Nonhalogenated alkane anesthetics fail to potentiate agonist actions on two ligand-gated ion channels
Nonhalogenated alkane anesthetics fail to potentiate agonist actions on two ligand-gated ion channels
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DOI：
10.1097/00000542-200108000-00032
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发表时间：
2001-08-01
期刊：
影响因子：
8.8
通讯作者：
Forman, SA
中科院分区：
文献类型：
--
作者：
Raines, DE;Claycomb, RJ;Forman, SA
背景资料。尽管乙醚、乙醇和卤代烷烃麻醉剂在临床相关浓度下可增强配体门控离子通道的激动剂作用或增加其表观的激动剂亲和力，但非平衡烷烃麻醉剂对配体门控离子通道的影响尚未被研究。目前的研究评估了两个具有代表性的非卤化能力。烷基麻醉剂(环丙烷和丁烷)，以增强激动剂的作用或增加两个典型的配基门控离子通道的表观激动剂亲和力：烟碱型乙酰胆碱受体和γ-氨基丁酸A型(GABA(A))受体。烟碱型乙酰胆碱受体从鱼雷电浆器官中获得，人GABA受体(α(1)、β(2)、γ(21))在人胚胎肾293细胞中表达。通过测量一系列乙酰胆碱浓度引起的表观脱敏速率，评估了在麻醉剂存在和不存在的情况下，鱼雷烟碱受体表观激动剂的亲和力。通过测量不同浓度的GABA诱导的峰值电流，评估在麻醉剂存在和不存在的情况下，GABA(A)受体的表观激动剂亲和力。环丙烷和丁烷都不能增强鱼雷烟碱型乙酰胆碱受体或GABA(A)受体的激动剂作用或增加其表观激动剂亲和力(降低表观激动剂解离常数)。在临床相关浓度下，环丙烷和丁烷可降低低浓度激动剂诱导的鱼雷烟碱型乙酰胆碱受体脱敏的表现率。我们的结果表明，非卤代烷类麻醉剂在体内的中枢神经系统抑制作用不是由于它们增强了配体门控离子通道上的激动剂作用。其他靶点或机制更可能解释非卤代烷类麻醉剂的麻醉活性。
Background. Although ether, alcohol, and halogenated alkane anesthetics potentiate agonist actions or increase the apparent agonist affinity of ligand-gated ion channels at clinically relevant concentrations, the effects of nonbalogenated alkane anesthetics on ligand-gated ion channels have not been studied. The current study assessed the abilities of two representative nonhalogenated. alkane anesthetics (cyclopropane and butane) to potentiate agonist actions or increase the apparent agonist affinity of two representative ligand-gated ion channels: the nicotinic acetylcholine receptor and gamma -aminobutyric acid type A (GABA(A)) receptor.Methods. Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana, and human GABA, receptors (alpha (1)beta (2)gamma (21)) were expressed in human embryonic kidney 293 cells. The Torpedo nicotinic acetylcholine receptors apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the apparent rates of desensitization induced by a range of acetylcholine concentrations. The GABA(A), receptor's apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the peak currents induced by a range of GABA concentrations.Results. Neither cyclopropane nor butane potentiated agonist actions or increased the apparent agonist affinity (reduced the apparent agonist dissociation constant) of the Torpedo nicotinic acetylcholine receptor or GABA(A) receptor. At clinically relevant concentrations, cyclopropane and butane reduced the apparent rate of Torpedo nicotinic acetylcholine receptor desensitization induced by low concentrations of agonist.Conclusions. Our results suggest that the in vivo central nervous system depressant effects of nonhalogenated alkane anesthetics do not result from their abilities to potentiate agonist actions on ligand-gated ion channels. Other targets or mechanisms more likely account for the anesthetic activities of nonhalogenated alkane anesthetics.