Mechanisms of inhibition by volatile anesthetics on beta-adrenoceptor-mediated relaxation in the vascular smooth muscle

本研究旨在确定挥发性麻醉药氟烷和异氟烷是否抑制β -肾上腺素受体介导的反应，以及哪些信号转导步骤对于抑制作用是重要的。我们发现在临床相关浓度下使用的挥发性麻醉剂可以干扰β -肾上腺素能受体激动剂异丙肾上腺素介导的反应。氟烷和异氟烷损害了异丙肾上腺素诱导的血管舒张和细胞内Ca^<2+>浓度的下降（[Ca^<2+>]i），而它们仅轻微影响腺苷酸环化酶激活剂forskolin和膜渗透性环AMP dbcAMP诱导的血管舒张。这一发现与另外的结果一致，即两种麻醉剂都抑制异丙肾上腺素诱导的环AMP含量的增加，而不是福斯克林诱导的。此外，两种药物都不会干扰β -肾上腺素能受体的配体结合特性。这些结果表明，氟烷和异氟烷主要干扰β -肾上腺素受体介导的β -肾上腺素受体和腺苷酸环化酶之间的反应；因此，逻辑位点应该包含g蛋白。除了β -肾上腺素能-环AMP系统介导的血管松弛外，我们还研究了氟烷对一氧化氮(NO)-环GMP系统介导的血管松弛的影响。我们使用硝酸甘油作为一氧化氮供体。我们发现氟烷以浓度依赖性的方式干扰硝酸甘油诱导的血管松弛。此外，氟烷的抑制作用由[Ca^<2+>]i依赖性和[Ca^<2+>]非依赖性机制共同控制。

This study was designed to determine whether the volatile anesthetics halothane and isoflurane inhibit beta-adrenoceptor-mediated responses, and which signal transduction steps are important for the inhibition if they do. We found that the volatile anesthetics used at clinically relevant concentrations can interfere with responses mediated by the beta-adrenoceptor agonist, isoproterenol. Halothane and isoflurane impaired isoproterenol-induced vasodilation and a decline of cytosolic concentrations of Ca^<2+> ([Ca^<2+>]i), whereas they only slightly affected vasodilation induced by the adenylyl cyclase activator, forskolin, and the membrane-permeable cyclic AMP, dbcAMP.This finding is consistent with the additional result that both anesthetics inhibited isoproterenol-induced, but not forskolin-induced, increases in cyclic AMP contents. Furthermore, both agents did not interfere with the ligand-binding property to the beta-adrenoceptor. These results indicate that halothane and isoflurane predominantly interfere with beta-adrenoceptor-mediated responses at the step between the beta-adrenoceptor and adenylyl cyclase ; the logical site would therefore include Gproteins.In addition to the vasorelaxation mediated by the beta-adrenoceptor-cyclic AMP system, we also investigated the effect of halothane on the vasorelaxation mediated by the nitric oxide (NO)-cyclic GMP system. We used nitroglycerin as a NO donor. We found that halothane interfered with nitroglycerin-induced vasorelaxation in a concentration-dependent fashion. Furthermore, halothane's inhibition was govemed by both [Ca^<2+>]i-dependent and [Ca^<2+>]i-independent mechanisms.