RELAXANT RESPONSES OF RABBIT AORTA - INFLUENCE OF CYTOCHROME-P450 INHIBITORS

Based on the use of inhibitors, cytochrome P450 has been implicated in endothelium-dependent relaxant responses via metabolism of arachidoni c acid (AA). However, the contribution of cytochrome P450 and its AA m etabolites to the regulation of vascular tone has not been established due, in part, to questions of specificity of cytochrome P450 inhibito rs which have not been extensively characterized in terms of their vas cular effects. Consequently, we addressed the effects of several inhib itors on vasorelaxant responses of phenylephrine-contracted, rabbit, a ortic rings to agents that utilize different transduction mechanisms t o determine any actions unrelated to inhibition of cytochrome P450 and /or AA metabolism. Octadecynoic acid (2.5 and 5 mu M), a mechanism-bas ed inhibitor of cytochrome P450 metabolism of fatty acids, and eicosat etrayenoic acid (10 and 20 mu M), an inhibitor of AA metabolism, were without effect on vasorelaxant responses to acetylcholine, sodium nitr oprusside, isoproterenol and diazoxide. 7-Ethoxyresorufin (2-10 mu M), a substrate for cytochrome P450, and clotrimazole (2.5-10 mu M) which binds to the heme moiety of the enzyme, concentration-dependently red uced responses to acetylcholine but not the other agonists indicating an effect on nitric oxide synthesis although neither affected the conv ersion of L-arginine to L-citrulline by endothelial cells. SKF 525A (5 0-200 mu M), the prototypical inhibitor of cytochrome P450, which is m etabolized to an inhibitory intermediate, also reduced responses to ac etylcholine and, in addition, impaired the vasorelaxant activities of isoproterenol and diazoxide.