryngeal mask airway (LMA) has been described, the influence of the LMA on the submandibular gland is unknown. We measured the width and length of the submandibular glands by using ultrasonography in patients in whom the LMA was used. An increased intracuff pressure of the LMA, up to 150 cm H2O, was used in a prospective study of adult patients scheduled for elective surgery. The width of the gland increased with an increasing intracuff pressure from 50 to 100 cm H2O (P < 0.01) and 100 to 150 cm, H2O (P < 0.01) but did not change from 0 to 50 cm H2O. There was no change in the length of the gland. We conclude that the submandibular gland was deformed by the insertion of the LMA.
  • M Shiraishi, K Minami, Y Uezono, N Yanagihara, A Shigematsu
    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 299 (1) 255 - 260 0022-3565 2001/10 [Refereed][Not invited]
     
    Tramadol is a widely used, centrally acting analgesic, but its mechanisms of action are not completely understood. Muscarinic receptors are known to be involved in neuronal function in the brain and autonomic nervous system, and much attention has been paid to these receptors as targets of analgesic drugs in the central nervous system. This study investigated the effects of tramadol on muscarinic receptors by using two different systems, i.e., a Xenopus laevis oocyte expression system and cultured bovine adrenal medullary cells. Tramadol (10 nM-100 muM) inhibited acetylcholine-induced currents in oocytes expressing the M-1 receptor. Although GF109203X, a protein kinase C inhibitor, increased the basal current, it had little effect on the inhibition of acetylcholine-induced currents by tramadol. On the other hand, tramadol did not inhibit the current induced by AlF4-, a direct activator of GTP-binding protein. In cultured bovine adrenal medullary cells, tramadol (100 nM-100 muM) suppressed muscarine-induced cyclic GMP accumulation. Moreover, tramadol inhibited the specific binding of [H-3]quinuclidinyl benzilate (QNB). Scatchard analysis showed that tramadol increases the apparent dissociation constant (K-d) value without changing the maximal binding (B-max) indicating competitive inhibition. These findings suggest that tramadol at clinically relevant concentrations inhibits muscarinic receptor function via QNB-binding sites. This may explain the neuronal function and anticholinergic effect of tramadol.
  • J Ogata, K Nakano, K Sakamoto, K Minami
    ANESTHESIA AND ANALGESIA 93 (4) 1079 - 1080 0003-2999 2001/10 [Refereed][Not invited]
  • A leak in a capnography sampling line induced a difference between arterial and end-tidal CO2
    ANESTHESIOLOGY
    95 (3) 815 - 815 2001/09 [Refereed][Not invited]
  • M Shiraishi, K Minami
    CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE 48 (8) 828 - 828 0832-610X 2001/09 [Refereed][Not invited]
  • 白石 宗大, 南 浩一郎, 堀下 貴文
    麻酔 克誠堂出版 50 (7) 776 - 778 0021-4892 2001/07 [Not refereed][Not invited]
     
    5歳女児.出生時に2分脊椎,キアリ奇形(II型)と診断され経過観察されていた.今回,股関節拘縮に対する股関節骨切除術が予定された.気道系に関しては食事時にむせ易いという以外には頸部運動障害などは認められず,術前検査でも特に問題なかった.麻酔は自発呼吸下にマスクでセボフルランの緩徐導入で行い,0.5%から5%まで上げて意識消失と同時に自発呼吸は消失した.自発呼吸消失直後にマスク換気が突然できなくなり,喉頭痙攣を疑って喉頭展開を行なったところ,展開直後は声帯が完全に閉鎖していたが,20秒後には声帯が開き換気可能となったので100%酸素によるマスク換気下に覚醒後に再度麻酔導入を行った.チアミラール 50mgで意識消失後,ベクロニウム 2mgで筋弛緩後に挿管し,亜硝酸窒素60%,酸素40%,セボフルラン 2〜3%で維持した.手術は無事完了したが,抜管直後に導入時と同様の息こらえと1分間の無呼吸が起ったが,SpO2が90%まで低下時点で呼吸が再開した.その後,徐々に換気は正常化した
  • K Minami, K Segawa, Y Uezono, Y Shiga, M Shiraishi, J Ogata, A Shigematsu
    JAPANESE JOURNAL OF PHARMACOLOGY 86 (2) 159 - 164 0021-5198 2001/06 [Refereed][Not invited]
     
    Adrenomedullin (AM), a hypotensive peptide originally isolated from human pheochromocytoma, has been reported to regulate renal functions. In patients with glomerulonephritis, the serum levels of AM are elevated as well as hypertensive agents norepinephrine (NE) and angiotensin II (AII). The effects of AM on the NE- or AII-induced presser effects and renal blood flow responses, however, are not well clarified. We examined the effects of AM on blood pressure and renal blood flow induced by NE or AII in anesthetized rats. Arterial blood pressure and renal blood flow were measured using a calibrated pressure transducer and a laser Doppler flowmeter, respectively. Drugs were injected into the tail vein with a syringe. Intravenous administration of AM (1-3 nmol/kg) decreased the arterial blood pressure in anesthetized rats in a dose-dependent manner, whereas it did not affect the renal blood flow. NE or AII administration in anesthetized rats caused both increases in blood pressure and decreases in renal blood flow. Simultaneous administration of AM with NE or AII prevented the increasing effects of blood pressure and inhibited the decreases in renal blood flow caused by NE or AII. These findings suggest that AM may have a protective role against the presser effects and decrease in renal blood flow caused by NE or AII.
  • 白石 宗大, 南 浩一郎, 堀下 貴文, 重松 昭生
    麻酔 克誠堂出版(株) 50 (6) 637 - 638 0021-4892 2001/06 [Not refereed][Not invited]
     
    14歳男児.1歳時に先天性多発性関節拘縮症と診断され,今回,両股関節の屈曲拘縮に対し,両股関節周囲軟部組織解離術が予定された.術前検査では呼吸・循環系に問題はなく,血液生化学ではCPKの軽度高値を示した以外,正常であった.術3日前より,悪性高熱予防目的にダントロレンを経口投与した.麻酔は,プロポフォール 30mg静注後,ベクロニウムを計2mg投与した.挿管後,亜酸化窒素-酸素-プロポフォールで維持し,執刀前にペンタゾシン投与を行った.手術中の呼吸・循環系,体温は安定し,術後も良好であった
  • 中村 元洋, 南 浩一郎, 白石 宗大
    麻酔 克誠堂出版 50 (5) 541 - 544 0021-4892 2001/05 [Not refereed][Not invited]
     
    68歳女で,腹部巨大腫瘍の手術前日に腫瘍の栄養動静脈を確認する目的で血管造影を行ったところ突然肺塞栓症を発症した.この為周術期の再塞栓に備えてワーファリン,ウロキナーゼによる抗凝固線溶療法を開始すると共に,麻酔中に発生した場合の早期発見の為に呼気終末二酸化炭素濃度測定,カプノグラムの装着,肺動脈圧モニタとしてのSwan-Ganzカテーテル挿入などを行った.Swan-Ganzカテーテルは抗血栓療法のルートとしても使えるようにしておいた.また緊急percutaneous cardio-pulmonary support挿入に備えて右大腿動脈に9Fのシースを挿入した.術後の塞栓予防にはA-Vインパルスシステムを用いた.手術は術中再塞栓を起こすことなく終了し,術後も問題なく経過した
  • T Narahashi, K Kuriyama, P Illes, K Wirkner, W Fischer, K Muhlberg, P Scheibler, C Allgaier, K Minami, D Lovinger, F Lallemand, RJ Ward, P DeWitte, T Itatsu, Y Takei, H Oide, M Hirose, XE Wang, S Watanabe, M Tateyama, R Ochi, N Sato
    ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH 25 (5) 182S - 188S 0145-6008 2001/05 [Refereed][Not invited]
     
    This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Toshio Narahashi and Kinya Kuriyama. The presentations were (1) Modulation of neuroreceptors and ion channels by alcohol, by T. Narahashi; (2) Inhibition by ethanol of NMDA and AMPA receptor-channels, by P. Illes, K. Wirkner, W. Fischer, K. Muhlberg, P. Scheibler, and C. Allgaier; (3) Effects of ethanol on metabotropic glutamate receptors, by K. Minami; (4) Acute alcohol actions on the 5-HT3 ligand-gated ion channel, by D. Lovinger; (5) Inhibition of NMDA receptors by MK801 attenuates ethanol-induced taurine release from the hippocampus, by F. Lallemand, R.J. Ward, and P. DeWitte; and (6) Effect of ethanol on voltage-operated Ca2+ channels in hepatic stellate cells, by T. Itatsu, Y. Takei, II. Oide, M. Hirose, X. E. Wang, S. Watanabe, M. Tateyama, R. Ochi, and N. Sato.
  • K Segawa, K Minami, Y Shiga, M Shiraishi, T Sata, Y Nakashima, A Shigematsu
    NEPHRON 87 (3) 263 - 268 0028-2766 2001/03 [Refereed][Not invited]
     
    We investigated the effects of nicorandil, which is a hybrid between a nitrate and an ATP-sensitive potassium channel (K-ATP) opener, on cultured rat mesangial cell proliferation. Nicorandil (1 muM to 1 mM inhibited [H-3]thymidine incorporation into rat mesangial cells in a concentration-dependent manner. Nicorandil (1 muM to 1 mM) also inhibited the number of cells. Nicorandil increased cyclic guanosine 3',5'-cyclic monophosphate accumulation in mesangial cells. A protein kinase G inhibitor, KT5823, partially eliminated the inhibition of mesangial cell proliferation by nicorandil. Methylene blue, a guanylate cyclase inhibitor, blocked the inhibitory effect of nicorandil on mesangial cell proliferation. We also examined the effects of KATP mediators. Cromakalim, a KATP activator, and glibenclamide, a KATP inhibitor, had little effect on the proliferation of mesangial cells. These results suggest that the inhibitory effects of nicorandil on mesangial cell proliferation are mediated via the protein kinase G pathway. Copyright (C) 2001 S. Karger AG, Basel.
  • M. Nakamura, K. Minami, M. Shiraishi, K. Kohriyama, A. Shigematsu
    Japanese Journal of Anesthesiology 50 (5) 541 - 544 0021-4892 2001 [Refereed][Not invited]
     
    Several reports have highlighted the risk of pulmonary embolisms during the preoperative period in patients with large abdominal tumors obstructing the inferior vena cava. We describe a patient who developed pulmonary embolism just before surgery. A 64-year-old female was scheduled to undergo elective resection of a large abdominal tumor under general anesthesia. She had no signs of deep venous thrombosis, but on the day of the operation, pulmonary embolism developed suddenly. Anticoagulant therapy was performed. Capnography and pulmonary artery pressure were monitored during the perioperative period to detect the recurrence of pulmonary embolism. The percutaneous cardio-pulmonary support (PCPS) was also prepared. The operation was performed successfully. In this patient, the pulmonary embolism occurred suddenly during the preoperative period, even though we had ruled out the existence of deep venous thrombosis. This case report emphasizes the risk of pulmonary embolism in any patient with a large abdominal tumor obstructing the inferior vena cava. This case of a large abdominal tumor suggests that capnography, monitoring of pulmonary artery pressure and preparation of a PCPS in case of pulmonary embolism during surgery are necessary even in patients without signs of deep venous thrombosis.
  • M. Shiraishi, K. Minami, A. Shigematsu
    Japanese Journal of Anesthesiology 50 (6) 637 - 638 0021-4892 2001 [Refereed][Not invited]
     
    Arthrogryposis multiplex congenita (AMC) is a syndrome with multiple persistent limb contractures, often accompanied by associated anomalies. Pediatric patients with AMC frequently require operations, necessitating general endotracheal anesthesia. We report on the anesthesia used for a 14-year-old male with AMC, who required the surgical removal of soft tissue from both hip joints. We used propofol and vecuronium bromide to induce anesthesia, and maintained anesthesia with 40% nitrous oxide, oxygen, and propofol at 6 mg · kg-1 · 1 hr-1. Both induction and maintenance were smooth, and no hyperthermia occurred perioperatively. Propofol can be safely used for anesthesia in AMC patients.
  • M. Shiraishi, K. Minami, T. Horishita, A. Shigematsu
    Japanese Journal of Anesthesiology 50 (7) 776 - 778 0021-4892 2001 [Refereed][Not invited]
     
    Arnold-Chiari malformation is a congenital disorder with caudal displacement of the cerebellar tonsils through the foramen magnum into the cervical canal. We report difficulty with ventilation during the induction of anesthesia due to apnea and laryngospasm in a 5-year-old female with Arnold-Chiari malformation type II diagnosed at birth. She had had short periods of apnea during infancy, but was asymptomatic recently. Slow induction of anesthesia was performed using sevoflurane, but just after induction, the patient developed apnea and we could not ventilate her due to laryngospasm. We woke her up, and induced anesthesia with barbiturates. The operation was performed without complications, but she had another apnea attack with laryngospasm at extubation. This case suggests that it is important to be aware of the possibility of apnea due to disorder of the respiratory center in patients with Arnold-Chiari deformity.
  • ABE Kenichi, MINAMI Kouichirou, NISHIMURA Masahiro, HONDA Miki, SATA Takeyoshi, SHIGEMATSU Akio
    THE JOURNAL OF JAPAN SOCIETY FOR CLINICAL ANESTHESIA 日本臨床麻酔学会 21 (1) 46 - 48 0285-4945 2001 [Not refereed][Not invited]
     
    Angelman syndrome is characterized by severe mental retardation, seizures, inappropriate outbursts of laughter, a puppet-like ataxic gait and dysmorphic facial features such as a small head and large lower jaw. There is potential difficulty with the airway management of patients with this syndrome, because of the severe mental retardation, the small head and large lower jaw, hypotonia and large tongue. We report here a case of anesthetic management for a 4-year-old boy with Angelman syndrome. He was scheduled for a tonsillectomy and adenotomy under general anesthesia for sleep apnea syndrome. Preanesthetic medication and a muscle relaxant were not administered, because he had sleep apnea and hypotonia. Anesthesia was slowly induced with sevoflurane in oxygen and maintained with sevoflurane in nitrous oxide and oxygen. There were no difficulties with the intratracheal intubation, and the anesthesia was completed uneventfully.
  • MINAMI Kouichiro, SHIGA Yousuke, SAGATA Kenichiro, KOGA Kazunori
    Journal of Japan Society of Pain Clinicians 一般社団法人 日本ペインクリニック学会 8 (1) 22 - 24 1340-4903 2001 [Not refereed][Not invited]
     
    We report a subarachnoid cyst in a 66-year-old woman who was evaluated with MRI after epidural anesthesia for gynecological surgery. Three days after the continuos epidural analgesia for the postoperative pain, the patient complained of motor weakness, hypesthesia and dysesthesia in both legs. An epidural hematoma was suspected with MRI, and a laminectomy was performed.
    There was no hematoma, but a cyst was found under the subarachnoid space. Her neurologic symptoms partially improved over 6 months. We reviewed the complications of epidural anesthesia and arachnoid cysts.
  • Structure and function of GABAA receptors: recent studies by site-directed mutagenesis.
    Ueno S, Minami K, Yanagihara N
    Tanpakushitsu Kakusan Koso. 2001;46:2042-51 46 2045 - 51 2001 [Refereed][Not invited]
  • K Hara, N Yanagihara, K Minami, H Hirano, T Sata, A Shigematsu, F Izumi
    ANESTHESIOLOGY 93 (5) 1329 - 1335 0003-3022 2000/11 [Refereed][Not invited]
     
    Background: Norepinephrine transporters (NETs) terminate the neuronal transmission of norepinephrine, which is released from noradrenergic neurons. To investigate the interaction with NET, the authors examined the effects of short- and long-term treatment with anesthetics on the activity and mRNA level of NET Methods: To assay [H-3]norepinephrine uptake, bovine adrenal medullary cells in culture were incubated with [H-3]norepinephrine in the presence of intravenous anesthetics, including propofol thiamylal, and diazepam, To study the direct interaction between the anesthetics and NET, the effect of propofol on the binding of [H-3]desipramine to the plasma membrane was examined. To study the long-term effect of anesthetics, [H-3]norepinephrine uptake by cells pretreated with propofol for 6-24 h and [H-3]desipramine binding after pretreatment for 12 h were measured. Simultaneously, we examined the effect of anesthetics on the expression of NET mRNA using the reverse transcriptase-polymerase chain reaction. Results: All of the intravenous anesthetics inhibited [H-3]norepinephrine uptake In a concentration-dependent manner. The active concentrations of propofol (1-3 muM) and thiamylal (less than or equal to 30 muM) were Similar to those encountered clinically. The kinetic analysis revealed that all the anesthetics noncompetitively inhibited [H-3]norepinephrine uptake. Propofol inhibited [H-3]desipramine binding with a potency similar to that observed in [H-3]norepinephrine uptake. Scatchard analysis showed that propofol competitively inhibited [H-3]desipramine binding. On the other hand, long-term treatment of cells with propofol (10 mum) enhanced the NET functional activity and [3H]desipramine binding, and also increased the level of NET mRNA, Conclusions: These results suggest that intravenous anesthetics have a dual effect on NET; short-term treatment causes inhibition, whereas long-term treatment leads to up-regulation. The interaction of intravenous anesthetics with NET may modulate the neuronal transmission of norepinephrine during anesthesia.
  • 尾方 純一, 南 浩一郎, 大石 美希子
    麻酔 克誠堂出版 49 (10) 1139 - 1141 0021-4892 2000/10 [Not refereed][Not invited]
     
    40歳女.全身麻酔下で腹式単純子宮全摘術中,サイズ3のラリンジアルマスク(LMA)の挿入15分後に両側の急性顎下部腫大を認めた.この原因がLMA挿入であることを確認するため,カフ内圧を上昇させてLMA体積を増大させると,顎下腺は有意に増大し大きく変形した.LMA抜去直後に腫大は消失した.耳鼻科診療で唾石症や唾液腺疾患は指摘されず,後遺症は無かった.LMAが顎下腺を圧排し変形し直接刺激したため,唾液分泌が亢進したことが顎下腺腫大を来したと考察した
  • K Uryu, K Minami, N Yanagihara, K Hara, Y Toyohira, F Izumi, A Shigematsu
    ANESTHESIA AND ANALGESIA 91 (3) 546 - 551 0003-2999 2000/09 [Refereed][Not invited]
     
    Pancuronium stimulates the cardiovascular system, whereas vecuronium, a derivative of pancuronium, has far fewer effects. The inhibition of norepinephrine transporter (NET) in the sympathetic nervous system may partly account for the stimulatory actions of pancuronium. To investigate the mechanism of action of pancuronium on NET, we examined the effects of pancuronium on NET activity by using cultured bovine adrenal medullary, cells and compared pancuronium with other neuromuscular blocking drugs. Pancuronium (1-300 mu M) inhibited desipramine-sensitive [H-3]norepinephrine (NE) uptake in a concentration-dependent manner. Vecuronium (100-300 mu M) and d-tubocuarine (300 mu M) also decreased [H-3]NE uptake but were less potent than pancuronium at clinical concentrations. Succinylcholine had little effect on [H-3]NE uptake. Saturation analysis showed that pancuronium and vecuronium reduced an apparent maximum velocity (V-max) of [H-3]NE uptake without altering Michaelis-Menten constant, indicating noncompetitive inhibition. Pancuronium did not inhibit the specific binding of [H-3]desipramine to plasma membranes isolated from bovine adrenal medulla. A protein kinase C inhibitor, GF109203X, did not affect the inhibition of [H-3]NE uptake by pancuronium, Pancuronium enhanced the inhibition of NET induced by ketamine. These results suggest that pancuronium, with clinically relevant concentrations, inhibits NET activity by interacting with a site distinct from the recognition site for NE and the desipramine binding site on the transporter.
  • 郡山 一明, 後藤 京子, 南 浩一郎
    産業医学ジャーナル 産業医学振興財団 23 (3) 38 - 41 0388-337X 2000/05 [Not refereed][Not invited]
     
