Endothelium-dependent hyperpolarization and cytochrome p450 monooxygenases (P450) inhibitors

Abstract

Endothelium-dependent hyperpolarization of vascular smooth muscle has been attributed to metabolites of arachidonic acid via the P450 pathway. The purpose of this work was to study various chemically unrelated inhibitors of P450 on endothelium-dependent hyperpolarizations. Transmembrane potentials were recorded in isolated guinea-pig carotid arteries impaled with glass microelectrodes from the adventitial side, in the presence of inhibitors of cyclooxygenase and NOsynthase. Acetylcholine induced endothelium-dependent hyperpolarizations which were abolished by elevated K+ concentration (30 mM) or by the presence of inhibitors of Ca2+-dependent K+ channels (charybdotoxin plus apamin). Various inhibitors of P450 (SKF525a, tnetyrapone, clotrimazole, 17-octadecynoic acid, methoxsalen), an inhibitor of phospholipase A2 (quinacrine) and a nonselective inhibitor of cyclooxygenase/lipoxygenase/P450 (eicosatetraynoic acid) did not affect significantly the acetylcholineinduced hyperpolarizations. These results indicate that, in the carotid artery of the guinea-pig, acetylcholine induced an endotheliumdependent hyperpolarization which involves the opening of Ca2+-dependent K+ channels. The metabolism of arachidonic acid through the P450 pathway does not seem to be involved.