ETOMIDATE AND THIOPENTAL INHIBIT THE RELEASE OF ENDOTHELIUM-DERIVED HYPERPOLARIZING FACTOR IN THE HUMAN RENAL-ARTERY

Background: Endothelium-derived hyperpolarizing factor is thought to b e a cytochrome P450-derived arachidonic acid metabolite that hyperpola rizes vascular smooth muscle cells by opening Ca2+-activated K+ channe ls (K-Ca(+) channels), In the rabbit carotid artery both volatile and intravenous anesthetics inhibit the acetylcholine-stimulated release o f endothelium-derived hyperpolarizing factor. Because the release of t his factor may help to maintain vascular tone in humans under conditio ns of a failing nitric oxide synthesis, e.g,, in atherosclerosis, the effects of two intravenous anesthetics, thiopental and etomidate, on t he endothelium-derived hyperpolarizing factor-mediated relaxant respon se to acetylcholine were investigated in human isolated renal artery s egments, Methods: The segments were suspended in Krebs-Henseleit solut ion (37 degrees C) containing the cyclooxygenase inhibitor diclofenac (1 mu M) and preconstricted with norepinephrine (6 mu M). Relaxations caused by acetylcholine (1 mu M) were compared in the presence and abs ence of the nitric oxide synthase inhibitor N-G-nitro-L-arginine (0.1 mM) in control segments and in segments exposed to etomidate or thiope ntal (0.03-0.3 mM). In addition, the effects of the two anesthetics on the relaxant response to the nitric oxide donors glyceryl trinitrate (3 mu M) and sodium nitroprusside (0.1 mu M) were examined. Results: T he relaxant response to acetylcholine, which was resistant to both nit ric oxide synthase and cyclooxygenase blockade, was markedly reduced b y the K-Ca(+) channel antagonist tetrabutyl ammonium (3 mM) and the cy tochrome P450 inhibitor clotrimazole (30 mu M). Both etomidate and thi opental, at a concentration of 0.3 mM, selectively attenuated the rela xant response to acetylcholine in N-G-nitro-L-arginine-treated segment s, but did not affect relaxations elicited by glyceryl trinitrate or s odium nitroprusside. Conclusions: Etomidate and thiopental inhibit the endothelium-derived hyperpolarizing factor-mediated relaxant response to acetylcholine in the human renal artery, an effect that appears to be attributable to the cytochrome P450-inhibiting properties of these anesthetics.