    就業中の化学物質曝露中毒事例の情報提供のあり方を検討した.産業現場では多種多様の化学物質が使用されており,ヒトでの毒性がよくわかっていない物質による中毒事例も少なくなかった.中毒事例は経気道曝露が多かった.就業中の化学物質曝露中毒事例の情報提供には,起因物質の毒性情報の提供と共に,曝露時の作業環境,臨床経過等を産業医学的かつ臨床医学的に解析したデータを提供することが必要と考えられた
  • J. Ogata, K. Minami, M. Oishi, K. Mekata, M. Nishimura, T. Sata
    Japanese Journal of Anesthesiology 49 (10) 1139 - 1141 0021-4892 2000 [Refereed][Not invited]
     
    A 40-year-old woman was scheduled for abdominal hysterectomy. Moderate difficulty in tracheal intubation was expected on preoperative evaluation. A size 3 laryngeal mask airway (LMA) was inserted after the induction of general anesthesia. The LMA insertion was accomplished smoothly at the first attempt and there was no air leakage during manual ventilation. Soon after the insertion, acute swellings were noted in the bilateral submandibular triangle regions. Enlargement and deformity of the submandibular glands were diagnosed by ultrasonography. The enlargements increased with elevated pressure of the LMA cuff, but disappeared completely in five minutes after removal of the LMA. Such enlargement did not occur with subsequent tracheal intubation. The patient had an uneventful postoperative course without any residual sequelae. We should pay attention to possible submandibular gland swellings by LMA insertion.
  • K Hara, K Minami, K Takamoto, M Shiraishi, T Sata
    ANESTHESIA AND ANALGESIA 90 (1) 224 - 226 0003-2999 2000/01 [Refereed][Not invited]
  • M Ooishi, K Minami, T Sata, J Ogata, S Koyama, A Shigematsu
    CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE 46 (11) 1097 - 1098 0832-610X 1999/11 [Refereed][Not invited]
  • Rh陰性小児巨大縦隔腫瘍の麻酔経験
    原 幸治, 南 浩一郎, 相方 謙一郎, 佐多 竹良, 重松 昭生
    臨床麻酔 真興交易(株)医書出版部 23 (7) 1131 - 1134 0387-3668 1999/07 [Not refereed][Not invited]
  • T Noguchi, K Minami, T Iwagaki, H Takara, T Sata, A Shigematsu
    JOURNAL OF CLINICAL ANESTHESIA 11 (4) 339 - 341 0952-8180 1999/06 [Refereed][Not invited]
     
    A 73-year-old woman who suffered from progressive hoarseness for 6 years and dysphagia without pain for 1 year presented with a soft tissue deposition on the posterior region of the vocal cords and narrowing in the subglottic area. Biopsy of this soft tissue and histological examination revealed laryngeal amyloidosis. A tracheostomy and partial removal of the amyloid were performed with general anesthesia. The airway was secured with a smaller diameter endotracheal tube which was inserted atraumatically with Magill's forceps. The larynx is a rare site for amyloidosis. Laryngeal amyloidosis is fragile and hemorrhagic. Therefore, massive bleeding may occur during intubation. Anesthetists should take care in intubating the tracheas of these patients and be aware of other systemic diseases in laryngeal amyloidosis. (C) 1999 by Elsevier Science Inc.
  • 伊福 弥生, 南 浩一郎, 佐多 竹良, 井上 義崇, 藤井 健, 重松 昭生
    麻酔 克誠堂出版(株) 48 (4) 424 - 426 0021-4892 1999/04 [Not refereed][Not invited]
  • OCHIAI Hideo, IFUKU Yayoi, URYU Kayo, MINAMI Kouichiro, IWANO Wataru, SATA Takeyosi
    THE JOURNAL OF JAPAN SOCIETY FOR CLINICAL ANESTHESIA 日本臨床麻酔学会 19 (5) 348 - 350 0285-4945 1999 [Not refereed][Not invited]
     
    A 4-month-old boy was scheduled for resection of a tracheal tumor which occupied about 90% of the tracheal lumen. Intubation of an tracheal tube was deemed impossible. Anesthesia was induced by inhalation of sevoflurane in oxygen and fentanyl iv. After insertion of the LMA, anesthesia was maintained with O2-sevoflurane-fentanyl while maintaining his spontaneous ventilation. Fiberoptic tracheobronchoscopy was performed through the LMA to observe the tumor and the operation site lest the tumor obstructs the tracheal lumen during surgical manipulation. Anesthesia was completed uneventfully. We conclude that the combination of LMA and fiberoptic observation of the trachea is useful for airway management of the tracheal tumor in infants.
  • Ketamine interacts with the noradrenaline transporter at a site partly overlapping the desipramine binding site (vol 358, pg 328, 1998)
    K Hara, N Yanagihara, K Minami, S Ueno, Y Toyohira, T Sata, M Kawamura, M Bruss, H Bonisch, A Shigematsu, F Izumi
    NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY 358 (5) 600 - 600 1998/11 [Refereed][Not invited]
  • K Hara, N Yanagihara, K Minami, S Ueno, Y Toyohira, T Sata, M Kawamura, M Bruss, H Bonisch, A Shigematsu, F Izumi
    NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY 358 (3) 328 - 333 0028-1298 1998/09 [Refereed][Not invited]
     
    Effects of the intravenous anaesthetic ketamine on the desipramine-sensitive noradrenaline transporter (NAT) were examined in cultured bovine adrenal medullary cells and in transfected Xenopus laevis oocytes expressing the bovine NAT (bNAT). Incubation (1-3 h) of adrenal medullary cells with ketamine (10-300 mu M) caused an in crease in appearance of catecholamines in culture medium. Ketamine (10-1000 mu M) inhibited desipramine-sensitive uptake of [H-3] noradrenaline (NA) (IC50=97 mu M) Saturation analysis showed that ketamine reduced V-max of [H-3]NA uptake without changing K-m, indicating a non-competitive inhibition. Other inhibitors of NAT, namely cocaine and desipramine, showed a competitive inhibition of [H-3]NA uptake while a derivative of ketamine, phencyclidine, showed a mixed type of inhibition. Ketamine (10-1000 mu M) also inhibited the specific binding of [H-3]desipramine to plasma membranes isolated from bovine adrenal medulla. Scatchard analysis of [H-3]desipramine binding revealed that ketamine increased K-d without altering B-max, indicating a competitive inhibition. In transfected Xenopus oocytes expressing the bNAT, ketamine attenuated [H-3]NA uptake with a kinetic characteristic similar to that of cultured adrenal medullary cells. These findings are compatible with the idea that ketamine non-competitively inhibits the transport of NA by interacting with a site which partly overlaps the desipramine binding site on the NAT.
  • 経鼻挿管でのカフ付き口咽頭チューブの有用性
    小山 俊, 南 浩一郎, 佐多 竹良, 池村 邦男, 重松 昭生
    臨床麻酔 真興交易(株)医書出版部 22 (7) 998 - 999 0387-3668 1998/07 [Not refereed][Not invited]
  • NOGUCHI Takashi, MINAMI Kouichiro, SATA Takeyoshi, SHIGEMATSU Akio
    日本臨床麻酔学会誌 = The Journal of Japan Society for Clinical Anesthesia 日本臨床麻酔学会 18 (5) 518 - 520 0285-4945 1998/06 [Not refereed][Not invited]
     
    両側性先天性眼瞼下垂と外斜視を伴ったmyotubular myopathy患者の左水平筋前後転術の周術期管理を経験した.患者は術前より全身性び漫性の筋萎縮と筋力低下及び呼吸機能の低下が認められたため,筋弛緩薬を使用せずチアミラール-セボフルラン-亜酸化窒素で麻酔を行った.手術後,患者は覚醒遅延をきたし,更に術後約20時間以上にわたる筋脱力状態をきたした.Myotubular myopathyを呈する患者の麻酔においては麻酔薬により筋脱力状態が遷延することに注意が必要である
  • Y Toyohira, N Yanagihara, K Minami, S Ueno, Y Uezono, E Tachikawa, Y Kondo, T Kashimoto, F Izumi
    JOURNAL OF NEUROCHEMISTRY 70 (4) 1441 - 1447 0022-3042 1998/04 [Refereed][Not invited]
     
    The aim of this study was to investigate the effect of long-term treatment with interferon (IFN)-alpha on the noradrenaline transporter of bovine adrenal medullary cells. Treatment of cultured adrenal medullary cells with IFN-alpha caused a decrease in uptake of [H-3]noradrenaline by the cells in time (4-48 h)- and concentration (300-1,000 U/ml)-dependent manners. IFN-beta also inhibited [H-3]noradrenaline uptake to a lesser extent than did IFN-alpha, whereas IFN-gamma had little effect. An anti-IFN-alpha antibody reduced the effect of IFN-alpha on [H-3]noradrenaline uptake. Saturation analysis of [H-3]noradrenaline uptake showed that the inhibitory effect of IFN-alpha was due to a reduction in the maximal uptake velocity (V-max values without altering apparent Michaelis constant (K-m) values. Incubation of cells with IFN-alpha caused a translocation of protein kinase C from the soluble to the particulate fraction in the cells. The effect of IFN-alpha on [H-3]noradrenaline uptake was diminished in protein kinase C-down-regulated cells. Incubation of cells with IFN-alpha for 48 h significantly reduced the specific binding of [H-3]desipramine to crude plasma membranes isolated from cells. Scatchard analysis of [H-3]desipramine binding revealed that IFN-alpha decreased the maximal binding (B-max) values without any change in the dissociation constant (K-m) values. These findings suggest that IFN-alpha suppresses the function of noradrenaline transporter by reducing the density of the transporter in cell membranes through, at least in part, a protein kinase C pathway.
  • K Minami, MJ Wick, Y Stern-Bach, JE Dildy-Mayfield, SJ Brozowski, EL Gonzales, Trudell, JR, RA Harris
    JOURNAL OF BIOLOGICAL CHEMISTRY 273 (14) 8248 - 8255 0021-9258 1998/04 [Refereed][Not invited]
     
    Molecular mechanisms of anesthetic action on neurotransmitter receptors are poorly understood. The major excitatory neurotransmitter in the central nervous system is glutamate, and recent studies found that volatile anesthetics inhibit the function of the alpha-amino-3-hydroxyisoxazolepropionic acid subtype of glutamate receptors (e.g. glutamate receptor 3 (GluR3)), but enhance kainate (GluR6) receptor function, We used this dissimilar pharmacology to identify sites of anesthetic action on the kainate GluR6 receptor by constructing chimeric GluR3/GluR6 receptors, Results with chimeric receptors implicated a transmembrane region (TM4) of GluR6 in the action of halothane. Site directed mutagenesis subsequently showed that a specific amino acid, glycine 819 in TM4, is important for enhancement of receptor function by halothane (0.2-2 mM). Mutations of Gly-819 also markedly decreased the response to isoflurane (0.2-2 mM), enflurane (0.2-2 mM), and 1-chloro-1,2,2-trifluorocyclobutane (0.2-2 mM). The nonanesthetics 1,2-dichlorohexafluorocyclobutane and 2,3-dichlorooctafluorobutane had no effect on the functions of either wild-type GluR6 or receptors mutated at Gly-819. Ethanol and pentobarbital inhibited the function of both wild-type and mutant receptors. These results suggest that a specific amino acid, Gly-819, is critical for the action of volatile anesthetics, but not of ethanol or pentobarbital, on the GluR6 receptor.
  • R Yoshimura, N Yanagihara, T Terao, K Minami, Y Toyohira, S Ueno, Y Uezono, K Abe, F Izumi
    PSYCHOPHARMACOLOGY 135 (4) 368 - 373 0033-3158 1998/02 [Refereed][Not invited]
     
    We have recently reported inhibitory effects of carbamazepine (CBZ) on ion channel-mediated secretion of catecholamines in bovine adrenal medullary cells. Here, we report the effects of carbamazepine-10,li-epoxide (CBZ-E), an active metabolite of CBZ, and carbamazepine-10,11-diol (CBZ-D), a non-active metabolite, on Na-22(+) influx, Ca-45(2+) influx and catecholamine secretion in cultured adrenal medullary cells. CBZ-E, but not CBZ-D inhibited Na-22(+) influx. Ca-45(2+) influx and catecholamine secretion induced by carbachol or veratridine with a half-maximal inhibitory concentration (IC50) of 0.26 or 0.68 mu g/ml, respectively. CBZ-E also inhibited high K+-evoked Ca-45(2+) influx and catecholamine secretion (IC50 = 0.3 mu g/ml), but CBZ-D did not. These findings suggest that CBZ-E, but not CBZ-D, attenuates catecholamine secretion by inhibiting nicotinic acetylcholine receptor-associated ion channels: voltage-dependent Na+ channels and voltage-dependent Ca2+ channels in the cells. This inhibition of CBZ-E as well as CBZ may be related to the clinical effects in neuropsychiatric disorders.
  • N Yanagihara, K Hara, K Kajiwara, K Minami, Y Toyohira, Y Uezono, S Ueno, H Hirano, U Yamashita, F Izumi
    NEUROSCIENCE LETTERS 243 (1-3) 25 - 28 0304-3940 1998/02 [Refereed][Not invited]
     
    The effects of lymphocytes and their conditioned medium on catecholamine efflux and uptake were examined in cultured bovine adrenal medullary cells. Go-culture of adrenal medullary cells with lymphocytes for 3 days caused an increase in appearance of catecholamines in the culture medium. Treatment of adrenal medullary cells with a conditioned medium prepared from lymphocytes also enhanced the appearance of catecholamines in culture medium in time- (8-48 h) and concentration-dependent manners. Heat treatment of the conditioned medium at 60 and 100 degrees C for 10 min reduced its stimulatory effect to 59 and 20% of control, respectively. After gel filtration on a Sephadex G-25 column or dialysis (<8 kDa molecular mass cutoff), the stimulatory activity of the conditioned medium was found in a high molecular fraction. The conditioned medium had little effect on the activity of lactate dehydrogenase in the medium of cultured adrenal medullary cells and on desipramine-sensitive [H-3]norepinephrine uptake by the cells. These findings suggest that lymphocytes release a heat-sensitive factor(s) (molecular mass of more than 8 kDa) which increases efflux of catecholamines from cultured adrenal medullary cells. (C) 1998 Elsevier Science Ireland Ltd.
  • H Ishimura, K Minami, T Sata, K Murashima, A Shigematsu
    ANAESTHESIA AND INTENSIVE CARE 26 (1) 110 - 111 0310-057X 1998/02 [Refereed][Not invited]
     
    We describe a case of an unco-operative patient with recessive dystrophic epidermolysis bullosa in whom difficult tracheal intubation was anticipated and fibreoptic bronchoscope guided tracheal intubation was successfully achieved after induction of general anaesthesia. Other problems in airway management associated with this disorder are discussed.
  • K Minami, RW Gereau, M Minami, SF Heinemann, RA Harris
    MOLECULAR PHARMACOLOGY 53 (1) 148 - 156 0026-895X 1998/01 [Refereed][Not invited]
     
    Previous studies have demonstrated that ethanol and volatile anesthetics inhibit the function of some metabotropic (G protein-coupled) receptors, including the 5-hydroxytryptamine(2), and muscarinic cholinergic receptors. The metabotropic glutamate receptors (mGluRs) show little sequence homology with most other metabotropic receptors and are important modulators of synaptic transmission in the mammalian central nervous system. It was of interest to determine drug actions on these receptors, and we investigated the effects of ethanol, halothane, the anesthetic compound F3 (I-chloro-l,2,2-trifluorocyclobutane), and the nonanesthetics F6 (1,2-dichlorohexafluorocyclobutane) and F8 (2,3-chlorooctafluorobutane) on the function of mGluR1 and mGluR5 expressed in Xenopus laevis oocytes. Halothane, F3, and ethanol inhibited mGluR5-induced Ca2+-dependent Cl- currents, yet pharmacologically relevant concentrations of these compounds had little effect on the glutamate-induced currents in the oocytes expressing mGluR1. F6 had inhibitory effects on both receptors, and F8 did not affect either mGluR1 or mGluR5 function. The protein kinase C (PKC) inhibitor GF109203X enhanced the glutamate-induced current, and the PKC activator phorbol-12-myristate-13-acetate inhibited this current in the oocytes expressing mGluR5, but these compounds had little effect on mGluR1 function. GF109203X abolished the inhibitory effects of halothane, F3, and ethanol on mGluR5s. Conversely, the phosphatase inhibitor calyculin A prolonged the action of halothane and ethanol. Furthermore, mutation of a PKC consensus site (Ser890) of mGluR5 abolished the inhibitory effects of halothane, F3, and ethanol. These results suggest that ethanol and volatile anesthetics inhibit mGluR5 because they promote PKC-mediated phosphorylation.
  • K Segawa, K Minami, N Jimi, Y Nakashima, A Shigematsu
    NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY 357 (1) 70 - 76 0028-1298 1998/01 [Refereed][Not invited]
     
    We studied the effects of C-type natriuretic peptide (CNP) on rat cultured mesangial cell proliferation. (1) Exposure to CNP (10 nM-1 mu M for 72 h) inhibited [H-3]thymidine incorporation into mesangial cells in a concentration-dependent manner. Atrial natriuretic peptide (1 nM-1 mu M), a peptide related to CNP, also decreased [3H]thymidine incorporation into these cells in a concentration-dependent manner. (2) Both CNP (10 nM-1 mu M) and atrial natriuretic peptide (10 nM-1 mu M) also decreased mesangial cell number. (3) The cyclic GMP analog, 8-bromo-cyclic GMP (100 mu M and 1 mM), mimicked the inhibitory effects of CNP and atrial natriuretic peptide on [H-3]thymidine incorporation into mesangial cells, whereas inhibitors of protein kinase C, protein kinase A, and protein kinase G reduced the effect of both natriuretic peptides. Moreover, the phoshpatase inhibitor, calyculin A, increased [H-3]thymidine incorporation into mesangial cells. (4) CNP and atrial natriuretic peptide decreased interleukin-1-, interleukin-6-, platelet derived growth factor-, angiotensin II-induced [H-3]thymidine incorporation into mesangial cells. These results suggest that CNP exerts inhibitory effects on mesangial cell proliferation and that this effects depend on protein phosphorylation pathways.
  • K Minami, TW Vanderah, M Minami, RA Harris
    EUROPEAN JOURNAL OF PHARMACOLOGY 339 (2-3) 237 - 244 0014-2999 1997/11 [Refereed][Not invited]
     
