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 arteries of the guinea-pig superfused with modified Krebs-Ringer bicarbonate solution. Smooth muscle cells were impaled with sharp intracellular microelectrodes. 2. Acetylcholine (1 microM) induced an endothelium-dependent hyperpolarization (14.3 +/- 2.8 mV, n = 6) which was not affected (15.1 +/- 1.1 mV, n = 35) by inhibitors of cyclo-oxygenase (indomethacin, 5 microM) and nitric oxide synthase (N omega nitro-L-arginine: L-NOARG, 100 microM). 3. The hyperpolarization produced by acetylcholine was abolished in the presence of elevated potassium (35 mM) in the superfusing physiological saline solution. 4. The acetylcholine-induced hyperpolarization was not affected by the inhibitors of cytochrome P450 mono-oxygenases, SKF525a (10 and 100 microM, 13.9 +/ 2.2 and 15.3 +/- 4.6 mV), metyrapone (100 microM, 13.1 +/- 1.9 mV), clotrimazole (100 microM, 13.5 +/- 2.7 mV), 17-octadecynoic acid (5 microM, 16.5 +/- 1.9 mV), methoxsalen (10 microM, 15.3 +/- 1.6 mV), the inhibitor of phospholipase A2 quinacrine (10 microM 12.8 +/- 2.5 mV) and the non specific lipoxygenases/cyclo-oxygenases/cytochrome P450 inhibitor, eicosatetraynoic acid (50 microM, 15.0 +/- 2.2 mV). However, the muscarinic antagonist, atropine (100 nM), abolished the hyperpolarization. 5. These results suggest that in guinea-pig carotid artery, the metabolism of arachidonic acid, either through cyclo-oxygenase, lipoxygenase or cytochrome p450 mono-oxygenase, is not involved in acetylcholine-induced endothelium-dependent hyperpolarizations.