SummaryThe volume overloading of the left ventricle which results from left to right (L-R) shunting through a ventricular septal defect (VSD) may be reduced by pharmacologic agents which lower systemic vascular resistance (Rs) in excess of pulmonary arteriolar vascular resistance (Rpa). To study agents capable of decreasing the L-R shunt through systemic vasodilatation, we created a chronic lamb model with VSD and administered three vasodilators, prazosin (0.05 mg/kg), hydralazine (0.75 mg/kg), and minoxidil (0.25 mg/kg). Prazosin increased the Rpawhile lowering Rs, resulting in an increase in Rpa/Rsby 43% {p≤ 0.005). Prazosin decreased the pulmonary flow (&OV0422;p) slightly, decreased L-R shunt by 16%, reduced the pulmonary to systemic flow ratio (&OV0422;p/&OV0422;s) by 22% (p≤ 0.005), and lowered the left atrial mean pressure (&OV0436;A) by 16% (p≤ 0.005) with no effect on heart rate. Hydralazine lowered the Rpaand Rsequally and thus did not change the Rpa/Rsor the volume of L-R shunt (7.6 versus 8.1 Iiters/min/m2). No change in &OV0436;A was seen with hydralazine but heart rate increased from 162 to 200/min (p≤ 0.01). Minoxidil did not change the L-R shunt (6.9versus6.8 liters/min/m2) and, in general, produced effects intermediate between prazosin and hydralazine. The data support a selective systemic vasodilation with prazosin, a property not shared by either minoxidil or hydralazine, which results in a reduction of shunting and left ventricular volume overloading in lambs with VSD. Furthermore, since prazosin did not decrease the pulmonary resistance, the data indicate that the elevation in pulmonary resistance in lambs with VSD is not mediated by the α1-adrenergic receptor.