Vasorelaxant effects of cromakalim in rats are mediated by glibenclamide-sensitive potassium channels.
Cromakalim (BRL 34915), a K+ channel activator, and diltiazem relaxed isolated rat aortic rings contracted with a low KCl concentration (25 mM). Gilbenclamide (0.1-3 microM) did not modify base-line resting tension or responses to KCl but prevented the vasorelaxant effects of cromakalim without affecting those of diltiazem or nitrendipine. Cromakalim, in contrast to the latter compounds, did not relax aortic rings contracted with 55 mM KCl. In pentobarbital-anesthetized rats prepared for hemodynamic measurements with Doppler flow probes, a 20-min i.v. infusion of cromakalim (5.0 micrograms/kg/min) lowered mean carotid artery blood pressure. This effect reached maximum after administration and was accompanied by decreases in systemic (35%), hindquarter (45%), mesenteric (27%), and renal (19%) vascular resistances. The blood pressure effects of cromakalim were not modified by BW 755C (lipo and cyclooxygenase inhibitor), idazoxan, methylatropine, methysergide, promethazine, propranolol, SCH 23390 (DA-1 receptor antagonist), S-sulpiride, RP 59227 (antagonist of platelet activating factor receptors) or by bilateral vagotomy associated with ligation of carotid arteries. However, in rats pretreated with the hypoglycemic sulfonylureas glibenclamide or glipizide (20 mg/kg i.v.), cromakalim, in contrast to diltiazem or dihydralazine, failed to produce hypotension. In rats deprived of sympathetic drive by pithing, cromakalim produced only a minor fall in blood pressure; however, this effect became pronounced when the low base-line blood pressure of this preparation was elevated by an i.v. infusion of vasopressin and could be prevented by glibenclamide. In conclusion, cromakalim posseses a novel mechanism of vasorelaxation that is consistent with the activation of a cellular outward K+ current.(ABSTRACT TRUNCATED AT 250 WORDS)
Cavero
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I
Rhone-Poulenc Sante, Centre de Recherches de Vitry, Virty-sur-Seine, France.
Mondot
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Mestre
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M
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019806:Cromakalim; D005905:Glyburide / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D015221:Potassium Channels / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D014664:Vasodilation / Q000187:drug effects*
D000959:Antihypertensive Agents; D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D005905:Glyburide