Akata T, Boyle W A
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110-1093.
Anesthesiology. 1995 Mar;82(3):700-12. doi: 10.1097/00000542-199503000-00012.
Volatile anesthetics have been shown to have vasodilating or vasoconstricting actions in vitro that may contribute to their cardiovascular effects in vivo. However, the precise mechanisms of these actions in vitro have not been fully elucidated. Moreover, there are no data regarding the mechanisms of volatile anesthetic action on small resistance arteries, which play a critical role in the regulation of blood pressure and blood flow.
With the use of isometric tension recording methods, volatile anesthetic actions were studied in intact and beta-escin-membrane-permeabilized smooth muscle strips from rat small mesenteric arteries. In experiments with intact muscle, the effects of-halothane (0.25-5.0%), isoflurane (0.25-5.0%), and enflurane (0.25-5.0%) were investigated on high K(+)-induced contractions at 22 degrees C and 35 degrees C. All experiments were performed on endothelium-denuded strips in the presence of 3 microM guanethidine and 0.3 microM tetrodotoxin to minimize the influence of nerve terminal activities. In experiments with membrane-permeabilized muscle, the effects of halothane (0.5-4.0%), isoflurane (0.5-4.0%), and enflurane (0.5-4.0%) on the half-maximal and maximal Ca(2+)-activated contractions were examined at 22 degrees C in the presence of 0.3 microM ionomycin to eliminate intracellular Ca2+ stores.
In the high K(+)-stimulated intact muscle, all three anesthetics generated transient contractions, which were followed by sustained vasorelaxation. The IC50 values for this vasorelaxing action of halothane, isoflurane, and enflurane were 0.47 vol% (0.27 mM), 0.66 vol% (0.32 mM), and 0.53 vol% (0.27 mM), respectively, at 22 degrees C and were 3.36 vol% (0.99 mM), 3.07 vol% (0.69 mM), and 3.19 vol% (0.95 mM), respectively, at 35 degrees C. Ryanodine (10 microM) eliminated the anesthetic-induced contractions but had no significant effect on the anesthetic-induced vasorelaxation in the presence of high K+. In addition, no significant differences were observed in the dose dependence of the direct vasodilating action among these anesthetics with or without ryanodine at either the low or the high temperature. However, significant differences were observed in the vasoconstricting actions among the anesthetics, and the order of potency was halothane > enflurane > isoflurane. The Ca(2+)-tension relation in the membrane-permeabilized muscle yielded a half-maximal effective Ca2+ concentration (EC50) of 2.02 microM. Halothane modestly but significantly inhibited 3 microM (approximately the EC50) and 30 microM (maximal) Ca(2+)-induced contractions. Enflurane slightly but significantly inhibited 3 microM but not 30 microM Ca2+ contractions. Isoflurane did not significantly inhibit either 3 microM or 30 microM Ca2+ contractions.
Halothane, isoflurane, and enflurane have both vasoconstricting and vasodilating actions on isolated small splanchnic resistance arteries. The direct vasoconstricting action appears to result from Ca2+ release from the ryanodine-sensitive intracellular Ca2+ store. The vasodilating action of isoflurane in the presence of high K+ appears to be attributable mainly to a decrease in intracellular Ca2+ concentration, possibly resulting from inhibition of voltage-gated Ca2+ channels. In contrast, the vasodilating actions of halothane and enflurane in the presence of high K+ appears to involve inhibition of Ca2+ activation of contractile proteins as well as a decrease in intracellular Ca2+ concentration in smooth muscle.
挥发性麻醉药在体外已显示出血管舒张或血管收缩作用，这可能是其在体内产生心血管效应的原因。然而，这些体外作用的确切机制尚未完全阐明。此外，关于挥发性麻醉药对小阻力动脉作用机制的数据尚无，而小阻力动脉在血压和血流调节中起关键作用。
采用等长张力记录方法，在大鼠小肠系膜动脉完整及经β-七叶皂苷膜通透化的平滑肌条上研究挥发性麻醉药的作用。在完整肌肉实验中，研究了22℃和35℃时氟烷（0.25 - 5.0%）、异氟烷（0.25 - 5.0%）和恩氟烷（0.25 - 5.0%）对高钾诱导收缩的影响。所有实验均在内皮剥脱条上进行，同时加入3μM胍乙啶和0.3μM河豚毒素，以尽量减少神经末梢活动的影响。在膜通透化肌肉实验中，在22℃、存在0.3μM离子霉素以消除细胞内钙库的条件下研究氟烷（0.5 - 4.0%）、异氟烷（0.5 - 4.0%）和恩氟烷（0.5 - 4.0%）对半数最大和最大钙激活收缩的影响。
在高钾刺激的完整肌肉中，所有三种麻醉药均产生短暂收缩，随后是持续的血管舒张。氟烷、异氟烷和恩氟烷这种血管舒张作用的半数抑制浓度（IC50）在22℃时分别为0.47体积%（0.27 mM）、0.66体积%（0.32 mM）和0.53体积%（0.27 mM），在35℃时分别为3.36体积%（0.99 mM）、3.07体积%（0.69 mM）和3.19体积%（0.95 mM）。Ryanodine（10μM）消除了麻醉药诱导的收缩，但在高钾存在时对麻醉药诱导的血管舒张无显著影响。此外，无论低温还是高温，在有或没有ryanodine的情况下，这些麻醉药直接血管舒张作用的剂量依赖性均未观察到显著差异。然而，在麻醉药的血管收缩作用之间观察到显著差异，其效能顺序为氟烷>恩氟烷>异氟烷。膜通透化肌肉中的钙-张力关系产生的半数有效钙浓度（EC50）为2.02μM。氟烷适度但显著抑制3μM（约为EC50）和30μM（最大）钙诱导的收缩。恩氟烷轻微但显著抑制3μM钙收缩，但不抑制30μM钙收缩。异氟烷对3μM或30μM钙收缩均无显著抑制作用。
氟烷、异氟烷和恩氟烷对离体小肠内脏小阻力动脉既有血管收缩作用又有血管舒张作用。直接血管收缩作用似乎源于对ryanodine敏感的细胞内钙库释放钙。高钾存在时异氟烷的血管舒张作用似乎主要归因于细胞内钙浓度降低，可能是由于抑制电压门控钙通道所致。相比之下，高钾存在时氟烷和恩氟烷的血管舒张作用似乎涉及抑制收缩蛋白的钙激活以及平滑肌细胞内钙浓度降低。
