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 part 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 metabolite of arachidonic acid. By using isometric tension measurements on rat main mesenteric arteries, the influence of four structurally and mechanistically different cytochrome P-450 inhibitors (proadifen, miconazole, 1-amino-benzotriazole, and 17-octadecynoic acid) was investigated on relaxations elicited by EDHF, assessed as the nitro-L-arginine-resistant component of acetylcholine-induced relaxation, and on relaxations provoked by the endothelium-independent potassium channel opener cromakalim. Proadifen (30 microM) inhibited the EDHF- as well as the cromakalim-induced relaxation, but not that elicited by nitroprusside. Also miconazole (30 microM) inhibited both the EDHF and the cromakalim-induced relaxation. On the other hand, 17-octadecynoic acid (5 microM) had no influence, and 1-aminobenzotriazole (1 mM) even potentiated EDHF- and cromakalim-induced relaxations. We conclude that the EDHF, released from the rat mesenteric artery by acetylcholine, is unlikely to be a cytochrome P-450-dependent monooxygenase metabolite of arachidonic acid and that proadifen and miconazole interfere with the action of cromakalim.
Van de Voorde
J
J
Department of Physiology and Physiopathology, University of Ghent, Belgium.
Vanheel
B
B
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001685:Biological Factors / Q000494:pharmacology*; D019806:Cromakalim; D065607:Cytochrome P-450 Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000187:drug effects; D008825:Miconazole / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019335:Nitroarginine / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014230:Triazoles / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D001685:Biological Factors; D065607:Cytochrome P-450 Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D011758:Pyrroles; D014230:Triazoles; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D019806:Cromakalim; C033020:1-aminobenzotriazole; D019335:Nitroarginine; C047008:17-octadecynoic acid; D008825:Miconazole; D011335:Proadifen; D000109:Acetylcholine; D009638:Norepinephrine