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 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.
Wang
J
J
Department of Physiology, New York Medical College, Valhalla 10595.
Zhao
G
G
Shen
W
W
Ochoa
M
M
Moore
D
D
Hubbard
J W
JW
Hintze
T H
TH
D000284:Administration, Oral; D000818:Animals; D002303:Cardiac Output, Low / Q000188:drug therapy*; D003326:Coronary Circulation / Q000187:drug effects*; D004285:Dogs; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D005996:Nitroglycerin / Q000627:therapeutic use; D013558:Sydnones / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D013558:Sydnones; D014665:Vasodilator Agents; C073303:pirsidomine; D005996:Nitroglycerin