COMPARISON OF THE HEMODYNAMIC-RESPONSES TO MOLSIDOMINE AND ISOSORBIDEDINITRATE IN CONGESTIVE-HEART-FAILURE

To evaluate the mechanisms involved in nitrate tolerance, we randomize d 23 patients with congestive heart failure resulting from coronary ar tery disease to an isosorbide dinitrate or a molsidomine infusion. The drugs were titrated to decrease pulmonary capillary wedge pressure by greater than or equal to 30% or greater than or equal to 10 mm Hg. Th en isosorbide dinitrate, molsidomine, or placebo was infused in a doub le-blind randomized manner for 24 hours. In all patients, treatment wi th enalapril was begun greater than or equal to 48 hours before the be ginning of the protocol and was continued throughout the study to avoi d renin-angiotensin activation. The pulmonary capillary wedge pressure remained significantly decreased at 24 hours during molsidomine infus ion only. No significant increase in catecholamines occurred. Because molsidomine differs from organic nitrates by its property of directly stimulating guanylate cyclase without depending on thiol group availab ility, these results suggest that impaired biotransformation of nitrat es is involved in tolerance induced by high doses of isosorbide dinitr ate in congestive heart failure.