    Anesthetics (and ethanol) are known to produce amnesia as well as immobilization. Recent identification of a nonimmobilizing (nonanesthetic) agent (F6 or 1,2-dichlorohexafluorocyclobutane) that impairs learning and memory suggests that distinct mechanisms may be responsible for these two actions of anesthetic agents. Muscarinic receptors are believed to play a role in memory and learning, and we asked if a specific subtype of these receptors is affected by anesthetics as well as the new nonanesthetic. We investigated the effects of halothane, a novel halogenated anesthetic compound F3 (1-chloro-1,2,2-trifluorocyclobutane) and ethanol on acetylcholine-induced current mediated by a muscarinic m(1) receptor expressed in Xenopus oocytes. We also studied the effects of halogenated nonanesthetic compounds, F6 and F8 (2,3-chlorooctafluorobutane) on muscarinic m(1) receptors. Halothane, F3, F6 and ethanol inhibited muscarinic m(1) receptor-induced Ca2+-dependent Cl- currents at pharmacologically relevant concentrations. F8 had no effect on acetylcholine-induced muscarinic m(1) receptor function. The protein kinase C inhibitor, bisindolylmaleimide I (GF109203X), enhanced the acetylcholine-induced current and the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), inhibited this current. GF109203X abolished the inhibitory effects of halothane, F3 and ethanol on muscarinic m(1) receptors but had no effect on actions of F6. These results demonstrate that anesthetics and a nonanesthetic inhibit the function of muscarinic m(1) receptors and suggest activation of protein kinase C as the mechanism of action of anesthetics and ethanol on these receptors. (C) 1997 Elsevier Science B.V.
  • K Segawa, K Minami
    CLINICAL NEPHROLOGY 47 (4) 272 - 273 0301-0430 1997/04 [Refereed][Not invited]
  • Ihibition of 5-Hydrothyptamine type 2A receptor-induced Currents by n-alchols and Anesthetics
    Kouichiro MInami, Makiko MInami, R.Adron Harris
    Journal of Experimental and Pharmacological Therapeutics 281 1136 - 1143 1997/02 [Refereed][Not invited]
  • N Jimi, K Segawa, K Minami, T Sata, A Shigematsu
    ANESTHESIA AND ANALGESIA 84 (1) 190 - 195 0003-2999 1997/01 [Refereed][Not invited]
     
    We studied the effects of ketamine and propofol on rat cultured mesangial cell (MC) proliferation. The 72-hexposure to ketamine (1-100 mu M) inhibited [H-3]thymidine incorporation into the MC in a concentration-dependent manner. Propofol, however, was not effective at inhibition of MC proliferation at doses from 1 to 100 mu M. Ketamine also decreased the cell number at clinically relevant concentrations and increased adenosine 3',5'-cyclic monophosphate (cAMP) levels in MC. We also studied the effects of ketamine on cytokine-induced [H-3]thymidine incorporation info the cells. Ketamine decreased the tumor necrosis factor-alpha (TNF-alpha)-, interleukin 1 (IL-1)-, and interleukin 6 (IL-6)- induced [H-3]thymidine incorporation into the cells. It also decreased angiotensin II (Ag II)-induced [H-3]thymidine incorporation. These results suggest that ketamine has inhibitory effects on MC proliferation, but that propofol does not. Because ketamine inhibits TNF-alpha-, IL-1-, and IL-6-induced MC proliferation, it may be useful in suppressing the cell growth clinically.
  • K Segawa, K Minami, T Sata, A Kuroiwa, A Shigematsu
    NEPHRON 74 (3) 577 - 579 0028-2766 1996/11 [Refereed][Not invited]
     
    We investigated the effects of adrenomedullin on rat mesangial cell proliferation. Adrenomedullin (10(-10)-10(-7) M) inhibited both [H-3]thymidine incorporation into cultured rat mesangial cells and cell proliferation in a concentration-dependent manner. Adrenomedullin (10(-10)-10(-6) M) stimulated cyclic adenosine monophosphate accumulation in rat mesangial cells in a-concentration-dependent manner. These findings suggest that adrenomedullin inhibits proliferation of rat mesangial cells probably through a cyclic adenosine monophosphate-dependent mechanism.
  • K Minami, N Yanagihara, K Segawa, T Sata, M Tsutsui, A Shigematsu, F Izumi
    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 279 (2) 838 - 843 0022-3565 1996/11 [Refereed][Not invited]
     
    To elucidate the mechanism of protamine-induced hypotension, we examined the effects of protamine on catecholamine secretion in bovine adrenal medullary cells and on the serum norepinephrine in the rat. 1) In bovine adrenal medullary cells in culture, protamine at concentrations of 10 to 100 mu g/ml inhibited catecholamine secretion stimulated by carbachol. The inhibitory effect of protamine was diminished by heparin at concentrations of 3.5 to 14 U/ml. Protamine suppressed carbachol-stimulated Na-22(+) influx and Ca-45(++) influx at a concentration similar to that which inhibited catecholamine secretion. Protamine (10-100 mu g/ml) also inhibited veratridine-induced Na-22(+) influx and Ca-45(++) influx and 56 mM K+-evoked Ca-45(++) influx. The inhibition of these ion influxes by protamine was closely correlated with that of catecholamine secretion. 2) In rats, i.v. administration of protamine (10 mg/kg) attenuated the arterial blood pressure and the serum norepinephrine. There was a high correlation (r = 0.96) between the serum norepinephrine and the arterial blood pressure in protamine-treated rats. Furthermore, pretreatment with heparin (1000 U/kg) abolished the protamine-induced decreases in arterial blood pressure and serum norepinephrine. Because protamine seems to inhibit catecholamine secretion by interfering with Na+ influx and Ca++ influx to adrenal medullary cells, the protamine-induced hypotension may be, at least in part, due to inhibition of norepinephrine release and ion channel activities of sympathetic nerve terminals in rats.
  • M Tsutsui, N Yanagihara, K Fukunaga, K Minami, Y Nakashima, A Kuroiwa, E Miyamoto, F Izumi
    JOURNAL OF NEUROCHEMISTRY 66 (6) 2517 - 2522 0022-3042 1996/06 [Refereed][Not invited]
     
    KN-62, an inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II), inhibited significantly catecholamine secretion and tyrosine hydroxylase activity stimulated by acetylcholine in cultured bovine adrenal medullary cells. KN-62, however, showed an additional inhibitory effect on acetylcholine-induced Ca-45(2+) influx, which is essential for functional responses. Carbachol-stimulated Na-22(+) influx, veratridine-induced Na-22(+) influx, and 56 mM K+-evoked Ca-45(2+) influx were also attenuated by KN-62. Inhibitions by KN-62 of these ion influxes were correlated closely with those of catecholamine secretion, KN-04, which is a structural analogue of KN-62 but does not inhibit CaM kinase II activity, elicited inhibitory effects on the three kinds of stimulant-evoked ion influxes with an inhibitory potency similar to KN-62. These results suggest that KN-62 inhibits catecholamine secretion and tyrosine hydroxylase activation due to mainly its ion channel blockade on the plasma membrane rather than the inhibition of CaM kinase II activity in the cells.
  • K Minami, N Yanagihara, K Segawa, M Tsutsui, A Shigematsu, F Izumi
    NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY 353 (5) 572 - 578 0028-1298 1996/04 [Refereed][Not invited]
     
    In the central and peripheral noradrenergic neurons, the balance between noradrenaline release and reuptake determines the level of noradrenaline at the synaptic cleft or the nerve ending. In the present study, we examined the effects of propofol, an intravenous general anaesthetic, on catecholamine secretion and noradrenaline uptake in cultured bovine adrenal medullary cells and on the serum noradrenaline and blood pressure in rats. In cultured adrenal medullary cells, propofol (10-50 mu mol/l) concentration-dependently inhibited catecholamine secretion stimulated by carbachol. Propofol suppressed carbachol-evoked Na-22(+) influx as well as Ca-45(2+) influx at concentrations similar to those which suppressed the catecholamine secretion. Propofol (10-50 mu mol/l) also inhibited veratridine-evoked Na-22(+) influx, Ca-45(2+) influx and catecholamine secretion, whereas it had little effect on the Ca-45(2+) influx and catecholamine secretion induced by 56 mmol/l K+. Cultured adrenal medullary cells show [H-3] noradrenaline uptake which is sensitive to imipramine. Propofol (10-50 mu mol/l) significantly inhibited the imipramine-sensitive uptake of [H-3] noradrenaline. In rats, intravenous administration of propofol(2.5 mg/kg) lowered serum noradrenaline and arterial blood pressure. From these findings, in spite of inhibiting noradrenaline uptake, propofol at anaesthetic concentrations (10-30 mu mol/l) seems to reduce catecholamine secretion by interfering with Na+ influx through voltage-dependent Na+ channels as well as nicotinic acetylcholine receptor-associated ion channels in the adrenal medulla and, probably, in the sympathetic nervous system. This may explain the propofol-induced hypotension during anaesthesia.
  • Kayoko Segawa, Kouichiro Minami, Takeyoshi Sata, Alcio Kuroiwa, Akio Shigematsu
    Nephron 74 (3) 577 - 579 2235-3186 1996 [Refereed][Not invited]
     
    We investigated the effects of adrenomedullin on rat mesangial cell proliferation. Adrenomedullin (10-10-10-7M) inhibited both [3H]thymidine incorporation into cultured rat mesangial cells and cell proliferation in a concentration-dependent manner. Adrenomedullin (10 -10 −10-6 M) stimulated cyclic adenosine monophosphate accumulation in rat mesangial cells in a concentration-dependent manner. These findings suggest that adrenomedullin inhibits proliferation of rat mesangial cells probably through a cyclic adenosine monophosphate-dependent mechanism. © 1996 S. Karger AG, Basel.
  • H ISHIMURA, K MINAMI, T SATA, A SHIGEMATSU, T KADOYA
    ANESTHESIOLOGY 83 (4) 867 - 869 0003-3022 1995/10 [Refereed][Not invited]
     
    THE laryngeal mask airway (LMA) has been used widely for airway management during general anesthesia in the last decade.(1) There have been reports in which the LMA successfully secured the airway as an alternative and as an aid to anticipated difficult tracheal intubation in patients with ankylosing spondylosis of the cervical spine or atlantooccipital joint due to severe rheumatoid arthritis.(2-4) However, Pennant and White suggested that the use of the LMA is contraindicated in patients who are unable to extend the neck because of ankylosing spondylitis, severe rheumatoid arthritis, or cervical spine instability.(1) This controversy remains unresolved. In this report, we describe anesthesia for a patient with advanced rheumatoid arthritis in whom LMA insertion was impossible. The reason was thought to be the acute angle between the oral and the pharyngeal axes at the back of the tongue. The investigated the correlation between the angle and difficulty of LMA insertion in an attempt to resolve the controversy.
  • R YOSHIMURA, N YANAGIHARA, T TERAO, K MINAMI, K ABE, F IZUMI
    NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY 352 (3) 297 - 303 0028-1298 1995/09 [Refereed][Not invited]
     
    The effects of carbamazepine (CBZ) on Na-22(+) influx, Ca-45(2+) influx, catecholamine secretion and cyclic GMP production were examined in cultured bovine adrenal medullary cells. 1) CBZ (40-120 mu mol/l) inhibited Na-22(+) influx evoked by carbachol in a concentration-dependent manner. CBZ inhibited carbachol-evoked Ca-45(2+) influx and catecholamine secretion at concentrations similar to those which suppressed Na-22(+) influx. 2) CBZ (4-120 mu mol/l) inhibited veratridine-induced Na-22(+) influx, Ca-45(2+) influx and catecholamine secretion. 3) CBZ (12 or 40-120 mu mol/l) suppressed 56 mmol/l K+-evoked Ca-45(2+) influx and catecholamine secretion, respectively. 4) Combination of CBZ with nitrendipine or omega-agatoxin-IVA produced further inhibition of 56 mmol/l K+- evoked Ca-45(2+) influx and catecholamine secretion, compared to the effect of CBZ alone, whereas CBZ-plus omega-conotoxin-GVIA did not produce any further inhibition. 5) CBZ (40 mu mol/l) attenuated the production of cyclic CMP caused by muscarine. These results suggest that CBZ at therapeutic concentrations (16-48 mu mol/l: 4-12 mu g/ml) inhibits catecholamine secretion by interfering with nicotinic acetylcholine receptor-associated ion channels, voltage-dependent Na+ channels and N-type voltage-dependent Ca2+ channels, and may have an antimuscarinic effect in adrenal medullary cells.
  • Kouichiro Minami, Takeyoshi Sata, Takao Takeda, Kenichiro Sagata, Koji Hara, Akio Shigematsu
    Journal of anesthesia 9 (3) 283 - 284 1995/09 [Refereed][Not invited]
  • K Minami, T Sata, A Shigematsu
    MUSCLE RELAXANTS 403 - 403 1995 [Refereed][Not invited]
  • K MINAMI, N YANAGIHARA, T SATA, F IZUMI, A SHIGEMATSU
    PROGRESS IN ANESTHETIC MECHANISM, VOL 3, SPECIAL ISSUE, 1995 336 - 341 1995 [Refereed][Not invited]
  • HARA Koji, MINAMI Kouichiro, SATA Takeyoshi, SHIGEMASTU Akio
    THE JOURNAL OF JAPAN SOCIETY FOR CLINICAL ANESTHESIA 日本臨床麻酔学会 15 (7) 580 - 582 0285-4945 1995 [Not refereed][Not invited]
     
    Hurler's syndrome is a rare group of progressive familial diseases of mucopolysaccha-ridoses metabolism caused by a defect of a-L-Iduronidase. Patients with this syndrome have full lips, macroglossia, short neck and thracolumbar kyphosis. The problems of anesthesia for a patient with this syndrome are as follows: (1) difficulty in airway managemaent, (2) difficulty in intubation of tracheal tube and (3) postoperative respiratory dysfunction.
    We conducted anesthesia for a 2-year-old female with this syndrome. We slowly induced anesthesia with sevoflurane using a mask. The anesthesia was maintained by 40% nitrous oxide and 1∼2% sevoflurane in oxygen. Her intra-and post-operative courses were uneventful. Careful management of the airway is essential in patients with Hurler's syn-drome.
  • Kouichiro Minami, Takeyoshi Sata, Hiroshi Ishimura, Yuko Tomotari, Akio Shigematsu
    Journal of anesthesia 8 (4) 482 - 483 1994/12 [Refereed][Not invited]
  • Kouichiro Minami, Takeyoshi Sata, Akio Shigematsu
    Journal of anesthesia 8 (2) 224 - 226 1994/06 [Refereed][Not invited]
  • K MINAMI, N YANAGIHARA, Y TOYOHIRA, M TSUTSUI, A SHIGEMATSU, A WADA, F IZUMI
    NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY 349 (3) 223 - 229 0028-1298 1994/03 [Refereed][Not invited]
     
    The effects of isoflurane on Na-22(+) influx, Ca-45(2+) influx, catecholamine secretion and cyclic GMP production induced by three kinds of secretagogue (nicotinic agonists, veratridine and a high concentration of K+) have been investigated using cultured bovine adrenal medullary cells. (1) Isoflurane (1-6%) inhibited catecholamine secretion stimulated by carbachol, nicotine and dimethyl-4-phenylpiperazinium in a concentration-dependent manner. Isoflurane suppressed carbachol-evoked Na-22(+) influx and Ca-45(2+) influx at concentrations similar to those which suppressed catecholamine secretion. The inhibition of catecholamine secretion by isoflurane was not overcome by increasing the concentration of carbachol. (2) The inhibitory effects of isoflurane on veratridine-induced Na-22(+) influx, Ca-45(2+) influx and catecholamine secretion became evident when the concentration of isoflurane was raised to 4-6%, i.e. 2-3 fold higher than the concentrations (1-2%) employed clinically. (3) High K+-evoked Ca-45(2+) influx and catecholamine secretion were not affected by isoflurane (1-6%). (4) Isoflurane (1-6%) attenuated the production of cyclic GMP caused by muscarine, but not that caused by atrial natriuretic peptide or by sodium nitroprusside. These results suggest that isoflurane, at clinical anesthetic concentrations, inhibits nicotinic acetylcholine receptor-mediated cell responses as well as muscarinic receptor-mediated cyclic GMP production in adrenal medullary cells.
  • N Yanagihara, K Minami, F Shirakawa, Y Uezono, H Kobayashi, S Eto, F Izumi
    Biochemical and biophysical research communications 198 (1) 81 - 7 0006-291X 1994/01 [Refereed][Not invited]
     
    We investigated the effect of recombinant human interleukin-1 beta (IL-1 beta) on catecholamine secretion from cultured bovine adrenal medullary cells. Treatment of cultured cells with IL-1 beta (10 ng/ml) for 24 hr caused an increase in accumulation of catecholamines in the cultured medium. The accumulation of catecholamines stimulated by IL-1 beta was observed in time (4-48 hr)- and concentration (3-30 ng/ml)-dependent manners. The stimulatory effect of IL-1 beta (10 ng/ml) was completely inhibited by recombinant human IL-1 receptor antagonist (1 microgram/ml). IL-1 beta had little effect on [3H]norepinephrine uptake to cultured cells. These results suggest that IL-1 beta stimulates catecholamine secretion through activation of IL-1 receptors in adrenal medullary cells.
  • M. Tsutsui, N. Yanagihara, K. Minami, H. Kobayashi, Y. Nakashima, A. Kuroiwa, F. Izumi
    Journal of Pharmacology and Experimental Therapeutics 268 (2) 584 - 589 0022-3565 1994 [Refereed][Not invited]
     
    We examined the effects of C-type natriuretic peptide (CNP) on cyclic GMP production and catecholamine synthesis in cultured bovine adrenal medullary cells. 1) CNP increased intracellular cyclic GMP content in a concentration- dependent manner (10-1000 nM). 2) The cyclic GMP production induced by 1 μM CNP reached a 200-fold increase, and the effect of CNP was most potent among the natriuretic peptide family. 3) The CNP-induced cyclic GMP production was attenuated by endothelin (1 μM) and angiotensin II (0.1-1 μM). 4) When the cells were cultured with hypertonic NaCl medium, the CNP-induced cyclic GMP production was potentiated in a time (1-4 days)- and concentration (25-100 mM)-dependent manner. 5) CNP stimulated the synthesis of 14C-labeled catecholamines from [14C]tyrosine but not from [14C]dopa. The stimulatory effect of CNP on the 14C-labeled catecholamine synthesis was observed at the concentrations of 100 to 1000 nM. 6) 8-Bromo cyclic GMP, a membrane- permeable cyclic GMP analog, and sodium nitroprusside, an activator of soluble guanylate cyclase, also stimulated the synthesis of 14C-labeled catecholamines from [14C]tyrosine, whereas C-ANP, a specific ligand for the ANP-C (clearance) receptor that does not increase cyclic GMP content, failed to stimulate the synthesis of 14C-labeled catecholamines. 7) CNP (1 μM) as well as 8-bromo cyclic GMP and sodium nitroprusside increased the activity of tyrosine hydroxylase in the cells. These results suggest that in the adrenal medulla, CNP is a potent agonist for cyclic GMP production, which is modulated by endothelin, angiotensin II and the hypertonic NaCl condition. CNP may stimulate the catecholamine synthesis through the cyclic GMP- dependent activation of tyrosine hydroxylase in the adrenal medulla.
  • H KOBAYASHI, T MIZUKI, M TSUTSUI, K MINAMI, N YANAGIHARA, T YUHI, F IZUMI
    BRAIN RESEARCH 617 (1) 163 - 166 0006-8993 1993/07 [Refereed][Not invited]
     
