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. CGS 26061 (10 microM) failed to inhibit binding of [125I]ET-1 in porcine thoracic aorta and was without effect on ET-1-induced [3H]inositol phosphate accumulation in A7r5 cells. However, CGS 26061 relaxed porcine coronary arterial rings precontracted with ET-1. In addition, contractions to PGF2 alpha and low K+ (20 mM) but not high K+ were attenuated, suggesting that CGS 26061 (1, 10 microM) is a potassium channel opener. Patch-clamp experiments confirmed the K+ channel activity (0.1-10 microM). The originally re ported inhibition of ET-1-induced pressor responses by Ex. 127 (CGS 26061) was not replicated in the anesthetized dog or conscious rat nor was it shown to be antihypertensive in SHR. These data have identified CGS 26061 as a novel K+ channel opener with a unique cardiovascular profile.
Webb
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Research Department, Ciba-Geigy Corporation, Summit, New Jersey 07901, USA.
Hu
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Sills
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Bazil
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Cioffi
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Shetty
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Lappe
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Rigel
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D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D008297:Male; D015221:Potassium Channels / Q000187:drug effects*; D011744:Pyrimidinones / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013552:Swine; D013843:Thiazines / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
C101885:CGS 26061; D019332:Endothelin-1; D015221:Potassium Channels; D011744:Pyrimidinones; D013843:Thiazines; D014665:Vasodilator Agents