Influence of some phospholipase A2 and cytochrome P450 inhibitors on rat arterial smooth muscle K+ currents.
The hyperpolarizing factor that is liberated by vascular endothelial cells in response to various agonists, and known to induce relaxation by opening of smooth muscle K+ channels, has been suggested to be a product of cytochrome P450 dependent arachidonic acid metabolism. In this study, the direct influence of two phospholipase A2 inhibitors and of five structurally and mechanistically different cytochrome P450 inhibitors on K+ currents in freshly isolated vascular smooth muscle cells from the rat aorta was investigated. On stepping the cell membrane potential from -70 mV to a series of depolarized test potentials, a noisy outward current developed at test potentials > +10 mV, which showed no appreciable inactivation during the voltage pulse. It was largely abolished by 3 mM external tetraethylammonium chloride (TEA), suggesting that it predominantly consisted of current through large-conductance Ca(2+)-activated K+ channels. The phospholipase A2 inhibitor quinacrine considerably inhibited this TEA-sensitive current, while 4-bromophenacylbromide exerted no effect. The cytochrome P450 inhibitors proadifen and miconazole reversibly decreased the amplitude of I(K), while clotrimazole and 1-aminobenzotriazole had no effect. Conversely, 17-octadecynoic acid increased whole-cell I(K). These results show that some phospholipase A2 and cytochrome P450 inhibitors may interfere with K+ channel activation in the rat arterial smooth muscle cell. The relevance of these findings to studies on the involvement of cytochrome P450 dependent metabolism in the generation of the endothelium-derived hyperpolarizing factor in intact arteries is discussed.
Vanheel
B
B
Department of Physiology and Physiopathology, University of Gent, Belgium. Bert.Vanheel@rug.ac.be
Calders
P
P
Van den Bossche
I
I
Van de Voorde
J
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008825:Miconazole / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D015221:Potassium Channels / Q000187:drug effects*; D011335:Proadifen / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D015221:Potassium Channels; D008825:Miconazole; D011335:Proadifen; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine; D002118:Calcium