IN-VITRO AND IN-VIVO EVALUATION OF AN ENDOTHELIN INHIBITOR REVEALS NOVEL K+ CHANNEL OPENING ACTIVITY

A low molecular weight endothelin (ET-1) inhibitor (Ex. 127, European Patent Application 404 525 A2, Takeda Chemical Ind., 1991), CGS 26061, was synthesized and evaluated to determine its mechanism of action. C GS 26061 (10 mu M) failed to inhibit binding of [I-125]ET-1 in porcine thoracic aorta and was without effect on ET-1-induced [H-3]inositol p hosphate accumulation in A7r5 cells, However, CGS 26061 relaxed porcin e coronary arterial rings precontracted with ET-1. In addition, contra ctions to PGF(2 alpha) and low K+ (20 mM) but not high K+ were attenua ted, suggesting that CGS 26061 (1, 10 mu M) is a potassium channel ope ner. Patch-clamp experiments confirmed the K+ channel activity (0.1-10 mu M). The originally re ported inhibition of ET-1-induced pressor re sponses by Ex. 127 (CGS 26061) was not replicated in the anesthetized dog or conscious rat nor was it shown to be antihypertensive in SHR. T hese data have identified CGS 26061 as a novel K+ channel opener with a unique cardiovascular profile. (C) 1996 Academic Press, Inc.