We studied the response of the renin-angiotensin system (RAS) to a surgically created ventricular septal defect (VSD) in immature ovines and also the role of angiotensin II in the pathophysiology of VSD in the chronically instrumented ovine. Plasma renin activity (PRA) was increased from 2.39±1.1 to 3.78±1.4 ng/ml/hr (p<0.05, n=17) after VSD but not after sham procedure. The change in PRA was positively correlated with the amount of left-to-right shunt through the VSD (r=0.74, p<0.05). Inhibition of angiotensin n effect with saralasin (10 μg/kg/ min) or angiotensin n production with captopril (2 mg/kg) lowered systemic resistance (RJ by 14percent; and 34percent;, respectively (p<0.05), and raised pulmonary resistance (Rp) by 35percent; and 77percent;, respectively (p<0.05). Thirty minutes following captopril, the ratio of pulmonary to systemic flow (Qp/Q±) decreased from 3.31±0.18 to 2.15±0.18 (p<0.05) while total pulmonary flow fell from 7.15±0.38 to 5.92±0.34 l/min/M2 (p<0.05, n=ll). Systemic flow increased from 2.17±0.14 to 2.86±0.33 l/min/M2 (p<0.05) despite a reduction in left atrial pressure (17.3±1.0 vs. 13.0±1.7, p<0.01). Reinfusion of angiotensin n (0.02 μg/kg/min) into the central aorta after captopril returned the hemodynamics to baseline including a rise in Rpand fall in Rp. Exogenous angiotensin II alone (0.08 μg/kg/min) or a threefold stimulation in PRA with furosemide (2 mg/kg) caused little hemodynamic effect. The flow disturbance with a large VSD causes near maximal stimulation/effect of the RAS as indicated by the rise in PRA, the lack of response to further increases in PRA, and the response to exogenous angiotensin II. The RAS appears to promote the pathophysiology of VSD, demonstrated with RAS antagonists, by increasing R±, lowering Rp, and causing a redistribution of left ventricular output to the pulmonary circulation.