    To characterize sites of action of C-type natriuretic peptide (CNP) in the glial cells, the effect of CNP on cGMP accumulation and the binding of [I-125]CNP in rat astrocyte RCR-1 cells were studied. CNP stimulated cGMP accumulation in the cells from 10(-9)) M in a dose-dependent manner, but ANP (atrial natriuretic peptide) had a negligible effect on cGMP accumulation in the cells. [I-125]CNP was bound to the cells and its K(d) value was 2 orders of magnitude lower than that of the ED50 value for stimulation of cGMP accumulation in the cells. Not only CNP but also ANP displaced [I-125]CNP binding to the cells. These results suggest that RCR-1 cells have a B-receptor which contains a guanylate cyclase domain and is preferentially activated by CNP, and that they also have a C-receptor which does not contain a guanylate cyclase domain that reacts with both ANP and CNP.
  • 人工心肺下での気管腫瘍切除術の麻酔経験
    南 浩一郎
    麻酔 克誠堂出版(株) 41 (8) 1354 - 1354 0021-4892 1992/08 [Not refereed][Not invited]
  • 南 浩一郎, 熊谷 由紀絵, 佐多 竹良
    臨牀と研究 大道学館出版部 69 (6) 1833 - 1834 0021-4965 1992/06 [Not refereed][Not invited]
  • 南 浩一郎
    麻酔 克誠堂出版(株) 41 (1) 156 - 156 0021-4892 1992/01 [Not refereed][Not invited]
  • Minami Kouichiro, Sata Takeyoshi, Hirano Kiyoyuki, Matsumoto Takahiro, Sigematsu Akio, Hanagiri Takeshi, Sirakusa Takayuki
    THE JOURNAL OF JAPAN SOCIETY FOR CLINICAL ANESTHESIA 日本臨床麻酔学会 12 (4) 560 - 563 0285-4945 1992 [Not refereed][Not invited]
     
    A 44 year-old man with tracheal tumor was scheduled for tracheoplasty. He had severe dyspnea due to tracheal stenosis. Anesthesia was induced with fentanyl 100μg iv and isoflurane 1% in oxygen. Respiration and gas exchange were maintained by assist ventilation with a mask and by partial cardiopulmonary bypass. Because of the difficulty in ventilating the patient after an unexpected rupture of the bilateral pleurae and difficulty in increasing the cardiopulmonaly bypass flow, hypercarbia developed until an endtracheal tube was placed in the trachea distal to the tumor. To obtain enough cardiopulmonary bypass flow for gas exchange, the number and size of cannulas should be carefully selected.
  • アナフィラキシー様反応の既往を持つ患者の胆嚢摘出術の麻酔経験.
    瓜生佳代, 南浩一郎, 松本尚浩, 佐多竹良, 重松昭生
    臨床麻酔 16 (12) 1623  1992 [Refereed][Not invited]
  • ガソリン中毒の1例
    松本 尚浩, 佐野 治彦, 南 浩一郎
    ICUとCCU 医学図書出版(株) 15 (11) 1197 - 1200 0389-1194 1991/11 [Not refereed][Not invited]
     
    44歳男.自動車内で意識不明で発見された.衣服はガソリンで濡れており,車内はガソリン臭が強かったが燃えた跡はなかった.広範な皮膚びらんがあり近医にて全身熱傷と診断された.びらんは体表面積の約50%であった.来院時には代謝性アシドーシス,CPK値の異常高値を示した.集中治療にもかかわらず多臓器不全で受傷後9日目に死亡した.吸収されたガソリンは代謝されず,肺からの呼出が主な排泄経路である.しかも呼出時に血管内皮を傷害し,呼吸器合併症を生じる
  • エンドトキシンショックにおけるPAF拮抗剤の影響
    南 浩一郎
    日本臨床麻酔学会誌 日本臨床麻酔学会 11 (6) 198 - 198 0285-4945 1991/10 [Not refereed][Not invited]
  • 肝切除術中,急性肺水腫を起こした1症例
    南 浩一郎, 佐野 治彦, 松本 尚浩
    臨床麻酔 真興交易(株)医書出版部 15 (9) 1221 - 1222 0387-3668 1991/09 [Not refereed][Not invited]
  • 術中QT延長症候群によりVTを起こした1例
    佐野 治彦, 南 浩一郎, 松本 尚浩
    臨床麻酔 真興交易(株)医書出版部 15 (5) 667 - 668 0387-3668 1991/05 [Not refereed][Not invited]
  • 深部静脈血栓症の血栓除去術にOcclusion Balloon Catheterを使用した2症例
    佐野 治彦, 南 浩一郎, 松本 尚浩
    臨床麻酔 真興交易(株)医書出版部 15 (4) 519 - 520 0387-3668 1991/04 [Not refereed][Not invited]
  • 上大静脈症候群における左腕頭静脈-右心耳バイパス術の麻酔経験
    南 浩一郎, 佐野 治彦, 松本 尚浩
    臨床麻酔 真興交易(株)医書出版部 15 (3) 393 - 394 0387-3668 1991/03 [Not refereed][Not invited]
  • 硬膜外麻酔によって陰茎勃起症になった1症例
    南 浩一郎, 佐野 治彦, 松本 尚浩
    臨床麻酔 真興交易(株)医書出版部 15 (2) 239 - 239 0387-3668 1991/02 [Not refereed][Not invited]
  • 術中QT延長症候群によりVTを引き起こしたことが疑われる1例
    佐野治彦, 南浩一郎, 松本尚浩, 門屋辰男
    麻酔 40 (11) 1745 - 1746 1991 [Refereed][Not invited]
  • 先天性副腎皮質過形成児の開心術症例
    南 浩一郎, 首藤 治, 緒方 政則
    臨床麻酔 真興交易(株)医書出版部 14 (9) 1347 - 1348 0387-3668 1990/09 [Not refereed][Not invited]
  • 南 浩一郎
    麻酔 克誠堂出版(株) 39 (7) 934 - 934 0021-4892 1990/07 [Not refereed][Not invited]

Books etc

  • Active POT 指導マニュアル
    南浩一郎 (Single work)
    ぱーそん書房 2019/06
  • 坂本, 哲也, 畑中, 哲生, 南浩一郎 (Joint work)
    ぱーそん書房 2017 9784907095376 1381p
  • 南, 浩一郎 (Single work)
    ぱーそん書房 2015/12 9784907095284 冊
  • 南, 浩一郎 ()
    ぱーそん書房 2015/12 9784907095284 冊
  • 南, 浩一郎 ()
    ぱーそん書房 2015/12 9784907095284 冊
  • 高崎, 眞弓, 河本, 昌志, 木内, 恵子, 白神, 豪太郎, 萩平, 哲, 南浩一郎 (Joint work結節性多発動脈炎 p423)
    文光堂 2015 9784830628276 680p
  • 麻酔科診療プラクティス20. 臨床麻酔の疑問に答える生理学IV. 腎臓
    (Joint work低血圧は腎循環にどのような影響を及ぼすか p152-156)
    文光堂 2006
  • 麻酔薬と細胞内情報伝達機構 新しい麻酔の流れ
    (Joint workp37-40)
    先端医療技術研究所 2005
  • The inhibitory effects of propofol on ion channels-mediated catecholamine secretion in cultured bovine adrenal medullary cells in Progress in Anesthetic Mechanism
    ()
    Research Group of Anesthetic Mechanism in Japan 1995
  • An anesthesia for the patient who was suspected the Lumbert-Eaton Syndrome by an unexpected prolongation of vecuroniume Muscle Relaxants -physiological and Pharmacological Aspects-
    ()
    Springer 1995

MISC

  • 日常診療に必要な治療手技(No.7) 心肺蘇生法
    南 浩一郎  日本医師会雑誌  147-  (7)  1432  -1433  2018/10  [Not refereed][Not invited]
  • 南 浩一郎  産業衛生学雑誌  60-  (5)  115  -115  2018/09  [Not refereed][Not invited]
  • 南 浩一郎  産業保健と看護 = The Japanese journal of occupational health and occupational health nursing : 働く人々の健康を守る産業看護職とすべてのスタッフのために  10-  (4)  334  -337  2018/07  [Not refereed][Not invited]
  • 南 浩一郎  産業保健と看護 = The Japanese journal of occupational health and occupational health nursing : 働く人々の健康を守る産業看護職とすべてのスタッフのために  10-  (4)  338  -341  2018/07  [Not refereed][Not invited]
  • 南 浩一郎  産業保健と看護 = The Japanese journal of occupational health and occupational health nursing : 働く人々の健康を守る産業看護職とすべてのスタッフのために  10-  (4)  342  -345  2018/07  [Not refereed][Not invited]
  • 南 浩一郎  産業保健と看護 = The Japanese journal of occupational health and occupational health nursing : 働く人々の健康を守る産業看護職とすべてのスタッフのために  10-  (4)  346  -348  2018/07  [Not refereed][Not invited]
  • 小久保 陽太, 前田 一之助, 日比野 真吾, 南 浩一郎  SEIテクニカルレビュー  (190)  164  -169  2017/01  [Not refereed][Not invited]
  • 南 浩一郎  産業医学ジャーナル  39-  (5)  13  -18  2016/09  [Not refereed][Not invited]
  • 【地域・職域で知っておくべき救急対応-基礎から最新の知見まで-】救急蘇生法の最新知識から教育方法まで 心肺蘇生法国際ガイドライン日本版の最新改訂版(2015年版)を踏まえて
    南 浩一郎  健康管理  (743)  2  -16  2016/05  [Not refereed][Not invited]
  • 職域の救急 産業医・産業保健スタッフの果たす役割 職域における救急の問題点とその解決法
    南 浩一郎  産業衛生学雑誌  58-  (臨増)  183  -183  2016/05  [Not refereed][Not invited]
  • 圧力センサを用いた胸骨圧迫Real time auto feedback機器
    南 浩一郎, 小久保 陽太, 日比野 真吾  日本臨床救急医学会雑誌  19-  (2)  340  -340  2016/04  [Not refereed][Not invited]
  • 南 浩一郎  健康開発 = Health development  19-  (4)  77  -82  2015/05  [Not refereed][Not invited]
  • 南 浩一郎, 日比野 真吾, 小久保 陽太  蘇生: 日本蘇生学会雑誌  34-  (3)  214b  -214b  2015  [Not refereed][Not invited]
     
    PDFファイルをご覧ください。
  • 尾方 純一, 横山 徹, 南 浩一郎  日本臨床救急医学会雑誌  16-  (3)  438  -438  2013/06  [Not refereed][Not invited]
  • 南 浩一郎, 尾方 純一, 横山 徹, 河合 誠義  日本臨床救急医学会雑誌  16-  (3)  466  -466  2013/06  [Not refereed][Not invited]
  • 【理想の救急救命士教育とは】消防職員に対する養成課程教育を中心に
    南 浩一郎  プレホスピタル・ケア  26-  (2)  28  -32  2013/04  [Not refereed][Not invited]
  • An analgesic drug tramadol selectively modulates the activity of TRPA1 but not TRPV1
    Kanako Miyano, Kouichiro Minami, Toni Yokoyama, Katsuya Ohbuchi, Masahiro Yamamoto, Seiji Shiraishi, Motohiro Matoba, Yasuhito Uezono  JOURNAL OF PHARMACOLOGICAL SCIENCES  121-  233P  -233P  2013  [Refereed][Not invited]
  • モーションキャプチャーを用いたReal time auto feed back機能付胸骨圧迫コーチングシステムの開発
    南 浩一郎, 尾方 純一, 河合 誠義, 青木 健光, 伊藤 嘉春, 吉江 正樹  J-ReSS  5-  38  -38  2012/06  [Not refereed][Not invited]
  • 尾方 純一, 南 浩一郎, 横山 徹, 鈴川 正之  日本臨床救急医学会雑誌  15-  (2)  160  -160  2012/04  [Not refereed][Not invited]
  • 南 浩一郎, 河合 誠義, 西脇 重弘, 篠崎 周造  日本臨床救急医学会雑誌  15-  (2)  255  -255  2012/04  [Not refereed][Not invited]
  • 横山 徹, 尾方 純一, 南 浩一郎, 河合 誠義  日本臨床救急医学会雑誌  15-  (2)  258  -258  2012/04  [Not refereed][Not invited]
  • 南 浩一郎, 河合 誠義  日本臨床救急医学会雑誌  15-  (2)  259  -259  2012/04  [Not refereed][Not invited]
  • 南 浩一郎, 尾方 純一, 横山 徹, 河合 誠義  日本臨床救急医学会雑誌  15-  (2)  332  -332  2012/04  [Not refereed][Not invited]
  • 南 浩一郎, 尾方 純一, 横山 徹, 鈴川 正之  日本臨床救急医学会雑誌  15-  (2)  334  -334  2012/04  [Not refereed][Not invited]
  • 横山 徹, 尾方 純一, 南 浩一郎, 鈴川 正之  日本臨床救急医学会雑誌  15-  (2)  335  -335  2012/04  [Not refereed][Not invited]
  • がん悪液質モデルラットでは視索上核大細胞性ニューロンでの浸透圧感受性が変化している(Changes in the osmo-sensitivity in the synaptic inputs to the magnocellular neurons of cancer cachexia model rat)
    横山 徹, 寺脇 潔, 南 浩一郎, 柳原 五吉, 上田 陽一, 上園 保仁  日本癌学会総会記事  70回-  454  -454  2011/09  [Not refereed][Not invited]
  • 村上 敏史, 白石 成二, 須藤 結香, 南 浩一郎, 三浦 耕資, 的場 元弘, 上園 保仁  日本ペインクリニック学会誌  18-  (3)  330  -330  2011/06  [Not refereed][Not invited]
  • 南 浩一郎, 河合 誠義  日本臨床救急医学会雑誌  14-  (2)  250  -250  2011/04  [Not refereed][Not invited]
  • 三澤 誠, 鈴木 伸一, 南 浩一郎, 河合 誠義  日本臨床救急医学会雑誌  14-  (2)  256  -256  2011/04  [Not refereed][Not invited]
  • 横山 徹, 南 浩一郎, 尾方 純一, 河合 誠義  日本臨床救急医学会雑誌  14-  (2)  268  -268  2011/04  [Not refereed][Not invited]
  • 尾方 純一, 南 浩一郎, 横山 徹, 三澤 誠, 鈴川 正之  日本臨床救急医学会雑誌  14-  (2)  340  -340  2011/04  [Not refereed][Not invited]
  • 南 浩一郎, 三澤 誠, 高木 修二, 河合 誠義, 鈴川 正之  日本臨床救急医学会雑誌  13-  (5)  611  -618  2010/10  [Not refereed][Not invited]
     
    これまでに救急救命士が複数乗務した体制による救急活動が、院外心肺機能停止患者の転帰にどのように影響するかは検討されていない。今回、2008年の神奈川県相模原市における院外心肺機能停止症例(467例)を対象として、救急救命士2人体制が院外心肺機能停止患者の転帰にどのように影響するかを検討した。ウツタイン様式および救急隊活動報告書に基づき、症例を1人体制(130例)と2人体制(337例)の2群に分け、心拍再開率、1ヵ月生存率を比較検討した。心肺機能停止症例全体、心原性心肺機能停止症例、目撃あり・心原性心肺機能停止症例では心拍再開率、1ヵ月生存率は体制による差はなかった。しかし、目撃あり・心原性・除細動適応心肺機能停止症例(28例)の1ヵ月生存率では2人体制53.3%(15例中8例、うち機能良好4例)、1人体制7.7%(13例中1例、うち機能良好1例)と有意差が認められた。さらに詳細な分析では、バイスタンダーCPRの有無や平均特定行為処置数には体制別で差がなかった。また、目撃から除細動開始までの時間も2人体制10.5±6.9分、1人体制12.5±8.2分で有意差はなかった。以上の結果より、目撃あり・心原性・除細動適応心肺機能停止症例では、2人体制が1人体制より1ヵ月生存率が有意に高いことが明らかになった。その原因として、目撃から除細動までの所要時間が短いことが考えられたが、短い傾向があることは認められたものの有意差はなかったので、目撃から除細動までの所要時間だけでなくその他の原因も考えられた。2人体制が院外心肺機能停止患者の転帰を改善する可能性が示唆された。(著者抄録)
  • 白石 成二, 南 浩一郎, 上園 保仁  日本ペインクリニック学会誌  17-  (3)  434  -434  2010/06  [Not refereed][Not invited]
  • 救急救命士教育前後の除細動の所要時間の比較検討
    南 浩一郎, 河合 誠義  日本臨床救急医学会雑誌  13-  (2)  242  -242  2010/04  [Not refereed][Not invited]
  • 複数名救命士体制での特定行為所要時間の短縮効果
    南 浩一郎, 河合 誠義  日本臨床救急医学会雑誌  13-  (2)  242  -242  2010/04  [Not refereed][Not invited]
  • 三澤 誠, 高木 修二, 南 浩一郎, 河合 誠義  日本臨床救急医学会雑誌  13-  (2)  244  -244  2010/04  [Not refereed][Not invited]
  • 尾方 純一, 宇高 毅, 因幡 剛, 門川 洋平, 南 浩一郎  麻酔  59-  (1)  109  -113  2010/01  [Not refereed][Not invited]
     
    睡眠時無呼吸症候群(SAS)が強く疑われた扁桃周囲炎患者に対して、マット型の無拘束睡眠時無呼吸検査器機、スリープレコーダーSD-101による睡眠時無呼吸検査を試みたところ、重度のSASと診断された。終夜ポリソムノグラフィー(PSG)による詳細な検査でも、やはり重度のSASと診断された。スリープレコーダーSD-101による検査は簡便であり、詳細な検査を受ける前のスクリーニングとしてより多くの対象者に用いることが可能である。(著者抄録)
  • 救急救命士2名乗車体制が心拍再開率、1ヵ月生存率に与える影響
    南 浩一郎, 河合 誠義, 鈴川 正之  日本救急医学会雑誌  20-  (8)  540  -540  2009/08  [Not refereed][Not invited]
  • 尾方 純一, 田村 公二, 宮西 圭太, 南 浩一郎, 原西 保典, 椿 隆行  麻酔  57-  (4)  439  -442  2008/04  [Not refereed][Not invited]
     
    75歳女。左大腿骨転子部骨折をきたし、左人工股関節全置換術を行った。42歳時にアルカプトン尿症と診断された。軽度の弁膜症と脊椎病変を考慮し、少量ブピバカインによる脊髄くも膜下麻酔を行った。腰椎椎間は著明な狭小化と石灰化のため穿刺が困難で、硬膜外カテーテル留置前に脊髄くも膜下麻酔を行った。カテーテルは時間経過とともに偶発的にくも膜下腔に迷入した。脊髄くも膜下麻酔は安全に行うことができた。
  • 寺田 忠徳, 南 浩一郎, 白石 宗大  麻酔  55-  (12)  1484  -1486  2006/12  [Not refereed][Not invited]
     
