The mechanism of action of
nitrates, compounds that have been used classically in the treatment of
heart failure, appears to be the stimulation of
guanylate cyclase in vascular smooth muscle, perhaps the same physiologic 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 compound,
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 after 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, but had no significant effects on coronary blood flow or vascular resistance. The metabolite 3754 caused dose-related increases in coronary artery diameter, and large reductions in LVEDP. The effect of these compounds on large coronary artery diameter was significantly greater (p < 0.05) than that of
nitroglycerin (25 micrograms/kg). After
heart failure, both
CAS 936 and 3754 caused significant increases in large coronary artery diameter (10%) and a reduction in preload, up to 10 mm Hg, which was even larger than in normal dogs. Thus, these NO-releasing agents are potent selective large-vessel dilators that also reduce preload and maintain this unique
vasodilator profile even in the failing heart.