It has been proposed thatendothelin-1 (HT-1) may play an important role in the development of hypertension and proteinuria in the rat model of renal mass reduction. Experiments were conducted to 1 ) characterize the ability of the ETA-selective antagonist. A-127722, to inhibit the hemodynamic effects of exogenous ET-1. and 2) evaluate the effect of A-127722 in rats with reduced renal mass. Male rats were acclimated to metabolism cages and baseline 24 hr urine collections obtained. A-127722 was then placed in the drinking water and concentrations adjusted to deliver doses from 1 to 30 mg/kg/day for 3 days. The compound had no effect on any of the variables measured including food and water intake, urine volume, or sodium excretion. ET, receptor blockade was verified acutely in anesthetized rats. A jugular vein catheter was inserted for infusions while a femoral artery catheter was used for monitoring arterial pressure. The presser response to intravenous injection of Big ET-1 was maximally inhibited (>50%) in rats given A-127722 at 10 rng/kg/day. These experiments demonstrate the oral efficacy of A-127722 in blocking ETA-mediated responses. In the second series of experiments, the right kidney was removed and 2 of 3 major branches of the left renal artery were ligated in anesthetized rats. Upon recovery, rats were returned to their cages and given A-127722 in the drinking water to deliver 1 or 10 mg/kg/day. Control rats underwent the same surgical procedures but were given tap water to drink. After 4 weeks, rats treated with A-127722 developed similar degrees of hypertension and proteinuria as rats receiving tap water. These results indicate that ET-1 does not play a significant role in the pathophysiology associated with reduced renal mass.