EFFECTS OF VOLATILE ANESTHETICS ON ACETYLCHOLINE-INDUCED RELAXATION IN THE RABBIT MESENTERIC RESISTANCE ARTERY

Background: Vascular endothelium plays an important role in the regula tion of vascular tone. Volatile anesthetics have been shown to attenua te endothelium-mediated relaxation in conductance arteries, such as ao rta. However, significant differences in volatile anesthetic pharmacol ogy between these large vessels and the small vessels that regulate sy stemic vascular resistance and blood flow have been documented, yet li ttle is known about volatile anesthetic action on endothelial function in resistance arteries. Furthermore, endothelium-dependent relaxation mediated by factors other than endothelium-derived relaxing factor (E DRF) has recently been recognized, and there is no information availab le regarding volatile anesthetic action on non-EDRF-mediated endotheli um-dependent relaxation. Methods: Employing isometric tension recordin g and microelectrode methods, the authors first characterized the endo thelium-dependent relaxing and hyperpolarizing actions of acetylcholin e (ACh) in rabbit small mesenteric arteries, and tested the sensitivit ies of these actions to EDRF pathway Inhibitors and K+ channel blocker s. They then examined the effects of the volatile anesthetics isoflura ne, enflurane, and sevoflurane on ACh-induced endothelium-dependent re laxation that was sensitive to EDRF inhibitors and that which was resi stant to the EDRF inhibitors but sensitive to blockers of ACh-induced hyperpolarization. The effects of the volatile anesthetics on endothel ium-independent sodium nitroprusside (SNP)-induced relaxation were als o studied. Results: Acetylcholine concentration-dependently caused bot h endothelium-dependent relaxation and hyperpolarization of vascular s mooth muscle. The relaxation elicited by low concentrations of ACh (le ss than or equal to 0.1 mu M) was almost completely abolished by the E DRF inhibitors N-G-nitro L-arginine (LNNA), oxyhemoglobin (HbO(2)), an d methylene blue (MB), The relaxation elicited by higher concentration s of ACh (greater than or equal to 0.3 mu M) was only attenuated by th e EDRF inhibitors. The remaining relaxation, as well as the ACh-induce d hyperpolarization that was also resistant to EDRF inhibitors, were b oth specifically blocked by tetraethylammonium (TEA greater than or eq ual to 10 mM). Sodium nitroprusside, a NO donor, produced dose-depende nt relaxation, but not hyperpolarization, in the endothelium-denuded ( E[-]) strips, and the relaxation was inhibited by MB and HbO(2), but n ot TEA (greater than or equal to 10 mM). One MAC isoflurane, enflurane , and sevoflurane inhibited both ACh relaxation that was sensitive to the EDRF inhibitors and the ACh relaxation resistant to the EDRF inhib itors and sensitive to TEA, but not SNP relaxation (in the E[-] strips ). An additional finding was that the anesthetics all significantly in hibited norepinephrine (NE) contractions in the presence and absence o f the endothelium or after exposure to the EDRF inhibitors. Conclusion s: The results confirm that ACh has a hyperpolarizing action in rabbit small mesenteric resistance arteries that is independent of EDRF inhi bitors but blocked by the K+ channel blocker TEA. The ACh relaxation i n these resistance arteries thus appears to consist of distinct EDRF-m ediated and hyperpolarization-mediated components. Isoflurane, enflura ne, and sevoflurane inhibited both components of the ACh-induced relax ation in these small arteries, indicating a more global depression of endothelial function or ACh signaling in endothelial cells, rather tha n a specific effect on the EDRF pathway. All these anesthetics exerted vasodilating action in the presence of NE, the primary neurotransmitt er of the sympathetic nervous system, which plays a major role in main taining vasomotor tone in vivo. This strongly indicates that the vasod ilating action of these anesthetics probably dominates over their inhi bitory action on the EDRF pathway and, presumably, contributes to thei r known hypotensive effects in vivo. Finally, the vasodilating action of these anesthetics is, at least in part, independent from endotheliu m.