| Project/Area Number |
03454369
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
麻酔学
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| Research Institution | Hokkaido University |
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Principal Investigator |
YAMAMURA Takeyasu (1992) MD,PhD Hokkaido University School of Medicine Department of anesthesiology Associate Professor, 医学部, 助教授 (40041842)
大野 幹夫 (1991) 北海道大学, 医学部附属病院, 助手 (70160588)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAO Yasuo MD,PhD Hokkaido University School of Medicine Department of anesthesiology, Inst, 医学部・附属病院, 助手 (30237218)
古御堂 均 北海道大学, 医学部附属病院, 助手 (10181463)
佐藤 賢一 北海道大学, 医学部, 助手 (70170743)
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| Project Period (FY) |
1991 – 1992
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| Project Status |
Completed (Fiscal Year 1992)
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| Budget Amount *help |
¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 1992: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1991: ¥4,700,000 (Direct Cost: ¥4,700,000)
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| Keywords | Volatile anesthetics / Synaptic Transmission / Transmitters / Ion Channel / General anesthetics / Second Messenger System / 脳スライス標本 / グルタミン酸受容体 / シナプス / ヤツメウナギ神経細胞 |
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| Research Abstract |
Behavioral anesthetic effects of halothane were compared with neurophysiological data obtained from monosynaptically coupled single axongiant neuron pairs in the isolated central nervous system of the lamprey in vitro. Based on the assumption that the number of halothane molecules at the site of anesthetic action is determined by molar concentration of the bath, depths of anesthesia were characterized in terms of synaptic events. The concentration producing anesthesia in 50% (AC_<50>) and 95% (AC_<95>) of the animals were 0.32 and 0.51 mM, respectively. With these concentrations, the depression of glutamate (GLUT)-mediated synaptic excitation remained less than 50%.
Maximum suppression of the excitatory synaptic transmission was observed in the presence of 1.7 mM halothane which would be equivalent to the inhalation of 5.5% of this agent at 37ﾟC.At these concentrations, postsynaptic membranes did not respond to the bath-applied GLUT agonists. The decrease of agonist-induced responses to
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almost the same extent as excitatory postsynaptic potential (EPSP) amplitudes in the presence of halothane argues against a presynaptic mechanism affecting transmitter release. Persistent voltage-gated Na^+-channel function at concentrations less than 2.4mM is an evidence against the involvement of this mechanism at these levels of anesthesia. The present results suggest that with depths between AC_<50> and AC_<95>, anesthesia is associated with a partial reduction of sensitivity of the postsynaptic membrane to the excitatory amino acid transmitters.
Depressant effects of volatile anesthetics on inositol trisphosphate (IP_3)-mediated signal transduction pathway were studied in order to identify the site of the action. For this, we used Xenopus laevis oocytes which translated and expressed 5-HT receptors after injection of mRNA isolated from the rat brain. In this system, binding of the agonist go G-protein coupled receptors activates phospholipase C which produces IP3. Mobilization of Ca^<2+> by IP_3 from the storage finally opens Ca^<2+> dependent Cl^- channels.
Halothane, isoflurane and methoxyflurane depressed Cl^- current elicited by 5-HT.For the further quantitative study, methoxyflurane was used because of its better solubility and less vapor pressure which avoided evapolation of the agent. The 5-HT elicited Cl^- current was depressed in a non-competitive fashin. The response was 80,60,20% of control in the presence of 0.5,1 and 3mM methoxyflurane, respectively. Responses elicited by a pressure-injection of Ca^<2+> or IP3 remained unchanged in the presence of very high concentrations of halothane, isoflurane or methoxyflurane. These results suggested that the depressant mechanism by volatile anesthetics on the signal transduction pathway involved neither Ca^<2+> dependent Cl^- channel dynamics nor intracellular Ca^<2+> mobilization by IP3. Changes of microdomain characteristics of the membrane in the presence of anesthetic molecules including membrane-bound proteins and enzyme system may be a main site of action of volatile anesthetics. Less
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