VOLATILE ANESTHETIC ACTIONS OUT CONTRACTILE PROTEINS IN MEMBRANE-PERMEABILIZED SMALL MESENTERIC-ARTERIES

Background: Volatile anesthetics have been shown to have vasodilating or vasoconstricting actions in vitro that may contribute to their card iovascular effects in vivo. However, the precise mechanisms of these a ctions 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 b lood pressure and blood flow. Methods: With the use of isometric tensi on recording methods, volatile anesthetic actions were studied in inta ct and beta escin-membrane-permeabilized smooth muscle strips from rat small mesenteric arteries. In experiments with intact muscle, the eff ects of halothane (0.25-5.0%), isoflurane (0.25-5.056), and enflurane (0.25-5.0%) were investigated on high K+-induced contractions at 22 de grees C and 35 degrees C. All experiments were performed on endotheliu m-denuded strips in the presence of 3 pni guanethidine and 0.3 mu M te trodotoxin to minimize the influence of nerve terminal activities, In experiments with membrane-permeabilized muscle, the effects of halotha ne (0.5-4.0%), isonurane (0.5-4.0%), and enflurane (0.5-4.0%) on the h alf-maximal and maximal Ca2+-activated contractions were examined at 2 2 degrees C.in the presence of 0.3 mu M ionomycin to eliminate intrace llular Ca2+ stores. Results: In the high K+-stimulated intact muscle, all three anesthetics generated transient contractions, which were fol lowed by sustained vasorelaxation. The IC50 values for this vasorelaxi ng 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 2 2 degrees C and were 3.36 vol% (0.99 mM), 3.07 vol% (0.69 mM), and 3.1 9 vol% (0.95 mM), respectively, at 35 degrees C. Ryanodine (10 mu M) e liminated the anesthetic-induced contractions but had no significant e ffect 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. H owever, significant differences were observed in the vasoconstricting actions among the anesthetics, and the order of potency was halothane > enflurane > isoflurane. The Ca2+-tension relation in the membrane-pe rmeabilized muscle yielded a half-maximal effective Ca2+ concentration (EC(50)> of 2.02 mu M. Halothane modestly but significantly inhibited 3 mu M (approximately the EC(50)) and 30 mu M (maximal) Ca2+-induced contractions. Enflurane slightly but significantly inhibited 3 mu M bu t not 30 mu M Ca2+ contractions. Isoflurane did not significantly inhi bit either 3 mu M or 30 mu M Ca2+ contractions. Conclusions: Halothane , isoflurane, and enflurane have both vasoconstricting and vasodilatin g actions on isolated small splanchnic resistance arteries. The direct vasoconstricting ac tion 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 m ainly to a decrease in intracellular Ca2+ concentration, possibly resu lting from inhibition of voltage-gated Ca2+ channels. In contrast, the vasodilating actions of halothane and enflurane in the presence of hi gh K+ appears to involve inhibition of Ca2+ activation of contractile proteins as well as a decrease in intracellular Ca2+ concentration in smooth muscle.