    症例は33歳の女性で、30歳時から結節性多発性動脈炎にてステロイドとシクロホスファミドを内服しており、ミノマイシン、ペニシリンやリドカインなどに対する薬剤アレルギーや食物アレルギーを合併しており、反復する扁桃炎に対する手術のために吸入麻酔をセボフルランと亜酸化窒素、フェンタニルによって行い、安全に手術が可能であったので、その概略を報告した。
  • 副甲状腺摘出術における麻酔中の合併症 透析患者と非透析患者の比較
    瀬川 賀世子, 南 浩一郎, 佐多 竹良  日本透析医学会雑誌  39-  (Suppl.1)  738  -738  2006/05  [Not refereed][Not invited]
  • 原 幸治, 古賀 和徳, 川崎 貴士, 南 浩一郎, 緒方 政則, 佐多 竹良  日本ペインクリニック学会誌  12-  (4)  420  -420  2005/10  [Not refereed][Not invited]
  • 星状神経節の神経鞘腫切除後に咽頭痛と偏頭痛を起こした症例
    南 浩一郎, 古賀 和徳, 原 幸治, 川崎 貴士, 佐多 竹良  日本ペインクリニック学会誌  12-  (3)  243  -243  2005/06  [Not refereed][Not invited]
  • 在宅看護を受けている患者の慢性疼痛に関する実態調査
    南 浩一郎, 古賀 和徳, 川崎 貴士, 佐多 竹良  日本ペインクリニック学会誌  12-  (3)  251  -251  2005/06  [Not refereed][Not invited]
  • 難治性下肢痛に対して総腓骨神経への高周波熱凝固療法が有効であったCRPSの1例
    古賀 和徳, 南 浩一郎, 堀下 貴文, 佐多 竹良  日本ペインクリニック学会誌  12-  (3)  277  -277  2005/06  [Not refereed][Not invited]
  • トラマドール,トラマドールの代謝産物M1のμオピオイド受容体に対する作用
    南 浩一郎, 堀下 貴文, 白石 宗大, 佐多 竹良, 重松 昭生  日本ペインクリニック学会誌  12-  (3)  279  -279  2005/06  [Not refereed][Not invited]
  • 南 浩一郎, 堀下 貴文, 白石 宗大, 寺田 忠徳, 尾方 純一, 工藤 香児, 井上 仁郎  産業医科大学雑誌  27-  (1)  122  -122  2005/03  [Not refereed][Not invited]
  • 南 浩一郎, 尾方 純一, 堀下 貴文  麻酔  54-  (3)  320  -326  2005/03  [Not refereed][Not invited]
     
    2003年度に手術室で行われた麻酔科管理2758例において発生した合併症を,麻酔方法別に検討した.合併症発生率は,症例全体の12.2%(337例)で,高齢となるに従って増える傾向を示した.また,ASAリスク分類が上がるに従って合併症の頻度も高くなった.麻酔方法別では,吸入麻酔薬で行った全身麻酔症例13.4%,吸入麻酔薬と硬膜外麻酔併用症例11.9%,脊髄くも膜下硬膜外併用麻酔症例8.9%,脊髄くも膜下麻酔症例7.5%になんらかの合併症が生じた.硬膜外麻酔症例には合併症の発生はなかった.合併症の種類は循環器系合併症がもっとも多く,呼吸器系,気道系合併症の順で,それぞれ症例全体の5.5%,1.4%,0.5%を占めた.全身麻酔に伴う合併症発生率は局所麻酔併用の場合とほほ同程度であることが明らかになった
  • 南 浩一郎, 上園 保仁  麻酔  54-  (2)  118  -125  2005/02  [Not refereed][Not invited]
  • 尾方 純一, 南 浩一郎, 中村 元洋  麻酔  53-  (11)  1286  -1289  2004/11  [Not refereed][Not invited]
     
    71歳男.結核の既往があり,5年前に結核に対する胸郭形成術後の慢性進行性血腫と診断された.その後も血腫は増大を続け,発熱を契機に慢性膿胸による発熱と胸椎圧迫による下肢不全麻痺と診断され,根治的手術が施行された.肝硬変と軽度の凝固機能異常を認め,術中に大量出血を生じたが,mean CVPとABPの持続的モニタリングによって迅速な循環動態の把握と対応が可能であった
  • 尾方 純一, 堀下 貴文, 南 浩一郎  麻酔  53-  (11)  1282  -1285  2004/11  [Not refereed][Not invited]
     
    9歳7ヵ月男児.脳性麻痺による重度精神発達遅滞があり,誤嚥性肺炎などによる呼吸不全を繰り返したために6歳9ヵ月時に気管切開を施行し,気管チューブを留置して在宅加療をしていた.しかし,吸気時に喘鳴が出現し次第に増悪したことから,気管内視鏡検査にて気管切開チューブが原因で生じたと考えられる肉芽による膜性狭窄を認めた.この症例に対してホルミニウムYAGレーザーを用いた肉げ焼灼術の麻酔管理を経験した.サイズ2.5のラリンジアルマスクエアウェイを経口挿入し,気管支内視鏡により気道を評価しながら麻酔を行ったところ,良好な結果を得た
  • 中村 元洋, 南 浩一郎, 原 幸治  麻酔  53-  (9)  1025  -1028  2004/09  [Not refereed][Not invited]
     
    33歳女.4ヵ月前より月経困難,月経過多が出現し,多剤に対するアレルギーのため保存的治療が難しく,腹式子宮全摘を行った.今までにアレルギーが認められた薬物は,メロキシカム,エペリゾン塩酸塩,消毒用アルコール,ジクロフェナクナトリウム,ベラプロストナトリウム,アスピリン,ペニシリン系抗生物質,ロキシスロマイシン,ヒドロキシジン塩酸塩,リドカインであった.局所麻酔薬でアナフィラキシーショックを起こした既往があることから,局所麻酔薬は避けた方が良いと判断し,セボフルラン-酸素-亜酸化窒素のみで導入した.術中の筋弛緩はベクロニウムを使用し,麻酔維持と術後鎮痛を考慮してフェンタニルを使用した.キウイフルーツでアレルギーが認められた既往もあり,ラテックスに対するアレルギーの既往はなかったが,ラテックスフリーの製品を使用した.術中,術後ともアレルギーの発生はなかった
  • 原 幸治, 南 浩一郎, 佐多 竹良  日本ペインクリニック学会誌  11-  (3)  308  -308  2004/06  [Not refereed][Not invited]
  • 南 浩一郎, 中村 元洋, 堀下 貴文, 尾方 純一, 白石 宗大, 佐多 竹良  日本ペインクリニック学会誌  11-  (3)  308  -308  2004/06  [Not refereed][Not invited]
  • 南 浩一郎, 尾方 純一, 堀下 貴文, 白石 宗大, 岡本 隆史, 佐多 竹良  日本ペインクリニック学会誌  11-  (3)  343  -343  2004/06  [Not refereed][Not invited]
  • Kahoru Nishina, Katsuya Mikawa, Yoji Yonemoto, Yasushi Sugimoto, Junichi Ogata, Toru Yokoyama, Takashi Okamoto, Kouichiro Minami  Anesthesia and Analgesia  98-  (3)  876  -878  2004/03  [Refereed][Not invited]
  • J Ogata, T Yokoyama, T Okamoto, K Minami  ANESTHESIA AND ANALGESIA  98-  (3)  877  -878  2004/03  [Refereed][Not invited]
  • 原 幸治, 南 浩一郎, 重松 昭生  日本ペインクリニック学会誌  10-  (3)  404  -404  2003/06  [Not refereed][Not invited]
  • 正常ラット腎臓におけるドーパミンレセプターサブタイプの分布
    瀬川 賀世子, 山本 千恵子, 南 浩一郎, 金 成泰, 高杉 昌幸  日本腎臓学会誌  45-  (3)  262  -262  2003/04  [Not refereed][Not invited]
  • 11βヒドロキシラーゼ欠損症患者の麻酔経験
    岡本 隆史, 南 浩一郎, 重松 昭生  麻酔  52-  (4)  449  -449  2003/04  [Not refereed][Not invited]
  • 南 浩一郎  産業医科大学雑誌  25-  (1)  132  -132  2003/03  [Not refereed][Not invited]
  • 食道挿管の診断が困難であったダブルルーメン気管挿管症例
    尾方 純一, 横山 徹, 山本 智徳, 南 浩一郎, 佐多 竹良  麻酔  52-  (3)  328  -328  2003/03  [Not refereed][Not invited]
  • 静脈麻酔薬のノルアドレナリントランスポーターへの作用
    南 浩一郎, 堀下 貴文, 原 幸治, 重松 昭生, 柳原 延章  日本薬理学雑誌  121-  (3)  75P  -75P  2003/03  [Not refereed][Not invited]
  • 南 浩一郎  Journal of UOEH  25-  (1)  132  -132  2003/03  [Not refereed][Not invited]
  • 南 浩一郎, 上原 浩文, 豊平 由美子, 重松 昭生  産業医科大学雑誌  25-  (1)  143  -143  2003/03  [Not refereed][Not invited]
  • 岡本 隆史, 南 浩一郎, 尾方 純一, 白石 宗大, 重松 昭生, 上田 陽一, 上園 保二  産業医科大学雑誌  25-  (1)  144  -144  2003/03  [Not refereed][Not invited]
  • ステロイド系麻酔薬アルファキサロン及びモルヒネ誘導体トラマドールの鎮痛作用機序解明 キメラG蛋白受容体,培養副腎髄質細胞を用いた解析方法による鎮痛剤の開発
    南 浩一郎  上原記念生命科学財団研究報告集  16-  438  -441  2002/11  [Not refereed][Not invited]
     
    副腎髄質細胞とアフリカツメガエル卵母細胞系を用いてアルファキサロンやトラマドールのカテコールアミン分泌に対する作用を調べるために,副腎髄質細胞をカルバコール,ベラトリジン,高濃度K+溶液で刺激し,カテコールアミン分泌にどのような作用を持つか検討したところ,ニコチン性受容体に作用することがわかった.さらにこれらの薬剤がカテコールアミン分泌に関与するニコチン性アセチルコリン受容体イオンチャンネルにどのうように作用するかをpatch clump法を用いて確認した.これらの薬剤はニコチン性アセチルコリン受容体イオンチャンネルに対して抑制的に作用した.これらの薬剤はNETに対しても抑制的に作用し,NE作動性神経を活性化することがその鎮痛作用の機序の1つであると考えられた
  • 難治性疼痛患者に対するクモ膜下腔ステロイド療法の効果
    古賀 和徳, 南 浩一郎, 池崎 晃, 寺田 忠徳, 重松 昭生  日本臨床麻酔学会誌  22-  (8)  S206  -S206  2002/09  [Not refereed][Not invited]
  • アフリカツメガエル卵母細胞発現系におけるキメラG蛋白を用いたG蛋白結合受容体の薬理学的解析方法
    南 浩一郎  臨床薬理の進歩  (23)  82  -86  2002/07  [Not refereed][Not invited]
     
    Gi蛋白結合受容体RNAとGiとGqとのキメラG蛋白RNAを同時にアフリカツメガエル卵母細胞に注入発現させて,Gq蛋白結合受容体と同じようにPLCを介した細胞内Ca2+の変動を利用した解析が可能かどうかを確かめてGi蛋白結合受容体の薬理学的解析方法を確立し.更にこの解析法を用いてGi蛋白結合受容体ムスカリン受容体M2とGi/GqとのキメラG蛋白RNAを同時に注入して発現させた場合とGq蛋白結合受容体ムスカリン受容体M1だけの場合を比較して,アセチルコリンに対する感受性等の薬理学的解析を行った.Gi蛋白結合受容体ムスカリン受容体M2とGi/GqとのキメラG蛋白RNAを同時にアフリカツメガエル卵母細胞に発現させ,Gq蛋白結合受容体と同様に電気生理学的に解析することができ,キメラG蛋白RNAを使用した場合も細胞内のPLCを介した細胞内Ca2+の変動が十分に得られると考えられた
  • 古賀 和徳, 野口 貴志, 川崎 貴士, 南 浩一郎, 佐多 竹良, 緒方 政則  日本ペインクリニック学会誌  9-  (3)  252  -252  2002/06  [Not refereed][Not invited]
  • ドーパミン長期投与によるドーパミン受容体サブタイプ3の組織学的変化
    瀬川 賀世子, 南 浩一郎, 山本 千恵子, 金 成泰, 高杉 昌幸  日本腎臓学会誌  44-  (3)  308  -308  2002/04  [Not refereed][Not invited]
  • 南 牧子, 日野 義之, 南 浩一郎, 櫻井 剛  産業衛生学雑誌  44-  (0)  574  -574  2002  [Not refereed][Not invited]
  • 南 浩一郎, 南 牧子, 堀下 貴文, 相方 謙一郎, 瀬戸 篤, 新島 邦行, 重松 昭生  産業衛生学雑誌  44-  (0)  617  -617  2002  [Not refereed][Not invited]
  • 上野 晋, 南 浩一郎, 柳原 延章  蛋白質核酸酵素  46-  (14)  2042  -2051  2001/11  [Not refereed][Not invited]
     
    GABAA受容体は中枢神経系における主要な抑制性の神経伝達物質受容体である.受容体蛋白質の構成アミノ酸に対し変異を導入する方法を用いて,これまでGABAA受容体の構造や,機能を修飾する薬物の作用部位などがアミノ酸レベルで解明されてきた.最近ではGABAA受容体におけるアルコールの結合部位が同定されたり,またGABAA受容体の遺伝子改変マウス(とくにノックインマウス)が確立されるなど,GABAA受容体の構造と機能について,蛋白質分子のレベルから生体行動に至るまでさらなる研究が進められている
  • カプノグラフ吸引チューブの微少リークの呼気終末時二酸化炭素濃度に与える影響
    横山 徹, 南 浩一郎, 堀下 貴文, 白石 宗大, 重松 昭生  日本臨床麻酔学会誌  21-  (8)  S283  -S283  2001/09  [Not refereed][Not invited]
  • 塩酸コルホルシンはドーパミン長期投与による尿量減少を改善する
    瀬川 賀世子, 南 浩一郎, 白石 宗大, 重松 昭生  日本腎臓学会誌  43-  (3)  289  -289  2001/04  [Not refereed][Not invited]
  • 南 浩一郎, 白石 宗大, 重松 昭生  産業医科大学雑誌  23-  (1)  99  -99  2001/03  [Not refereed][Not invited]
  • K Sagata, K Minami, K Hara, N Yanagihara, A Shigematsu  ANESTHESIOLOGY  93-  (3A)  U202  -U202  2000/09  [Not refereed][Not invited]
  • 塩酸コルホルシンの腎血流とメサンギウム細胞増殖に及ぼす影響
    瀬川 賀世子, 南 浩一郎, 穴井 博史, 岩本 昌子, 須田 健, 鐘江 香, 太田 孝行, 筬島 明彦, 田中 弘, 中島 康秀  日本腎臓学会誌  42-  (3)  239  -239  2000/04  [Not refereed][Not invited]
  • 瀬川 賀世子, 南 浩一郎, 志賀 洋介, 穴井 博史, 筬島 明彦, 田中 弘, 須田 健, 太田 孝行, 芹野 良太, 佐多 竹良, 重松 昭生, 中島 康秀  産業医科大学雑誌  22-  (1)  75  -75  2000/03  [Not refereed][Not invited]
  • 藤井 健, 南 浩一郎, 佐多 竹良, 重松 昭生  麻酔  49-  (2)  207  -207  2000/02  [Not refereed][Not invited]
  • 当院における挿管後の咽頭痛の発生頻度とその対策
    尾崎 将之, 南 浩一郎, 落合 秀夫, 岩野 歩, 佐多 竹良  麻酔  48-  (11)  1269  -1269  1999/11  [Not refereed][Not invited]
  • Y Shiga, K Minami, K Segawa, K Uryuu, A Shigematsu  ANESTHESIOLOGY  91-  (3A)  U237  -U237  1999/09  [Not refereed][Not invited]
  • K Hara, N Yanagihara, K Minami, F Izumi, A Shigematsu  ANESTHESIOLOGY  91-  (3A)  U211  -U211  1999/09  [Not refereed][Not invited]
  • K Uryu, K Minami, K Hara, Y Shiga, A Shigematsu  ANESTHESIOLOGY  91-  (3A)  U429  -U429  1999/09  [Not refereed][Not invited]
  • 麻酔導入中の気道確保が困難であったArnold-Chiari syndrome(II型)患者の麻酔経験
    西村 昌泰, 南 浩一郎, 米加田 啓介, 高杉 直哉, 佐多 竹良, 重松 昭生  日本臨床麻酔学会誌  19-  (8)  S210  -S210  1999/09  [Not refereed][Not invited]
  • 突然の完全房室ブロックをイソプロテレノール投与により救命しえた麻酔症例
    野口 貴志, 志賀 洋介, 南 浩一郎, 佐多 竹良, 重松 昭生  日本臨床麻酔学会誌  19-  (8)  S261  -S261  1999/09  [Not refereed][Not invited]
  • 歯牙充填物(レジン)が脱落し,発見に難渋した症例
    尾方 純一, 南 浩一郎, 川崎 貴士, 瓜生 佳代, 廣瀬 真帆, 米加田 啓介, 佐多 竹良  日本臨床麻酔学会誌  19-  (8)  S183  -S183  1999/09  [Not refereed][Not invited]
  • 先天性全身性関節拘縮症の麻酔経験
    米加田 啓介, 南 浩一郎, 西村 昌泰, 佐多 竹良, 重松 昭生  日本臨床麻酔学会誌  19-  (8)  S351  -S351  1999/09  [Not refereed][Not invited]
  • ラリンゲルマスクが顎下腺の形状に与える影響
    尾方 純一, 南 浩一郎, 川崎 貴士, 瓜生 佳代, 廣瀬 真帆, 佐多 竹良  日本臨床麻酔学会誌  19-  (8)  S349  -S349  1999/09  [Not refereed][Not invited]
  • Nicorandilのラットメサンギウム細胞増殖抑制作用
    瀬川 賀世子, 南 浩一郎, 穴井 博史, 筬島 明彦, 田中 弘, 須田 健, 太田 孝行, 芹野 良太, 佐多 竹良, 重松 昭生  日本腎臓学会誌  41-  (3)  354  -354  1999/05  [Not refereed][Not invited]
  • Crouzon病の麻酔管理
    瓜生 佳代, 南 浩一郎, 佐多 竹良, 重松 昭生  小児の脳神経  24-  (2)  240  -240  1999/04  [Not refereed][Not invited]
  • 南 浩一郎, 瓜生 佳代, 落合 秀夫, 佐多 竹良, 重松 昭生  産業医科大学雑誌  21-  (1)  82  -82  1999/03  [Not refereed][Not invited]
  • Noguchi T.  SANGYO EISEIGAKU ZASSHI  41-  (0)  191  -191  1999  [Not refereed][Not invited]
  • K Minami, MJ Wick, RA Harris  ANESTHESIOLOGY  89-  (3A)  U185  -U185  1998/09  [Not refereed][Not invited]
  • 筋弛緩薬の効果が遅延した慢性炎症性脱髄性多発根神経炎(Chronic Inframmatory Demyelinating polyradiculoneuropathy)(CIDP)の麻酔経験
    高本 勝博, 南 浩一郎, 佐多 竹良, 重松 昭生  日本臨床麻酔学会誌  18-  (8)  S238  -S238  1998/09  [Not refereed][Not invited]
  • 経鼻挿管時におけるカフ付口咽頭チューブ(COPA)の有用性の検討
    南 浩一郎, 植田 淳司, 佐多 竹良, 重松 昭生  日本臨床麻酔学会誌  18-  (8)  S206  -S206  1998/09  [Not refereed][Not invited]
  • プロタミンのラット血圧及び血中カテコールアミンレベルに及ぼす影響
    南 浩一郎  日本薬理学雑誌  105-  (2)  97P  -97P  1995/02  [Not refereed][Not invited]
  • 培養ウシ副腎髄質細胞に対する静脈麻酔薬プロポフォールの影響
    南 浩一郎  日本薬理学雑誌  103-  (2)  100P  -100P  1994/02  [Not refereed][Not invited]
  • 南 浩一郎  麻酔  42-  (10 Suppl.)  409  -409  1993/10  [Not refereed][Not invited]
  • プロポフォールのウシ培養副腎髄質細胞からのカテコールアミン分泌に及ぼす影響
    南 浩一郎  日本臨床麻酔学会誌  13-  (5)  452  -452  1993/10  [Not refereed][Not invited]
  • 南 浩一郎  日本薬理学雑誌  101-  (2)  40  -40  1993/02  [Not refereed][Not invited]
  • 培養副腎髄質細胞からのカテコールアミン分泌に及ぼすイソフルランの影響について
    南 浩一郎  日本臨床麻酔学会誌  12-  (6)  187  -187  1992/10  [Not refereed][Not invited]
  • Marinesco-Sjogren症候群の麻酔経験
    南 浩一郎  日本臨床麻酔学会誌  12-  (6)  153  -153  1992/10  [Not refereed][Not invited]
  • 南 浩一郎  麻酔  40-  (9号外)  S633  -S633  1991/09  [Not refereed][Not invited]

