ACTIVATION OF K+-CHANNEL IN VASCULAR SMOOTH MUSCLES BY CYTOCHROME-P450 METABOLITES OF ARACHIDONIC-ACID

被引:187
作者
HU, SL
KIM, HS
机构
[1] Research Department, Pharmaceuticals Division, Ciba-Geigy Corporation, Summit
关键词
ARACHIDONIC ACID; CYTOCHROME-P450; EPOXYGENASE; EPOXYEICOSATRIENOIC ACID; PATCH-CLAMP METHOD; K+-CHANNELS (CA-2+-ACTIVATED); K+-CHANNEL OPENERS;
D O I
10.1016/0014-2999(93)90805-R
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 Ca2+ 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 muM in portal vein and coronary artery, 0.3-1 muM in aorta and 1-3 muM in caudal artery. In caudal artery cells, K+ channel activation by 3 muM 5,6- and 1 muM 11,12-EET was blocked and reversed by glyburide at 0.5 muM. 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.
引用
收藏
页码:215 / 221
页数:7
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