INHALATION ANESTHETICS INHIBIT THE RELEASE OF ENDOTHELIUM-DERIVED HYPERPOLARIZING FACTOR IN THE RABBIT CAROTID-ARTERY

Background: Inhalation anesthetics may interfere with the synthesis or action of endothelium-derived vasoactive factors. We investigated the effects of desflurane, enflurane, halothane, isoflurane, and sevoflur ane on the release of nitric oxide and endothelium-derived hyperpolari zing factor (EDHF) in the isolated endothelium-intact carotid artery o f the rabbit. Methods: Isolated segments of the carotid artery were su spended in Krebs-Henseleit solution (37 degrees C) and preconstricted with phenylephrine (1 mu M). Relaxations caused by acetylcholine 0(ACh ) (0.03-10 mu M) or sodium nitroprusside (0.01-10 mu M) were compared in the presence or absence of the nitric oxide synthase inhibitor N-G- nitro-L-arginine (0.1 mM) in segments exposed to desflurane (8%), enfl urane (2-4%), halothane (2-3.5%), isoflurane (2-4%), or sevoflurane (2 %) as web as in N-G-nitro-L-arginine-tieated segments exposed to enflu rane (2%) in combination with the K-Ca(+)-channel blocker tetrabutylam monium (0.3 mar) or the cytochrome P450 inhibitor clotrimazole (3 mu M ). Results: Desflurane, enflurane, and sevoflurane selectively inhibit ed the ACh-induced release of EDHF. Halothane and isoflurane also weak ly affected the nitric oxide-mediated relaxant response to ACh. The in hibitory effect of these two anesthetics on EDHF release was concentra tion-dependent. Relaxations induced by sodium nitroprusside were not i nhibited by any of the anesthetics tested. Three structurally unrelate d cytochrome P450 inhibitors clotrimazole (0.1 mar), metyrapone (1 mM) , and SKF525a (proadifen, 0.1 mM) abolished the EDHF-mediated relaxati on elicited by ACh. The pharmacologic profile of the inhibitory effect of enflurane on the release of EDHF closely resembled that of clotrim azole but not that of tetrabutylammonium. Moreover, all anesthetics in hibited the cytochrome P450-catalyzed O-dealkylation of 7-ethoxycoumar in by rabbit Liver microsomes in a concentration-dependent manner. Con clusions: Inhalation anesthetics significantly attenuate the EDHF-medi ated relaxant response to ACh in the rabbit carotid artery. This effec t appears to be attributable to inhibition of the cytochrome P450-depe ndent synthesis of EDHF by the endothelium.