Industrial Property Rights

  • 特許6746347:心肺蘇生術補助装置  
    小久保陽太, 日比野真吾, 佐藤一徳, 南浩一郎  住友理工株式会社
  • 特許674330:心肺蘇生術補助装置  
    前田一之助, 伊藤弘昭, 小久保陽太, 日比野真吾, 山田博, 南浩一郎  住友理工株式会社
  • 特開2019-211550:胸骨圧迫訓練モデル  2019/12/12
    菅原暢高, 高橋太, 佐藤泰之, 南浩一郎  株式会社高研
  • 特開2018-146428:圧力センサー  2018/09/20
    小久保陽太, 佐藤一徳, 日比野真吾, 南浩一郎  住友理工株式会社
  • 特開2013-252180:生体電極及び生体電極ロール  2013/12/19
    西脇重弘, 南浩一郎  日本光電工業株式会社
  • 特開2013-153847:心臓マッサージ支援装置および心臓マッサージ支援用コンピュータプログラム  2013/08/15
    南浩一郎, 伊藤嘉春, 青木健光  キッセイコムテック株式会社
  • 特開2007-61203:体温センサ付き検出端を用いた睡眠中呼吸音の解析による睡眠時無呼吸症候群の検出・評価システム  2007/03/15
    南浩一郎, 堀江正信  財団法人北九州産業学術推進機構
  • 特開2006-320641:麻酔睡眠時の呼吸音の解析による睡眠時無呼吸症候群の検出・評価システム  2006/11/30
    南浩一郎, 五百旗頭正  財団法人北九州産業学術推進機構

Awards & Honors

  • 2002 産業医科大学学会長賞
     JPN

Research Grants & Projects

  • Functional analysis of voltage-gated sodium channel in anesthesia mechanism using dorsal root ganglion cells
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2019/04 -2022/03 
    Author : 南 浩一郎, 堀下 貴文
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2015/04 -2019/03 
    Author : Yokoyama Toru
     
    In this study, we found that the sensitivity to excitatory synaptic inputs to hyperosmotic stimulation and angiotensin II administration to magnocellular neurosecretory cells (MNCs) of hypothalamic supraoptic nucleus is significantly reduced in cancer cachexia model rats compared with normal rats by using whole-cell patch-clamp recordings. MNCs are related to body fluids regulation by secreting arginine vasopressin (AVP). AVP secretion by MNCs is depend on both excitatory and inhibitory synaptic activity such as alterations in plasma osmolarity and various peptides, including angiotensin II. This study is the first study to clarify that the sensitivity of MNCs changes in cancer cachexia. Our results suggest that Cancer cachexia may be involved in fluid regulation by altering the sensitivity of MNCs.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2015/04 -2019/03 
    Author : MINAMI KOUICHIRO
     
    In this study, we examined the effects of tramadol and its main active metabolite O-desmethyltramadol (M1), on the function of μORs using Xenopus oocytes expressing cloned human μORs. The effects of tramadol and M1 were evaluated using the Ca(2+)-activated Cl(-) current assay method for G(i/o)-protein-coupled receptors by using a μOR fused to G(qi5) (μOR-G(qi5)) in Xenopus oocytes. Tramadol and M1 also evoked Cl currents in the oocytes expressing μOR-G(qi5); however, relatively higher concentrations (compared to DMAGO [(D-Ala(2), N-MePhe(4), Gly(5)-ol)-enkephalin] ) were necessary to induce such currents. Tramadol and M1 had a direct effect on μORs expressed in Xenopus oocytes. The μOR signal by Hydromorphone was examined. Hydromorphone increased the electrical resistance in a concentration-dependent manner, suppressed the amount of cAMP.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2011/04 -2015/03 
    Author : OGATA Junichi
     
    G-protein-coupled receptors, such as opioid receptors, substance P receptors (Sub P receptor) have been attracting attention for pain mechanisms. On the other hand, the spinal cord dorsal root ganglion (DRG) cells are involved to pain, such as Sub-P receptor and opioid receptors are present. In this study, we studied the effects of anesthetics and analgesics on TRIPV1, opioid receptors and Sub P receptors using calcium kinetics in DRG and the Xenopus oocyte expression system. Consequently, inhaled anesthetics sevoflurane inhibited could opioid receptor function. Furthermore, analgesic tramadol and its metabolite M1 is no effect on TRIPV1, was demonstrated to inhibit TRIPA1.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2011 -2013 
    Author : TORU Yokoyama, MINAMI Kouichiro, UETA Yoichi, UEZONO Yasuhito, TERAWAKI Kiyoshi
     
    Cancer cachexia (CC), a syndrome characterized by anorexia and body weight loss due to low fat-free mass levels, including reduced musculature, markedly worsens patient quality of life. Body fluid balance may be changed by several conditions, such as anorexia, inflammation, dehydration and ascites in CC. Drinking behaviour and the release of arginine-vasopressin from the magnocellular neurosecretory cells in the supraoptic nucleus (SON) are crucial for body fluid homeostasis. We compared the reaction to osmotic pressure and angiotensin II of the CC model rat with the normal model rat in in vitro rat brain slice prepalation, using whole-cell patch-clamp recordings. Hyperosmotic stimulation and application of angiotensin II potentiate the frequency of miniature excitatory postsynaptic currents (mEPSCs) without affecting the amplitude in normal rats. However, this effect was attenuated in CC model rats. These results suggest that CC may change the sensation of mEPSCs in the SON.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2011 -2013 
    Author : MINAMI Kouichiro
     
    The effects of volatile anesthetics and intravenous anesthetics on the mu-opioid receptor functions were analyzed by using oocytes expressing mu-opioid receptors-Gqi5. Volatile anesthetics inhibited the DAMGO-induced Cl- currents at clinically used concentrations. Intravenous anesthetics, ketamine inhibited, but propofol had little effects on it. Tramadol has been used as an analgesic for several decades. mu-opioid receptors are the major receptors that mediate the analgesic effects of opioids. Although mu-opioid receptors have been thought to be one of the sites of action of tramadol, there has been no report that directly proves whether the tramadol is an agonist of mu-opioid receptor or not. In this study, we examined the effects of tramadol and its main active metabolite O-Desmethyltramadol (M1), on the function of mu-opioid receptors using Xenous oocytes expressing cloned human mu-opioid receptors.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2008 -2010 
    Author : YOKOYAMA Toru, MINAMI Kouichiro, UETA Yoichi
     
    We demonstrated pain sensor TRPV1 is essential for osmo-regulation in central nerves systems. TRPA1 agonists potentiate excitatory synaptic inputs to the SON. We found the possibility that vasopressin strongly participated in a pain.
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2007 -2008 
    Author : MINAMI Koichiro, UETA Yoichi, UEZONO Yasuhito, SEO Norimasa, SHIGEMATSU Akio
     
    麻酔薬や鎮痛薬の作用機序解明は危急的課題であるが、いまだにその解明には至っていない。脊髄後根神経節(DRG)細胞 は多くの神経ペプチドが含有され、疼痛への関与が強く示唆されている。申請者らは培養DRGを用いた研究ではムスカリン受容体やサブスタンスP受容体などが存在することを確認した。現在はこれらに対して麻酔薬がどのように反応するのかを確認しているところである。アフリカツメガエル卵母細胞系やスライスパッチ法を用いてこれらの受容体へ鎮痛薬、麻酔薬がどのように作用するのかを解析する予定である。
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2006 -2008 
    Author : SEGAWA Kayoko, MINAMI Koichiro, UEZONO Yasuhito, YOKOYAMA Toru
     
    モルヒネやフェンタネストなどのオピオイドと吸入麻酔薬の相互作用は不明である。アフリカツメガエル卵母細胞発現系を利用し、オピオイド受容体に対する麻酔薬の作用を電気生理学的に解析した。現在までの検討で、これらのGq/GiキメラG蛋白結合μオピオイド受容体の高率の発現を示し、麻酔薬ハロセンなどはμオピオイド受容体に影響することを明らかにした。現在までハロセンは多くのG蛋白結合受容体をリン酸化酵素プロテインキナーゼC(PKC)によって抑制することが報告されているため、μオピオイド受容体の機能にも燐酸化酵素によって影響があるかどうか検討している。これらの結果をもとにμオピオイド受容体への麻酔薬の作用の全貌を明らかにしたいと考えている。
  • The effects of dexmedetomidine on G protein coupled receptors
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2006 -2007 
    Author : YOKOYAMA Toru, MINAMI Kouichiro, UETA Yoichi, ATUSHI Takizuka, SHIRAISHI Munehiro
     
    Dexmedetomidine, an alpha (2)-adrenoceptor agonist, has been approved for clinical use, although the mechanism of dexmedetomidine action has not been fully elucidated. Several studies have shown that G protein-coupled receptors (GPCRs) are recognized as targets for anesthetics and analgesics. Therefore, it is of interest to determine whether dexmedetomidine affects the function of GPCRs other than the alpha (2)-adrenoceptor. We examined the effects of dexmedetomidine on M (1), M (3), 5-HT (2C), substance P, and orexin 1 receptors in Xenopus oocytes expressing individual receptors. In addition, we investigated the effects of dexmedetomidine on muscarinic receptor-mediated changes in[Ca (2+)] (i) in the dorsal root ganglia (DRG) of 3-week-old Wister rats. Dexmedetomidine did not affect the 5-HT (2C)-, or substance P-induced Cl (-) currents and had little inhibition on the orexin A-induced current in oocytes expressing the respective receptors. The compound also had little effect on the acetylcholine (ACh, 1 microM)-induced Ca (2+)-activated Cl (-) currents in Xenopus oocytes expressing M (1) receptors. In contrast, dexmedetomidine inhibited the ACh-induced currents in Xenopus oocytes expressing M (3) receptors; 1nM, 10nM, 100nM, and 1microM dexmedetomidine reduced the current to 66.5 +/-4.8, 51.3+/-12, 34.6+/-11, and 26.8+/-6.4% of the control value, respectively (EC (50)=3.5+/-0.7nM). Dexmedetomidine reduced the ACh-induced Cl (-) currents after treatment with the selective protein kinase C inhibitor GF109203X. Moreover, the compound inhibited the muscarinic receptor-mediated increases in[Ca (2+)] (i) in cultured DRG cells in a concentration-dependent manner. Dexmedetomidine inhibits the function of M (3) receptors, in addition to its agonistic effects on alpha (2)-adrenoceptors, which provides further insight into the pharmacological properties of dexmedetomidine.
  • Effects of phytoestrogens on neuronal functions in noradrenergic neurons during early life : Basic studies for risk assesment
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2006 -2007 
    Author : YOYOHIRA Yumiko, TANAKA Toshiko, UENO Susumu, SAKAMAKI Ruka
     
    There is considerable evidence to indicate that estrogens and phytoestrogens have beneficial effects on protection against cardiovascular diseases and on the inhibition of tumor growth. Although estrogens also have been reported to prevent neuronal degeneration caused by oxidative damage, it remains unknown whether the phytoestrogen could affect the functions of the noradrenergic and serotonergic neurons. Therefore, we investigated the effect of phytoestrogens on the catecholamine synthesis, secretion and reuptake. Resveratrol and Daidzein suppressed catecholamine secretion and ^<22>Na^+^ and ^<45>Ca^<2+> influx induced by acetylcholine (ACh). Resveratrol directly inhibited the current evoked by ACh in Xenopus oocytes expressing a3b4 neuronal nicotinic acetylcholine receptor. Daidzein at low concentration (10nM〜1μM) stimulates catecholamine synthesis through plasma membrane estrogen receptors. This stimulatory effect was not inhibited by IC1182, 780, a classical estrogen receptor inhibitor. Genistein was stimulated the functions of norepinephrine transporter (NET) and serotonin transporter (SERT) in a concentration-dependent manner (10nM-10RM). Other isoflavones, such as daidzein and cumestrol, had little effect. This stimulatory effect of genistein was altering an increase in the number of NET in the plasma membrane. These findings suggest that phytoestrogens play a role in the regulation of neuronal functions on noradrenergic neurons. To confirm the effects and risks of phytoestrogens on catecholaminergic neurons, further in vivo studies of the administration of phytoestrogens to mice are required.
  • 麻酔薬作用における中枢神経系各部位の果たす役割解析
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Exploratory Research
    Date (from‐to) : 2006 -2007 
    Author : 重松 昭生, 南 浩一郎, 瀬川 賀世子, 横山 徹, 上園 保仁
     
    中枢神経系や脊髄のどこの部位が麻酔薬の作用機序にどのように関わっているのかは,麻酔機序を解き明かす上で非常に興味深い。抗侵害刺激は一次痛覚神経が脊髄後角に入り脊髄を上行し中枢神経へ伝えているが,麻酔薬がどの部位で作用しているのかは明らかでない。 一方,動脈血管造影法が臨床でも広く使用され栄養動脈を選択的に造影できる。この技術を応用すれば,微小カテーテルを挿入し低容量の麻酔薬を投与することで,選択的な脊髄を麻酔することが可能である。今年度はウサギを用いて,鼠径動脈から微小カテーテルを栄養動脈に挿入し,低容量の静脈麻酔薬を持続的に注入し麻酔作用における中枢神経の部位の同定を行っているが,麻酔の方法などに改良の余地があり,本年度内には結論を得られなかった。しかし,中枢神経の部位において,受容体,イオンチャネルなどの麻酔薬ターゲット分子を同定の第一段階として脊髄後根神経節細胞にターゲットをしぼり,そこでのラットにおける神経相同部位をスライスし,パッチクランプ法を用いて,イオンチャネルに対する麻酔薬の影響について解析を開始し,麻酔薬は影響する事実を確認している。特に脊髄および,中脳レベルでのTRP受容体については麻酔薬の関与が強く疑われている。TRP受容体は麻酔機序だけでなく痛覚機序にも強く関与している所見をいくつか確認できている。 さらに今後は,これらのデータをもとに麻酔薬のターゲット受容体のRNAを組織から抽出し,アフリカツメガエル卵母細胞発現系に発現させ反応を解析する予定である。
  • The study of the pain mechanisms using rat dorsal root ganglia
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2005 -2007 
    Author : MINAMI Koucihiro, SHIRAISHI Munehiro, UEZONO Yasuhito, UETA Yoichi
     
    The dorsal root ganglion (DRG) neurons and associated primary afferent nerves transmit different sensory modalities, including nociception, to the spinal dorsal horn. Many types of neuronal cell have been found on primary afferent neurons, either on their central or peripheral processes or on the cell bodies of DRG cells and the presence of several GPCRs has been reported, including substance P, muscarinic, 5-HT_2 and orexin receptors. Consequently, the DRG has been used to study nociception. It is of interest to determine drug actions on these receptors, and we investigated the role of the glutamate receptor in DRG and the effects of anesthetics on the function of mGluR1 and mGluR5 expressed in Xenopus laevis oocytes. We examined the effects of halothane, isoflurane, enflurane, diethyl ether, and ethanol on SP-induced currents mediated by SPR expressed in Xenopus oocytes, by using a whole-cell voltage clamp. All the volatile anesthetics tested, and ethanol, inhibited SPR-induced Ca(2+)-activated Cl(-) currents at pharmacologically relevant concentrations. Neurosteroid, alphaxalone, inhibited the acetylcholine (Ach)-mediated responses of M(1) and M(3) receptors expressed in Xenopus oocytes, whereas DHEA did not. Moreover, we examined the the effects of Dexmedetomidine in this systems. Dexmedetomidine did not affect the 5-HT_2c-, substance P-, or orexin A-induced Cl^- currents in oocytes expressing the respective receptors. The compound also had little effect on the acetylcholine (Ach, 1μM)-induced Ca^<2+>-activated C1^- currents in Xenopus oocytes expressing M_1 receptors. In contrast, dexmedetomidine inhibited the Ach-induced currents in Xenopus oocytes expressing M_3 receptors. Dexmedetomidine reduced the Ach-induced C1^- currents after treatment with the selective protein kinase C inhibitor GF109203X. Moreover, the compound inhibited the muscarinic receptor-mediated increases in [Ca^<2+>; in cultured DRG cells in a concentration-dependent manner. From these results, the glutamate receptors may play the important role in pain transmission in DRG.
  • The role of the metabotropic gultamete receptor in the pain mechanism
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2005 -2007 
    Author : SHIGA Yousuke, MINAMI Koichiro, SHIRAISHI Munehiro, UEZONO Yasuhito
     
    The dorsal root ganglion (DRG) neurons and associated primary afferent nerves transmit different sensory modalities, including nociception, to the spinal dorsal horn. Many types of neuronal cell have been found on primary afferent neurons, either on their central or peripheral processes or on the cell bodies of DRG cells and the presence of several GPCRs has been reported, including substance P, muscarinic, 5 HT2 and orexin receptors. Consequently, the DRG has been used to study nociception. The metabotropic glutamate receptors (mGluRs) show little sequence homology with most other metabotropic receptors and are important modulators of synaptic transmission in the mammalian central nervous system. It was of interest to determine drug actions on these receptors, and we investigated the role of the glutamate receptor in DRG and the effects of anesthetics on the function of mGluR1 and mGluR5 expressed in Xenopus laevis oocytes. In the projects, we found the glutamate-evoked increase in Ca^<2+>i in cultured DRG cells that show the presence of the glutamate receptors. In the experiment using Xenopus oocytes systems, anesthetics inhibited mGluR5-induced Ca^<2+>-dependent currents, yet pharmacologically relevant concentrations of these compounds had little effect on the glutamate-induced currents in the oocytes expressing mGluR 1. Moreover, we examined the the effects of Dexmedetomidine in this systems. Dexmedetomidine did not affect the 5 HT2C-, substance P-, or orexin A-induced Cl- currents in oocytes expressing the respective receptors. The compound also had little effect on the acetylcholine (ACh, 1μM)-induced Ca^<2+>-activated Cl- currents in Xenopus oocytes expressing M_1 receptors. In contrast, dexmedetomicline inhibited the ACh-induced currents in Xenopus oocytes expressing M_3 receptors. Moreover, the compound inhibited the muscarinic receptor-mediated increases in Ca^<2+>i in cultured DRG cells in a concentration-dependent manner. From these results, the glutamate receptors may play the important role in pain transmission in DRG.
  • Attempt of obstinacy pain easing by spinal cord GABA-B receptor continuation activation.
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2005 -2006 
    Author : UEZONO Yasuhito, MINAMI Kohichiro, TANIYAMA Kohtaro
     
