The aim of this study was to assess the effect of HS-142-1, a recently discovered specific antagonist of endogenous natriuretic peptides, on systemic hemodynamics, renal function, and the renin-aldosterone system in rats with cirrhosis and ascites. The study consisted of three protocols, each including 10 conscious control rats and 10 conscious rats with carbontetrachloride-induced cirrhosis with ascites. In protocol 1, HS-142-1 administration (by intravenous bolus of 20 mg · kg−1 body weight in all protocols) was not associated with significant changes in mean arterial pressure, heart rate, cardiac output or total peripheral resistance in the two groups of animals. In protocol 2, HS-142-1 induced a significant reduction in glomerular filtration rate (from 4.2 ± 0.5 to 2.6 ± 0.3 ml/min, p < 0.025) in control animals. A decrease in renal plasma flow and an increase in renal vascular resistance also occurred, but these changes were not statistically significant. In cirrhotic rats, HS-142-1 resulted in a significant decrease in renal plasma flow (from 10.9 ± 0.7 to 4.3 ± 0.6 ml/min, p < 0.001) and a significant increase in renal vascular resistance (from 6.0 ± 0.6 to 16.3 ± 2.7 mm Hg · min · ml−1, p < 0.025). Glomerular filtration rate decreased more in cirrhotic rats with ascites than in control rats (from 3.8 ± 0.3 to 1.3 ± 0.2 ml/min, p < 0.001). Changes in urine flow rate and urinary sodium excretion rate paralleled those of glomerular filtration rate in both groups of animals. In protocol 3, HS-142-1 administration was associated with a marked increase in plasma renin activity (from 17 ± 3 to 39 ± 9 ng · ml−1 ± hr−1, p < 0.01) and plasma aldosterone concentration (from 130 ± 12 to 268 ± 48 pg · ml−1, p < 0.025) in cirrhotic rats with ascites. This association was not observed in control animals (plasma renin activity from 1.6 ± 0.3 to 1.6 ± 0.5 ng ± ml·1 · hr−1, aldosterone from 45 ± 15 to 44 ± 16 pg · ml−1). These findings indicate that endogenous natriuretic peptides play a critical role in the maintenance of renal function and in the regulation of the renin-aldosterone system in cirrhosis with ascites. These peptides, however, are not critical to arterial pressure homeostasis under the conditions studied. (Hepatology 1994;20:948–954).