EFFECTS OF AN ORALLY-ACTIVE NO-RELEASING AGENT, CAS-936, AND ITS ACTIVE METABOLITE, 3754, ON CARDIAC AND CORONARY DYNAMICS IN NORMAL CONSCIOUS DOGS AND AFTER PACING-INDUCED HEART-FAILURE

The mechanism of action of nitrates, compounds that have been used cla ssically in the treatment of heart failure, appears to be the stimulat ion of guanylate cyclase in vascular smooth muscle, perhaps the same p hysiologic action as endothelium-derived relaxing factor, now thought to be synonymous with nitric oxide (NO). Drugs that release NO either inside cells or in plasma have been developed recently. One such compo und, CAS 936, when taken orally, is converted to an active metabolite, 3754. The goal of our studies was to determine the effects of CAS 936 and 3754 on cardiovascular function in conscious dogs before and afte r the development of pacing-induced heart failure. CAS 936 (10 mg/kg, p.o.) increased large coronary artery diameter 9.1 +/-1.2% and reduced left ventricular end diastolic pressure (LVEDP) 2.5 +/- 0.5 mm Hg, bu t had no significant effects on coronary blood flow or vascular resist ance. The metabolite 3754 caused dose-related increases in coronary ar tery diameter, and large reductions in LVEDP. The effect of these comp ounds on large coronary artery diameter was significantly greater (p < 0.05) than that of nitroglycerin (25 mug/kg). After heart failure, bo th CAS 936 and 3754 caused significant increases in large coronary art ery diameter (10%) and a reduction in preload, up to 10 mm Hg, which w as even larger than in normal dogs. Thus, these NO-releasing agents ar e potent selective large-vessel dilators that also reduce pre-load and maintain this unique vasodilator profile even in the failing heart.