    Recent reports have shown that intrathecal administration of GABA_B receptor agonist baclofen (ITB, intrathecal baclofen) is effective for intolerable pain such as neuropathic pain. Even such effective ITB therapy, prolonged application of baclofen causes tolerance and then decreases analgesic effects in patients. The main cause of the tolerance of ITB therapy arises from desensitization of GABA_B receptors due to continuous activation of the receptors. We have recently reported that G protein-coupled receptor kinase 4 (GRK4) and GRK5 are involved in the desensitization processes of GABA_B receptors (Kanaide et al., J Cell Physiol. (2007)). In the present study we sought to find drugs that inhibit GRK4 and GRK5 activity to persistently stimulate GABA_B receptors. Our findings suggest that ketamine, an anesthetic and an inhibitor of NMDA receptors, efficiently inhibited the properties of GRK4 and GRK5 to finally cause attenuation of desensitization of GABA_B receptors induced by prolonged application of baclefen in the Xenopus oocyte and baby hamster kidney cell expression systems. These results imply that co-administration of both baclofen and ketamine may inhibit desensitization of GABA_B receptors and eventually cause persistent analgesic effects without tolerance in the ITB therapy. Further studies with the whole body animals and preliminary clinical trials would be required to confirm the 'safe and effective ITB therapy' for patients suffering from severe pain.
  • 麻酔薬、鎮痛薬の痙攣誘発作用におけるセロトニン受容体のはたす役割解明
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2004 -2006 
    Author : 相原 啓二, 南 浩一郎, 上園 保仁, 松井 稔, 佐多 竹良, 白石 宗大
     
    エンフルレンなどの麻酔薬やトラマドールなどの痙攣誘発はよく知られているが、これらの原因について詳しい結論は見られていない。しかし、最近セロトニン受容体のサブタイプである5HT_<2C>受容体が痙攣に密接に関係していることが報告され、これらに対する麻酔薬、鎮痛薬、局所麻酔薬の作用がどうなのか興味がもたれるところであるが、これらの5HT_<2C>受容体への作用はまったく報告されていない。今回の研究においては麻酔薬、鎮痛薬の痙攣誘発機序解明を行う目的でアフリカツメガエル卵母細胞系を用いて以下の研究を行った。吸入麻酔薬(エンフルラン、イソフルラン)が5HT_<2C>受容体にいかに作用するかを検討した。その結果、エンフルラン、イソフルランは、5HT_<2C>受容体を抑制する結果を得た(論文作成中)。これらの抑制機序については、現在まで、麻酔薬やアルコールはProtein Kinase C(PKC)をはじめとした燐酸化酵素を介してG蛋白結合受容体を抑制していることが明らかとなっているので、5HT_<2C>受容体においても燐酸化酵素が何らかの作用を及ぼしているのかどうか検討中である。もしそうであれば、5HT_<2C>受容体の燐酸化部位であるPKCの燐酸化部位を燐酸化をうけない他のアミノ酸に変えて、吸入麻酔薬などがこのMUTANT5HT_<2C>受容体にいかに作用するかも検討する。また、トラマドールとその代謝産物M1も抑制する結果を得た。これらの抑制機序を解析してみたところ燐酸化酵素を介さず、受容体に直接作用して抑制していることが確認できた。 今後この研究を踏まえて、さらに、MUTANT5HT_<2C>受容体をもった遺伝子変異マウスを形成し、これらに対して麻酔薬、鎮痛薬がどのように作用するのかを行動薬理的に解析する。これらの結果を踏まえての麻酔薬の痙攣誘発機序への5HT_<2C>受容体の関与を明らかにしたいと考えている。
  • 麻酔薬の動脈硬化予防作用の臨床応用を目指した研究-麻酔薬の新たなる作用の検討-
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Exploratory Research
    Date (from‐to) : 2004 -2005 
    Author : 重松 昭生, 南 浩一郎, 堀下 貴文, 上園 保仁, 佐多 竹良, 白石 宗大
     
    近年、虚血性心疾患の合併症をもつ患者の手術件数は増加の一途をたどっている。これらの予防に血管平滑筋増殖を抑制することがこれらの発生予防につながり種々の対策が模索されている。一方、麻酔薬は手術に広く使用されているにもかかわらず、現在まで麻酔薬の動脈平滑筋の増殖に与える影響については良く知られていない。申請者らは現在までに静脈性麻酔薬ケタミンは細胞内cAMPの上昇を介して細胞増殖を抑制するという麻酔薬の新たな作用を見いだした。この麻酔薬の細胞増殖抑制作用は血管平滑筋増殖にも大きな影響を及ぼしているだろうと考えられるが、短期的、長期的にも血管平滑筋への作用を検討した報告はない。今回申請者らは血管平滑筋細胞の増殖機能にどのように麻酔薬が作用するか検討する目的で、培養ヒト冠動脈、大動脈平滑筋細胞を用いて、 1.静脈性麻酔薬が培養ヒト大動脈平滑筋細胞の増殖にどのように作用するかを[^3H]-thymidineの取り込みおよび細胞数の増加を解析した結果、ケタミンが培養ヒト大動脈平滑筋細胞への[^3H]-thymidineの取り込みおよび細胞数の増加を抑制した。 2.これらの反応の機序に細胞内燐酸化酵素Protein Kinase Cが関与していることが明らかとなった。 3.さらに、ラットを用いてバルーンカテーテルによる血管障害性動脈硬化を作り、ケタミン投与がその増殖を病理学的にも抑制していることを確認した。以上の研究で本研究の目的を達成したと考えられる。 現在は、先天的に動脈硬化を容易に起こす動脈硬化モデルマウスを用いて、長期間経口により投与し、病理学的に麻酔薬の持続低量投与が細胞増殖を抑えて動脈硬化を予防しえるか検討し、培養ガン細胞に対しても増殖抑制作用があるのかもスクリーニングを行っており、本研究により麻酔薬の生活習慣病予防につながる新たな作用が今後発見される可能性が示唆された。
  • The study of antinociceptive effects of anesthetics and analgesics using dorsal root ganglia cells.
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2003 -2005 
    Author : SHIGEMATSU Akio, MINAMI Kouichiro, UEZONO Yasuhito, UETA Yoichi, HORISHITA Takahumi, SHIRAISHI Minehiro
     
    The effects of anesthetics on ion channels have been the focus of several studies. During the last decade, major advances have been made in our understanding of the physiology and pharmacology of G-protein coupled receptor (GPCR) signaling. Further studies have shown that GPCRs are targets for anesthetics. However, less is known about the mechanisms of action of anesthetics on GPCRs, ion channels and ligand-gated ion channels in spinal cords levels. The Xenopus oocyte expression system has been used widely to study numerous brain ion channels and GPCRs. A large number of types have been found on primary afferent neurons, either on their central or peripheral processes or on the cell bodies of the dorsal root ganglion (DRG) cells and it is have been reported the presence of several GPCRs. Therefore the DRG have been used for the study of nociception. (1)We studied the effects of anesthetics on substance P-evoked intracellular [Ca^<2+>] ([Ca^<2+>]_i)increasing in cultured DRG cells. Substance P induced a rapid [Ca^<2+>]_i increase in single DRG cell. Volatile anesthetics halothane inhibited the substance P-evoked increases in [Ca^<2+>]_i. (2)Tramadol, metabolite M1 and alphaxalone inhibited voltage dependent Na channels expressed in Xenopus oocytes that expressed M_3. High concentration of dexmedetomidine inhibited voltage dependent Na channels expressed in Xenopus oocytes that expressed M_3. (3)Most volatile anesthetics inhibited substance P receptor function expressed in Xenopus oocytes that expressed M_3. Moreover, ketamine and pentobarbital inhibited substance P receptor function expressed in Xenopus oocytes that expressed M_3. (4)We studied the effects of anesthetics on orexin A and neuropeptide FF-evoked [Ca^<2+>]_i increasing in cultured DRG cells. Orexin A and neuropeptide FF induced a rapid [Ca^<2+>]_i increase in single DRG cell suggesting that these receptors exist in DRG. Our present results would be useful for understanding the mechanisms of anesthetics.
  • The effects of anesthetics and ethanol on cannabinoid receptor function.
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2002 -2004 
    Author : KAMOCHI Masayuki, MINAMI Kouitiro, UEZONO Yasuhito, SHIGEMATSU Akio, HORISHITA Takahumi, SHIRAISHI Munehiro
     
    Metabotropic G protein-coupled receptors have recently been recognized as targets for anesthetics and analgesics. In particular, G_q-coupled receptors such as muscarinic M, receptors (M_1R) and 5-hydroxytryptamine (5-HT) type 2A receptors have been reported to be targets for anesthetics. Much less is known, however, about the effects of anesthetics on G_i-coupled receptors. Here we report a method to analyze functions of Gi-coupled receptors (muscarinic M_2receptors (M_2R) and cannabinoid 1 receptors (CB1R) in Xenopus oocytes expressing a chimeric G α protein. We determined acetylcholine (ACh)-induced Ca^<2+> -activated Cl^- currents in Xenopus oocytes coexpressing G_i-coupled M_2R with the chimeric G α_. Although ACh did not induce any currents in oocytes expressing M_2R alone, it caused robust Cl^- currents in oocytes coexpressing M_2R with G α_. The EC_<50> of the ACh-induced Cl^- current mediated through G α_ was 0.2 μmol/l, which was 2.2 times higher than that of the ACh-induced G protein-activated inwardly rectifying K^+ currents activated by G beta gamma subunits liberated from endogenously expressed G α_i in Xenopus oocytes. Other G_i-coupled somatostatin type 2, 5-HT_<1A> and delta-opioid receptors, when coexpressed with G α_ in oocytes, also caused robust Ca^<2+> -activated Cl^- currents. In oocytes coexpressing M_2R and G α_, a volatile anesthetic halothane inhibited M_2R-induced Cl^- currents in a concentration-dependent manner with the IC_<50> of 1.1 μmol/l, suggesting that halothane inhibits M_2R-induced cellular responses at clinically relevant concentrations. Treatment with the protein kinase C inhibitor GF109203X produced a 3.5-fold enhancement of the initial Cl^- currents induced by 1 μmol/l ACh in oocytes expressing M_2R and G_. The rate of halothane-induced inhibition of Cl^- currents elicited by ACh, however, was not changed in such oocytes pretreated with GF109203X. These findings suggest that halothane inhibits the M_2R-induced signaling by acting at sites other than PKC activity. Collectively these findings suggest that the use of oocyte expressing G α_ would be helpful to examine the effects of anesthetics or analgesics on the function of Gi-coupled receptors in the Xenopus oocyte expression system. A chimeric G α_q protein G α_, which contains carboxy-terminus five amino acids of G α_i, enables G_i-coupled receptors to couple to Gq-coupled receptor-mediated downstream pathways such as activation of phospholipase C. We determined anandamide-induced Ca^<2+>-activated Cl^- currents in Xenopus oocytes coexpressing G_i-coupled CB1R with the chimeric G α_. Although anandamide did not induce any currents in oocytes expressing CB1R alone, it caused robust Cl^-currents in oocytes coexpressing CB1R with Gα_. In oocytes coexpressing CB1R and G α_, a volatile anesthetic halothane inhibited CB1R-induced Cl^- currents, suggesting that halothane inhibits CB1R-induced cellular responses at clinically relevant concentrations. These findings suggest that halothane inhibits the CBIR-induced signaling. Collectively these findings suggest that the use of oocyte expressing G α_ would be helpful to examine the effects of anesthetics or analgesics on the function of G_i-coupled receptors in the Xenopus oocyte expression system. Although much attention has been paid to ion channels in the CNS as targets for anesthetics, several lines of study have shown that GPCRs are also targets for anesthetics. Gi-coupled receptors might also be targets for anesthetics. More information about Gi coupled receptors might help to elucidate the role of GPCRs in the mechanisms of anesthetics.
  • オレキシンレセプターの細胞内情報伝達の解明
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (A)
    Date (from‐to) : 2002 -2004 
    Author : 南 浩一郎
     
    オレキシン受容体は、最近睡眠覚醒にオレキシンが重要な役割を演じていることが示唆されているGタンパク結合受容体である。一方、麻酔薬はすべて就眠作用をもち、その機序に興味が持たれているが、未だにその作用機序は完全に解明されていない。麻酔中の動物の脳内にオレキシンを注入すると、麻酔から直ちに覚醒する事が研究者間で観察されている。これらの事からオレキシンと麻酔就眠作用との間で何らかの関係が考えられるが、詳しい検討は全くなされていない。一方、アフリカツメガエル卵母細胞発現系はCa^<2+>依存性C1^-チャンネルをもち、PLCを介した細胞内Ca^<2+>の変動により、容易にGq蛋白結合受容体への薬物の反応を電気生理学的に解析でき、更に、細胞内リン酸化酵素の解析も同時にできるため、麻酔薬のG蛋白結合受容体に対する作用を解析する手段として非常に有効である。今年度の研究においては昨年に引き続き、オレキシン受容体の細胞内情報伝達系の解明とこれらの麻酔機序との関わりを明らかとするために、オレキシン受容体RNAをアフリカツメガエル卵母細胞発現系に注入し発現させ、吸入麻酔薬や静脈麻酔薬がオレキシA受容体にいかに作用するかを検討した。オレキシン受容体Aは吸入麻酔薬ハロセン、イソフルラン、エンフルラン、ジエチルエーテルによって臨床濃度内で濃度依存性に抑制されていることが明らかとなった。さらにオレキシン受容体Aは静脈麻酔薬ペントバルビツレート、プロポフォール、ケタミンによっても臨床濃度内で濃度依存性に抑制されていることが明らかとなった。予備的な結果であるがオレキシンBに関しては吸入麻酔薬イソフルランや静脈麻酔薬ペントバルビツレートが抑制をしている結果を得た。現在、その機序を検討中であり、プロテインキナーゼCなどの燐酸化酵素などの作用に注目し、今後はこれら機序を中心に明らかにしたいと考えている。
  • 新たな鎮痛薬の開発を目指す脊髄後根神経節細胞における新しい痛覚伝達物質の検索および機能解析(脊髄後根神経節細胞のオーファンレセプターの解析)
    産業医科大学:高度研究
    Date (from‐to) : 2004 
    Author : 南浩一郎
  • ニューロステロイドのG蛋白結合受容体及びリガンド結合イオンチャンネルに及ぼす影響
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Exploratory Research
    Date (from‐to) : 2002 -2003 
    Author : 南 浩一郎, 尾方 純一, 渋谷 泉, 上園 保仁, 堀下 貴文
     
    プロゲステロンをはじめとするコレステロールから生成されるニューロステロイドは、中枢、末梢神経に存在し、鎮痛効果、麻酔効果を持つ事が知られているが、その鎮痛機序は未だ明らかとなっていない。現在、鎮痛のメカニズムは中枢、末梢、脊髄レベルでの機序が明らかとなり、ノルアドレナリンの分泌に関与するニコチン受容体や再吸収に作用するトランスポーター(NET)、サブスタンス-P受容体、ムスカリン受容体といったG蛋白結合受容体、ニコチン受容体などのイオンチャンネルが疼痛に強く関与していることが示唆されている。しかし、ニューロステロイドの鎮痛作用にこれらの受容体への作用を解析した報告はない。現在まで、麻酔薬や鎮痛薬の鎮痛作用機序にイオンチャンネルやG蛋白結合受容体が関与する事が明らかとなってきている。アフリカツメガエル卵母細胞発現系は中枢神経系のGq蛋白結合受容体やニコチン受容体イオンチャンネルに対する薬剤の作用を、電気生理学的に検討する実験系として広く使用されている。また、副腎髄質細胞はニコチン受容体を介してカテコールアミンを放出するだけでなく、細胞膜にはNETやGABA受容体も存在しており、麻酔薬や鎮痛薬の中枢神経でのノルアドレナリン神経のシナプス間隙での神経伝達物質動態への影響を詳細に調べられる。 今年度は昨年度はAlphaxaloneでの検討に引き続き、アフリカツメガエル卵母細胞発現系を用いて、アフリカツメガエル卵母細胞にM1、M3受容体のcRNAを注入し発現させ、これらに対するニューロステロイド(プレグナノロン、プロゲステロン、DHEA)の作用をvoltage-Clampにて電気生理学的に解析した。その結果、プレグネノロン、プロゲステロン、DHEA)はM1、M3受容体を臨床濃度で抑制しその抑制形式は拮抗阻害形式でムスカリン作用部位に近い部位で作用していることが明らかになった。現在、より麻酔作用の強いプレグナノロンの、ムスカリン、ニコチン受容体への作用を検討しており、来年度中には明らかにしたいと考えている。
  • The mechanisms of analgesic effects of Tramadol and Alphaxalone
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2001 -2002 
    Author : SHIGEMATSU Akio, SAGATA Kenichiro, MINAMI Kouichiro
     
    The mode of action of the analgesic tramadol and alphaxalone, a neurosteroid anestheticis not well understood. We assayed the effect of tramadol and alphaxalone on [^3H]-norepinephrine ([^3H]-NE) uptake and [^3H]-desipramine binding to plasma membranes isolated from bovine adrenal medulla. We also investigated the effects of tramadol and alphaxalone on muscarinic receptors type 1 and 3, using a Xenopus oocyte expression system. Finally, we investigated the effect of tramadol and alphaxalone on catecholamine secretion, nicotine-induced calcium rises and inward currents using a Ca^<2+>-imaging system and the whole-cell patch clamp technique in bovine adrenal chromaffin cells. (1) Both tramadol and alphaxalone competitively inhibited norepinephrine transporter function at desipramine binding sites. (2) Both tramadol and alphaxalone at clinically relevant concentrations inhibits m1 and m3 function via QNB-binding sites. (3) Tramadol and alphaxalone inhibits catecholamine secretion by inhibiting nicotinic acetylcholine receptor functions and suggest that such inhibitory effects could be one of the antinociceptive mechanisms exerted by tramadol.
  • Effects of Anesthetics on tachykinin Receptors Expressed in Xenopus Oocytes
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2000 -2001 
    Author : SATA Takeyoshi, MINAMI Kouichiro, SHIGEMATSU Akio
     
    The neuropeptide substance P (SP) and substance K(SK) modulate nociceptive transmission within the spinal cord. SPand SK are unique to a subpopulation of C-fibers found within primary afferent nerves. However, the effects of anesthetics on the substance P receptor (SPR) are not clear. In this study, we investigated the effects of volatile anesthetics and ethanol on SPR expressed in Xenopus oocytes. We examined the effects of halothane, isoflurane, enflurane, diethyl ether, and ethanol on SP-induced currents mediated by SPR expressed in Xenopus oocytes, using a whole-cell voltage clamp. All the volatile anesthetics tested and ethanol inhibited SPRinduced Ca^<2+>-activated C1^- currents at pharmacologically relevant concentrations. The protein kinase C (PKC) inhibitor bisindolylmaleimide I (GF109203X) enhanced the SP-induced CI^-currents. On the other hand, GF109203X abolished the inhibitory effects on SPR of the volatile anesthetics examined and of ethanol. These results demonstrate that halothane, isoflurane, enflurane, diethyl ether, and ethanol inhibit the function of SPR, and suggest that activation of PKC is involved in the mechanism of action of anesthetics and ethanol on the inhibitory effects of SPR.
  • Analgesic mechanisms of Tramadol
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2000 -2001 
    Author : NANDATE Koichiroh, URYU Kayo, MINAMI Kouichiro
     
