Terasako K, Nakamura K, Miyawaki I, Toda H, Kakuyama M, Mori K
Department of Anesthesia, Kyoto University Hospital, Japan.
Anesth Analg. 1994 Nov;79(5):921-6. doi: 10.1213/00000539-199411000-00018.
General anesthetics, including halothane, isoflurane, and barbiturates, suppress endothelium-dependent formation of 3',5'-cyclic guanosine monophosphate (cGMP) in the systemic and cerebral vasculature. The present study was conducted to determine whether these anesthetics have similar effects on the nitric oxide (NO)-cGMP system in the brain, and to elucidate the mechanism responsible. In rat cerebellar slices, formation of cGMP was suppressed by halothane after stimulation by N-methyl-D-aspartate (NMDA, 0.1 mM) and D-aspartate (1.0 mM) but not after stimulation by sodium nitroprusside (SNP, 0.3 mM). Isoflurane (2%) suppressed NMDA (0.1 mM)-stimulated, but not D-aspartate (1.0 mM)- and nitroprusside (0.3 mM)-stimulated formation of cGMP. In contrast, thiopental (0.1-1.0 mM) suppressed NMDA (0.1 mM)-, D-aspartate (1.0 mM)-, and nitroprusside (0.3 mM)-stimulated formation of cGMP. Treatment with aminophylline (0.1 mM), a phosphodiesterase inhibitor, did not influence the effect of thiopental, suggesting that the effect of thiopental was not mediated by activation of phosphodiesterase. D-Aspartate increases intracellular calcium, which in turn activates NO synthase, and nitroprusside generates NO without activation of NO synthase. Therefore, the present findings strongly suggest that halothane inactivates NO synthase (or related cofactors) without marked interaction with the NMDA receptor, that isoflurane may interact with the NMDA receptor, receptor-coupled G-protein, or calcium channels, and that thiopental suppresses guanylate cyclase activity.
包括氟烷、异氟烷和巴比妥类药物在内的全身麻醉药，会抑制全身和脑血管系统中内皮依赖性3',5'-环鸟苷单磷酸（cGMP）的形成。本研究旨在确定这些麻醉药对大脑中一氧化氮（NO）-cGMP系统是否有类似作用，并阐明其作用机制。在大鼠小脑切片中，氟烷在N-甲基-D-天冬氨酸（NMDA，0.1 mM）和D-天冬氨酸（1.0 mM）刺激后可抑制cGMP的形成，但在硝普钠（SNP，0.3 mM）刺激后则不会。异氟烷（2%）可抑制NMDA（0.1 mM）刺激引起的cGMP形成，但对D-天冬氨酸（1.0 mM）和硝普钠（0.3 mM）刺激引起的cGMP形成无抑制作用。相比之下，硫喷妥钠（0.1 - 1.0 mM）可抑制NMDA（0.1 mM）、D-天冬氨酸（1.0 mM）和硝普钠（0.3 mM）刺激引起的cGMP形成。用磷酸二酯酶抑制剂氨茶碱（0.1 mM）处理并不影响硫喷妥钠的作用，这表明硫喷妥钠的作用不是由磷酸二酯酶的激活介导。D-天冬氨酸可增加细胞内钙，进而激活一氧化氮合酶，而硝普钠可在不激活一氧化氮合酶的情况下产生NO。因此，本研究结果强烈表明，氟烷可使一氧化氮合酶（或相关辅助因子）失活，而与NMDA受体无明显相互作用；异氟烷可能与NMDA受体、受体偶联的G蛋白或钙通道相互作用；硫喷妥钠可抑制鸟苷酸环化酶活性。
