CARDIOVASCULAR EFFECTS OF THE K-ATP CHANNEL BLOCKER U-37883A AND STRUCTURALLY RELATED MORPHOLINOGUANIDINES

The cardiovascular effects of the K-ATP channel blocker U-37883A and 5 related morpholinoguanidines were determined in 6 Experimental prepar ations. In anesthetized dogs, U-37883A (0.5-8.0 mg/kg i.v.) increased mean arterial pressure (MAP; +18%) and left ventricular (LV) effective refractory period (ERP; +35%), and decreased LV contractility (-41%). Higher doses of U-37883A (16-32 mg/kg) fatally reduced MAP (-84%), he art rate (HR; -57%) and LV contractility (-72%). In anesthetized rats, U-37883A (1.0-50 mg/kg i.v.) also maximally reduced MAP, HR and LV co ntractility by 68, 77 and 48%, respectively. U-37883A and its analogs were diuretic in conscious rats (1.5-15 mg/kg i.v.) and blocked pinaci dil in rabbit mesenteric artery (EC(50) = 0.5-50 mu M). In rabbit papi llary muscle, 50 mu M U-37883A significantly reduced force of contract ion (-33%) and prolonged conduction time (+244%). Milder papillary eff ects were seen with the N'-OH analog U-45194A, which did not depress L V contractility in intact rats. In conscious dogs, oral U-45194A (50 m g/kg) was diuretic but reduced LV stroke volume and increased peripher al vascular resistance. These studies characterize U-37883A's systemic cardiovascular and direct myocardial effects, and identify U-45194A a s a less cardiac depressant analog having U-37883A-like diuretic and f unctional K-ATP channel blocking[ activities.