Key result
Cytochrome P-450 inhibitors proadifen and miconazole inhibited EDHF- and cromakalim-induced relaxation in rat mesenteric arteries, suggesting EDHF is unlikely a cytochrome P-450 metabolite.
EDHF released from rat mesenteric arteries by acetylcholine is unlikely to be a cytochrome P-450-dependent monooxygenase metabolite of arachidonic acid.
Challenges P450 metabolite hypothesis for EDHF in rat vessels; leaves open its identity and relevance to human 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.
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Voorde et al. (1997) studied this question. Cytochrome P-450 inhibitors (proadifen, miconazole, 1-amino-benzotriazole, 17-octadecynoic acid) was evaluated on Relaxations elicited by EDHF and cromakalim. Cytochrome P-450 inhibitors proadifen and miconazole inhibited EDHF- and cromakalim-induced relaxation in rat mesenteric arteries, suggesting EDHF is unlikely a cytochrome P-450 metabolite.