Volatile Anesthetic Actions on Contractile Proteins in Membrane-permeabilized Small Mesenteric Arteries


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Abstract

BackgroundVolatile 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.MethodsWith 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 Potassium sup + -induced contractions at 22 degrees Celsius and 35 degrees Celsius. All experiments were performed on endothelium-denuded strips in the presence of 3 micro Meter guanethidine and 0.3 micro Meter 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 Calcium2+ -activated contractions were examined at 22 degrees Celsius in the presence of 0.3 micro Meter ionomycin to eliminate intracellular Calcium sup 2+ stores.ResultsIn the high Potassium sup + -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 Celsius 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 Celsius. Ryanodine (10 micro Meter) eliminated the anesthetic-induced contractions but had no significant effect on the anesthetic-induced vasorelaxation in the presence of high Potassium sup +. 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 Calcium sup 2+ -tension relation in the membrane-permeabilized muscle yielded a half-maximal effective Calcium2+ concentration (EC50) of 2.02 micro Meter. Halothane modestly but significantly inhibited 3 micro Meter (approximately the EC50) and 30 micro Meter (maximal) Calcium sup 2+ -induced contractions. Enflurane slightly but significantly inhibited 3 micro Meter but not 30 micro Meter Calcium2+ contractions. Isoflurane did not significantly inhibit either 3 micro Meter or 30 micro Meter Calcium2+ contractions.ConclusionsHalothane, isoflurane, and enflurane have both vasoconstricting and vasodilating actions on isolated small splanchnic resistance arteries. The direct vasoconstricting action appears to result from Calcium2+ release from the ryanodine-sensitive intracellular Calcium2+ store. The vasodilating action of isoflurane in the presence of high Potassium sup + appears to be attributable mainly to a decrease in intracellular Calcium2+ concentration, possibly resulting from inhibition of voltage-gated Calcium2+ channels. In contrast, the vasodilating actions of halothane and enflurane in the presence of high Potassium sup + appears to involve inhibition of Calcium2+ activation of contractile proteins as well as a decrease in intracellular Calcium2+ concentration in smooth muscle.

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