OBJECTIVE We sought to compare the effects of captopril plus isosorbide dinitrate versus monotherapy on infarct collagen content and left ventricular remodeling and function during healing after myocardial infarction. BACKGROUND Captopril or isosorbide dinitrate monotherapy can limit postinfarction dilation. Whether captopril inhibits infarct collagen content, or whether captopril plus isosorbide dinitrate might be more beneficial, is not known. METHODS In vivo remodeling variables and function (echocardiography), hemodynamic variables, postmortem topography (planimetry) and collagen content (hydroxyproline) were measured in 48 chronically instrumented dogs that were randomized 2 days after left anterior descending coronary artery ligation to 6 weeks of therapy with captopril, isosorbide dinitrate, captopril plus isosorbide dinitrate or placebo. RESULTS Compared with placebo, the three active therapies decreased blood pressure and left atrial pressure; limited infarct expansion, infarct thinning, noninfarct wall stretching and thickening; limited left ventricular dilation and increase in left ventricular mass; and decreased regional bulging, aneurysm frequency and left ventricular dysfunction. However, the decrease in asynergy and increase in volume ejection fraction were less with captopril or captopril plus isosorbide dinitrate than with isosorbide dinitrate. Infarct thinning and bulging at 6 weeks was also less with isosorbide dinitrate than with captopril. Although initial left ventricular asynergy, final scar sizes and noninfarct collagen content at 6 weeks were similar among the groups, collagen in the center of the infarct scar was less with captopril or captopril plus isosorbide dinitrate than with placebo or isosorbide dinitrate. CONCLUSIONS Monotherapy with captopril or isosorbide dinitrate, or their combination, improved all remodeling variables, but isosorbide dinitrate improved function more than captopril or captopril plus isosorbide dinitrate. Inhibition of infarct collagen content by captopril suggests that benefits with captopril represent a balance between positive and negative effects, and its combination with isosorbide dinitrate might be advantageous.