Inhibitors of the cytochrome P450‐mono‐oxygenase and endothelium‐dependent hyperpolarizations in the guinea‐pig isolated carotid artery

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Abstract
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 (I μm) 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 μm) and nitric oxde synthase (Nωnitro-L-arginine: L-NOARG, 100 μm). 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 μm, 13.9±2.2 and 15.3±4.6 mV), metyrapone (100 μm, 13.1±1.9 mV), clotrimazole (100 μm, 13.5±2.7 mV), 17-octadecynoic acid (5 μm 16.5±1.9 mV), methoxsalen (10 μm, 15.3±1.6 mV), the inhibitor of phospholipase A2 quinacrine (10 μm 12.8±2.5 mV) and the non specific lipoxygenases/cyclo-oxygenases/cytochrome P450 inhibitor, eicosatetraynoic acid (50 μm, 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.