    Tramadol is awidely used analgesic, but its mode of action is not well understood. (1) To study the effects of tramadol on norepinephrine transporter (NET) function, we assayed the effect of tramadol on [3^]-norepinephrine ([3^]-NE) uptake and [ 3^]-desipramine binding to plasma membranes isolated from bovine adrenal medulla. Tramadol inhibited the desipramine-sensitive uptake of [ 3^]-NE by the cells in a concentration-dependent manner. Tramadol inhibited the specific binding of [ 3^]-desipramine to plasma membranes. These findings indicate that tramadol competitively inhibits norepinephrine transporter function at desipramine binding sites. (2) Tramadol inhibited acetylchοDime-induced currents in oocytes expressing the m1 receptor. Although GF109203X, a protein kinase C inhibitor, increased the basal current, it had little effect on the inhibition of acetylcholine-induced currents by tramadol. In cultured bovine adrenal medullary cells, tramadol (100 nM-100 mM) suppressed muscarine-induced cyclic GMP accumulation. Moreover, tramadol inhibited the sped fie binding of [ 3^]quinuclydinyl benzylate ([ 3^]QNB). Scatchard analysis showed that tramadol increases the apparent dissociation constant (Kd) value without changing the maximal binding (Bmax), indicating competitive inhibition. These findings suggest that tramadol at clinically relevant concentrations Inhibits muscarinic receptor function via QNB-binding sites. (3) We investigated the effect of tramadol on ion channel-mediated catecholamine secretion, nicotine-induced cytosolic Ca^<2+> concentration ([Ca<2+>]i) increases and membrane currents using Ca<2+>-imaging and whole-cell patch-clamp techniques in these cells. We also investigated the effects of tramadol on a7 nicotinic acetylcholine receptor ion channels expressed in Xenopus oocytes. Tramadol concentration-dependently inhibited carbachol-induced catecholamine secretion, whereas it had little effect on veratridine- or high K^+-induced catecholamine secretion. Tramadol suppressed nicotine-induced [Ca<2+>]i in a concentration-dependent manner.
  • 麻酔薬のムスカリンtype2受容体およびアドレナリンβ2受容体への作用解析
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Encouragement of Young Scientists (A)
    Date (from‐to) : 2000 -2001 
    Author : 南 浩一郎
     
    麻酔薬の作用はイオンチャンネルや受容体に作用することが知られているが、そのメカニズムはいまだに解明されていない。最近、G蛋白結合受容体が中枢神経系において麻酔機序に関与しているという報告がなされ麻酔作用に大きく関与していることが明らかとなってきた。G蛋白結合受容体にはGq蛋白結合受容体だけでなくM2受容体やアドレナリンβ2受容体を始めとしたGi及びGs蛋白結合受容体も多く存在し、これらは麻酔薬による不整脈や心筋抑制作用をはじめとした作用に大きく関与していると考えられている。 現在まで、私はアフリカツメガエル卵母細胞発現系を利用してメタポトロピックグルタミン受容体、セロトニン受容体、M1受容体、サブスタンスーP受容体といったGq蛋白結合受容体に対する麻酔薬の作用を検討してきた(Minami et al.,1997,1997,1998、2002)。Gq蛋白結合受容体はアフリカツメガエル卵母細胞発現系などでPLCを介した細胞内Ca^<2+>の変動により容易に解析できるが、しかし、M2受容体やアドレナリンβ2受容体などのGi及びGs蛋白結合受容体はKchannelやアデニレートシクラーゼに作用しており、PLCを介した細胞内Ca^<2+>の変動を利用した解析ができないため、麻酔薬のM2受容体やアドレナリンβ2受容体に対する詳しい検討は行われていないのが現状である。そこで、今回の私の研究においては、(1)GiとGqと間でキメラG蛋白RNAを新たに合成し、このキメラG蛋白RNAとGi蛋白結合受容体RNAを同時にアフリカツメガエル卵母細胞に注入発現させて、Gq蛋白結合受容体と同じようにPLCを介した細胞内Ca^<2+>の変動を利用した、新しいGi蛋白結合受容体の薬理学的解析方法を確立した(2)本年度はこの方法を用いてGi蛋白結合受容体ムスカリン受容体M2に対する麻酔薬ハロセンの作用を電気生理学的に解析した結果、ハロセンはM2受容体を抑制することが明らかとなった(現在投稿準備中)。現在、これらの実験系を利用して鎮痛薬トラマドールのM1,M2への影響を検討している最中である。 (Shiraishi et al.,2001)以上によりGi蛋白結合受容体の新しい薬理学的解析方法を用いた麻酔薬のM2への詳細な作用解析を行い、Gi蛋白結合受容体も麻酔薬のターゲットになりうることが示唆された。
  • 静脈麻酔薬のノルアドレナリントランスポーターに対する作用機序の解析
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Exploratory Research
    Date (from‐to) : 2000 -2001 
    Author : 相原 啓二, 重松 昭生, 南 浩一郎
     
    生体におけるノルアドレナリン性神経の働きは交感神経系の根幹となってその調節を行っているばかりでではなく、下行性疼痛抑制系を構成するなど様々な機能に関与している。ノルアドレナリントランスポーター(以下NAT)はシナプスにおけるノルアドレナリンの神経伝達の終了に大きな役割を持っている。一方、麻酔薬は興奮期に一過性の精神運動興奮作用や交感神経刺激作用を発現し、一部の麻酔薬においては痙攣を誘発する作用を持つなど麻酔管理上好ましくない生体の反応を認める。しかしこれらの作用の機序は現在まで解明されていない。精神を昂揚させたり心悸興奮作用を有するコカインや三環系抗うつ薬は古くからNATの機能を抑制することが知られている。筆者らは今回麻酔薬のすでに述べた作用がNATをはじめ、その他の相同性の高いモノアミントアンスポーター機能の抑制に起因すると考え、麻酔薬とトランスポーター蛋白との相互作用を分子レベルで検討した。その結果、(1)静脈麻酔薬(プロポフォール、ケタミン)がノルアドレナリントランスポーターを抑制する結果を明らかにした。(Minami et al.,1996,Hara et al.1998,Hara 2001,In press)(1)静脈麻酔薬(プロポフォール、ケタミン)に長時間反応させた細胞を用いて[3H]-ノルアドレナリンの細胞内取り込みに対する影響を調べた結果その取り込みが増加していた。(Hara et al.,In press)(3)さらに長時間反応させた紬胞からNATmRNAを調製し、NAT遺伝子の塩基配列に基づいて作成したNATcDNAに対する2つのプライマーを用いてRT-PCR(reverse transcriptase-polymerase chain reaction)法でmRNAを定量し、麻酔薬の長時間作用によるmRNAの変動を調べた結果、NETmRNAは増加していることが明らかとなった(Hara et al.,In press)。これらのことは、プロポフォール、ケタミンを長時間使用するとそのNETの発現量に影響を与えていることを示唆しており、これらのNETの静脈麻酔薬の長時間使用による薬理効果の変化に何らかの影響を与えていると考えられた。現在、これらの実験結果を基に鎮痛薬トラマドールにもNETの機能に影響するかどうかを検討している(Sagata et al.,In press)。
  • 長時間緊張労働状態におけるストレスの評価法. —手術室内での長時間緊張状態が交感神経系へ与える影響について—.
    産業医科大学:産業医科大学 産業医学重点研究
    Date (from‐to) : 2001 
    Author : 南浩一郎, 豊平由美子, 上原浩文
  • The effects of intravenous anesthetics on aortic smooth muscle cells proliferation in vivo and in vitro
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 1999 -2000 
    Author : SHIGEMATSU Akio, SATA Takeyoshi, MINAMI Kouichiro
     
    Intravenous anesthetics, such as ketamine, have been widely used for the cardiovascular anesthesia. However, the effects of these anesthetics on the vascular smooth muscle cell proliferations are poorly understood. In this study, we investigated the effects of ketamine, propofol, lidocaine and fentanyl on rat aorta smooth muscle cell proliferation. Rat aortic smooth muscle cells are cultured in medium containing 5% fetal calf serum. The cells at second to third passage were used. For growth assay, the effects of anesthetics on the amount of [^3H]-thymidine incorporated into the cells and cell counts were measured. Statistical evaluation was performed with Student's t-test or analysis of variance (ANOVA). Ketamine (10-200 mM) inhibited [^3H]-thymidine incorporation into rat cultured aorta smooth muscle cell in a concentration-dependent manner. However, propofol (100 mM), lidocaine (300 mM) and fentanyl (100 nM) were not effective at inhibition of aortic smooth muscle cells proliferations. Ketamine also decreased the cell number at clinical relevant concentrations. The inhibition of ketamine on aortic smooth muscle cells proliferations was abolished by protein kinase C (PKC) inhibitor, GF109203X. These findings suggest that ketamine inhibits proliferation of rat aortic smooth muscle cells proliferations via PKC pathway.
  • ステロイド系麻酔薬アルファキサロン及びモルヒネ誘導体トラマドールの鎮痛作用機序解明-キメラG蛋白受容体、培養副腎髄質細胞を用いた解析方法による鎮痛剤の開発-.
    上原記念生命科学財団:上原記念生命科学財団
    Date (from‐to) : 2000 
    Author : 南浩一郎, 重松昭生, 柳原延章, 白石宗大, 瀬川賀世子
  • メタボトロピックグルタミンレセプターに対する麻酔薬、アルコールの作用機序解明
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Encouragement of Young Scientists (A)
    Date (from‐to) : 1998 -1999 
    Author : 南 浩一郎
     
    麻酔薬やアルコールの作用の一つとして、記憶の抑制や健忘作用があることが知られているが、そのメカニズムは未だに解明されていない。最近、G蛋白結合受容体が中枢神経系において記憶に関与しているという報告がなされている。G蛋白結合受容体のなかでもメタボトロピックグルタミン受容体はムスカリン受容体と大きくその構造が異なり、麻酔薬やアルコールがこれら構造の異なるメタボトロピックグルタミン受容体にどのように作用するか関心がもたれている。一方、アフリカツメガエル卵母細胞発現系は中枢神経系のG蛋白結合受容体に対する薬剤の作用を検討する実験系として広く使用されている。今回の私の研究(Mol Pharmacol,53:148-156,1998)においては麻酔薬の記憶障害作用や健忘作用を詳しく探る目的で(1)アフリカツメガエル卵母細胞発現系を用いて、麻酔薬イソフルラン、ハロセン、エンフルランとアルコールが2つのメタボトロピックグルタミン受容体のサブタイプ(mG1uR1,mG1uR5)にいかに作用するかを検討し、イソフルラン、ハロセン、エンフルラン、とアルコールはmG1uR5に対して抑制効果を持つが、mG1uR1に対しては影響がないこと、さらに(2)燐酸化酵素阻害薬を用いてこれらの抑制作用に細胞内燐酸化酵素がどのように関与しているかを検討した結果、Protein Kinase Cの選択的阻害薬GF109203Xはイソフルラン、ハロセン、エンフルランとアルコールはmG1uR5に対する抑制効果を消失させた。更に、(3)燐酸化酸素と麻酔薬、アルコールの関係を明かにするためmG1uR5のProtein Kinase Cの燐酸化部位を他のアミノ酸に変えたMutant receptorをつくり、麻酔薬やアルコールの作用を調べた結果、Ser890をG1yに変換したものにはイソフルラン、ハロセン、エンフルランとアルコールのみられなかった。これらの結果より麻酔薬やアルコールのメタボトロピックグルタミン受容体への抑制機序としてPotein KinaseCが関与していることを明かにした。現在、これらの結果をさらに他のG蛋白結合受容体や循環作動物質についても検討している。(Anesth Analg84:190-195,1997,J Parmacol Experi Thera,281:1136-1143,1997;Naunyn-Schmiedeberg's Arch Pharmacol,357:70-76,1998,Eur J Pharmacol Eur J Pharmacol Vol.339:237-244,1997)
  • キメラG蛋白を用いたGi及びGs蛋白結合受容体の薬理学的解析方法の開発.
    金原一郎記念医学医療振興財団:
    Date (from‐to) : 1999
  • Kainate, AMPAレセプターを利用した麻酔作用機序の解明.
    笹川科学研究助成金:笹川科学研究助成金
    Date (from‐to) : 1999 
    Author : 原幸治, 南浩一郎, 重松昭生
  • キメラG蛋白を用いたGi及びGs蛋白結合受容体の薬理学的解析方法の開発
    産業医科大学:産業医科大学 産業医学重点研究
    Date (from‐to) : 1999 
    Author : 南 浩一郎
  • キメラG蛋白を用いたGi及びGs蛋白結合受容体の薬理学的解析方法の開発
    臨床薬理研究振興財団:
    Date (from‐to) : 1999 
    Author : 南浩一郎, 重松昭生, 瓜生佳代
  • The effect of anesthetics on mesangial cells proliferation via protein kinase pathway.
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 1997 -1998 
    Author : SHIGEMATSU Akio, MINAMI Koichiro, KOGA Kazunori, KOHRIYAMA Kazuaki, ISHIMURA Hiroshi
     
    We studied the effects of intravenous anesthetics ketamine and propofol on rat mesangial cell (MC) proliferation. (1)Ketamine inhibited [^3Hltymidine incorporation into the mesangial cells in a concentration-dependent manner (10 mM 1 mM). But, Propofol had no effects n [3H]tyrnidine incorporation. (2)Ketamine also attenuated the cell number at clinical concentrations and increased cAMP levels in MC. (3)Protein Kinase A inhibitor recoverd the inhibition of ketamine on MC proliferation. (4)Moreover, anesthetics (halothane and isoflurane) inhibited the 5HT2A and Muscarinic receptor type1 function via Protein kinase C pathway in Xenopus oocytes. These results suggested that anesthetics have effects on protein kinase activity in the cells and regulated the MC proliferation and receptor function via protein kinase.
  • The effect of anesthetics and anesthetic metbolite on mesangial cells proliferation.
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 1997 -1998 
    Author : SATA Takeyoshi, KAWASAKI Takashi, MINAMI Koichiro, SEGAWA Kayoko
     
    We studied the effects of intravenous anesthetics ketamine and propofol on rat mesangial cell (MC) proliferation. Ketamine inhibited [3H]tymidine incorporation into the mesangial cells in a concentration-dependent manner (10 mM*1 mM). But, Propofol had no effects on [3H]tymidine incorporation. Ketamine also attenuated the cell number at clinical concentrations and increased cAMP levels in MC.Protein Kinase A inhibitor recovered the inhibition of ketamine on MC proliferation. Ketamine kept the renal blood flow in Rat in vivo. These results suggested that ketamine have inhibitory effects on the MC proliferation via protein kinase pathway and ketamine may be useful to suppress the progression of chronic renal failure.
  • G蛋白結合受容体に対する麻酔薬、アルコールの作用機序解明. -アフリカツメガエル卵母細胞発現系を用いた解析
    産業医科大学:産業医科大学 産業医学重点研究助成
    Date (from‐to) : 1997 
    Author : 南浩一郎
  • アドレノメデュリンの腎臓血流に関する作用の検討. -腎炎モデルラットおよび培養メサンギウム細胞、血管平滑筋細胞を用いた検討-
    循環器学研究振興財団:
    Date (from‐to) : 1997 
    Author : 南浩一郎
  • 新しい麻酔薬(F3)の基礎及臨床治験
    財団法人横山臨床薬理:
    Date (from‐to) : 1996 
    Author : 南浩一郎
  • 卵母細胞翻訳系を用いた麻酔薬、アルコールの機序解析. -新しい麻酔薬およびアルコール依存症治療薬の開発を目指して-
    上原記念生命科学財団:
    Date (from‐to) : 1996 
    Author : 南浩一郎
  • 麻酔薬の腎機能保護作用の解析-ラット腎培養メサンギウム細胞を用いた検討-
    Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for General Scientific Research (C)
    Date (from‐to) : 1995 -1995 
    Author : 重松 昭生, 南 浩一郎, 末永 俊郎
     
    最近腎機能の低下している患者の手術件数が増加し周術期において残存する腎機能をいかにして保護するかが重大な問題となる。最近の病理学的、免疫学的研究により、in vivoにおける腎炎モデルが開発されつつある現在そのなかでもメサンギウム細胞の障害と腎機能の関係が注目されており、周術期に使用される麻酔薬がどのようにメサンギウム細胞の機能に作用するか注目されている。今回我々はメサンギウム細胞を用いた研究において、静脈性麻酔薬ケタミンの細胞増殖に対する作用を検討し以下の結果を得た。1.ケタミン(10^<-7>〜10^<-4>M)は、[^3H]-thymidineの取り込みと細胞数の増加を濃度依存性に抑制した。2.フォルスコリン(10^<-6>M)は[^3H]-thymidineの取り込みを抑制したが、ケタミン(10^<-4>M)とフォルスコリン(10^<-6>M)で同時に刺激しても相加作用はなかった。3.ケタミンは細胞内のcAMP濃度を濃度依存性に増加させた。以上の結果より、ケタミンはフォルスコリンと同様に細胞内cAMP濃度を上昇させることにより、メサンギウム細胞への[^3H]-thymidineの取り込みと、細胞増殖を抑制することが示唆された。(これらの結果は平成7年日本麻酔学会総会(浜松)において発表している)さらに、われわれは最近臨床に使用され始めたプロポフォールがどのようにメサンギウム細胞の増殖に作用するかも検討しこれらは[^3H]-thymidineの取り込みおよび細胞数の増加には影響しないことも確認して(Minami et al.,Naunyn-Schmiedeberg's Archives of Pharmacology,In Press)ケタミンは細胞増殖に対して特異的な作用あることを示唆する結果を確認している。さらに我々は、麻酔薬に限らず、慢性の神経痛に効果のあるカルママゼピンがカテコールアミンを介してメサンギウム細胞の増殖に作用する可能性を現在検討している。現在は生体内の循環作動蛋白であるアドレノメデュリンやTNFに関してもメサンギウム細胞の増殖抑制作用があることを確認し、薬剤としての可能性を検討している(Segawa et al.,Nephron,In press,1996)。 今後はこれらの結果をふまえ、メサンギウム細胞の生理活性物質の産生能にどのように影響するかをELISAを用いて測定し、さらに立体光学顕微鏡を用いて収縮能にどのように影響するかも検討する。また将来的にはラットの腎炎モデルを用いて、in vivoにて上記の麻酔薬のケタミン、プロポフォールを長期に投与し、病理学的な検討を行い、in vitroで得られた結果を確認したいと考えている。
  • The study of the effects of general anesthetics on ion-channels using Xenopus-oocytes.
    日本学術振興会:海外の中核的研究拠点への派遣研究
    Date (from‐to) : 1995 
    Author : 南浩一郎
  • 全身麻酔薬のカテコールアミン分泌及びイオンチャンネルに対する作用の解析
    産業医科大学:産業医科大学 産業医学促進研究助成
    Date (from‐to) : 1994 
    Author : 南 浩一郎


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