The renin-angiotensin system is activated by congestive heart failure associated with a ventricular septal defect (VSD). To determine the effect of angiotensinconverting enzyme inhibition on the hemodynamics with VSD, the dose response curve of captopril was measured in lambs. Furthermore, the effect of captopril on the distribution of systemic output was determined by the radio-nuclide-labeled microsphere technique. A total of 12 lambs (less than 1 month old) with VSD were instrumented and a minimum of five animals was tested for each data point. Captopril (0.05–10 mg/kg) caused dose-dependent vascular changes. At a dose of 2 mg/kg, maximal hemodynamic effects were observed. The systemic resistance fell by 28 ± 9% (mean ± SD,p< 0.05,n= 9), whereas pulmonary arteriolar resistance rose by 113 ± 34% (p< 0.05). These vascular changes caused a reduction in the ratio of pulmonary to systemic flow from 3.31 ± 0.59 to 2.19 ± 0.29 (-34%,p< 0.05) and a reduction in left-to-right shunt volume by 30% (p< 0.05). The left atrial pressure fell from 17.3 ± 3.4 to 10.8 ± 2.8 mm Hg (-38%,p< 0.05). Mean aortic pressure was unchanged (71.2 ± 8.1versus67.4 ± 9.1). Forward flow from the left ventricle increased from 2.17 ± 0.46 to 2.86 ± 0.54 liter/min/M2(p< 0.05). Microsphere-determined organ blood flow to the heart, kidney, liver, duodenum, and skeletal muscle was preserved after a 5 mg/kg dose of captopril and, in fact, tended to increase, but the changes were not significant. The myocardial endocardial to epicardial flow ratio increased from 1.17 ± 0.27 to 1.49 ± 0.14 (+27%,p< 0.05). The data indicate that captopril caused dose-dependent changes in the distribution of left ventricular output in lambs with VSD, reducing total pulmonary flow while preserving organ blood flow. (Pediatr Res24: 499–503, 1988)