INFLUENCE OF CYTOCHROME-P-450 INHIBITORS ON ENDOTHELIUM-DEPENDENT NITRO-L-ARGININE-RESISTANT RELAXATION AND CROMAKALIM-INDUCED RELAXATION IN RAT MESENTERIC-ARTERIES

In several blood vessels, endothelium-dependent vasorelaxation is in p art mediated by an endothelium-derived hyperpolarizing factor (EDHF), the nature of which is as yet unknown. However, some evidence suggests that EDHF might be a cytochrome P-450-dependent monooxygenase metabol ite of arachidonic acid. By using isometric tension measurements on ra t main mesenteric arteries, the influence of four structurally and mec hanistically different cytochrome P-450 inhibitors (proadifen, miconaz ole, I-amino-benzotriazole, and 17-octadecynoic acid) was investigated on relaxations elicited by EDHF, assessed as the nitro-L-arginine-res istant component of acetylcholine-induced relaxation, and on relaxatio ns provoked by the endothelium-independent potassium channel opener cr omakalim. Proadifen (30 mu M) inhibited the EDHF- as well as the croma kalim-induced relaxation, but not that elicited by nitroprusside. Also miconazole (30 mu M) inhibited both the EDHF and the cromakalim-induc ed relaxation. On the other hand, 17-octadecynoic acid (5 mu M) had no influence, and 1-aminobenzotriazole (1 mM) even potentiated EDHF- and cromakalim-induced relaxations. We conclude that the EDHF released fr om the rat mesenteric artery by acetylcholine, is unlikely to be a cyt ochrome P-450-dependent monooxygenase metabolite of arachidonic acid a nd that proadifen and miconazole interfere with the action of cromakal im.