INHIBITORS OF THE CYTOCHROME P450-MONO-OXYGENASE AND ENDOTHELIUM-DEPENDENT HYPERPOLARIZATIONS IN THE GUINEA-PIG ISOLATED CAROTID-ARTERY

1 Transmembrane potentials were recorded from isolated carotid arterie s of the guinea-pig superfused with modified Krebs-Ringer bicarbonate solution. Smooth muscle cells were impaled with sharp intracellular mi croelectrodes. 2 Acetylcholine (1 mu M) induced an endothelium-depende nt hyperpolarization (14.3 +/- 2.8 mV, n = 6) which was not affected ( 15.1 +/- 1.1 mV, n = 35) by inhibitors of cyclo-oxygenase (indomethaci n, 5 mu M) and nitric oxide synthase (N(w)nitro-L-arginine:L-NOARG, 10 0 mu M). 3 The hyperpolarization produced by acetylcholine was abolish ed in the presence of elevated potassium (35 mM) in the superfusing ph ysiological saline solution. 4 The acetylcholine-induced hyperpolariza tion was not affected by the inhibitors of cytochrome P450 mono-oxygen ases, SKF525a (10 and 100 mu M, 13.9 +/- 2.2 and 15.3 +/- 4.6 mV), met yrapone (100 mu M, 13.1 +/- 1.9 mV), clotrimazole (100 mu M, 13.5 +/- 2.7 mV), 17-octadecynoic acid (5 mu M, 16.5 +/- 1.9 mV), methoxsalen ( 10 mu M, 15.3 +/- 1.6 mV), the inhibitor of phospholipase A(2) quinacr ine (10 mu M 12.8 +/- 2.5 mV) and the non specific lipoxygenases/cyclo -oxygenases/cytochrome P450 inhibitor, eicosatetraynoic acid (50 mu M, 15.0 +/- 2.2 mV). However, the muscarinic antagonist, atropine (100 n M), abolished the hyperpolarization. 5 These results suggest that in g uinea-pig carotid artery, the metabolism of arachidonic acid, either t hrough cyclo-oxygenase, lipoxygenase or cytochrome p450 mono-oxygenase , is not involved in acetylcholine-induced endothelium-dependent hyper polarizations.