Activation of K+ channel in vascular smooth muscles by cytochrome P450 metabolites of arachidonic acid.
Arachidonic acid can be oxidatively metabolized by cytochrome P450 epoxygenase to four regioisomeric epoxyeicosatrienoic acids (5,6-; 8,9-; 11,12-; 14,15-EET), which exhibit vasorelaxant effects in vivo and in vitro with unknown mechanisms. In this study, the patch-clamp method was used to examine the effects of EETs on the Ca(2+)-activated K+ channel in cells from rabbit portal vein, rat caudal artery, guinea pig aorta and porcine coronary artery. In all four cell types, EETs in the bath activated the K+ channel in cell-attached patches by increasing the single channel open-state probability. Potencies of the four EETs did not differ significantly for each cell type. The concentrations for doubling open-state probability were 0.1 microM in portal vein and coronary artery, 0.3-1 microM in aorta and 1-3 microM in caudal artery. In caudal artery cells, K+ channel activation by 3 microM 5,6- and 1 microM 11,12-EET was blocked and reversed by glyburide at 0.5 microM. In aorta, coronary artery, and caudal artery cells, micromolar EETs induced a dose-dependent and reversible augmentation of whole-cell K+ current by 50-120% and a 5-12 mV hyperpolarization. EETs on the cytosolic side of inside-out patches produced little or no potentiation of K+ channels, implying an interaction of receptor-mediated nature. Thus, EETs may promote vasodilation by functioning as endogenous K+ channel openers.
Hu
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Research Department, Ciba-Geigy Corporation, Summit, NJ 07901.
Kim
H S
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D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004357:Drug Synergism; D004594:Electrophysiology; D006168:Guinea Pigs; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013552:Swine
D001095:Arachidonic Acids; D015221:Potassium Channels; D003577:Cytochrome P-450 Enzyme System