The effects of atrial natriuretic factor (ANF) on splanchnic hemodynamics and renal function in portal hypertensive models are described incompletely. Furthermore, ANF-induced vasodilatation and hypotension may limit the assessment of its own renal physiological effects. We infused ANF (human ANF 102-126) to anesthetized portal vein-ligated rats, a model with prehepatic portal hypertension. Arterial pressure was reduced by 17%, but portal pressure was unaffected. Diuresis and natriuresis were explained in part by an increase in glomerular filtration rate; in addition, renal vascular resistance was significantly decreased. The natriuretic response to ANF was slightly, but significantly, decreased in portal hypertensive rats as compared to controls (fractional excretion of sodium, 1.8 ± 0.4 vs. 2.9 ± 0.3; P < .05). The addition of Phe-Ile-Orn-vasopressin, a V1 receptor agonist, normalized arterial pressure but induced a significant decrease in the portal pressure (15 ± 0.9 mm Hg base line vs. 12.8 ± 0.7 combination group; P < .01). Furthermore, the combination of both drugs markedly potentiated the natriuretic effects (0.4 ± 0.1 μEq/min of control vs. 10.0 ± 2.3 ANF vs. 32.2 ± 3.3 combination group; P < .001). The natriuretic potentiation resulted from increments in glomerular filtration rate and renal blood flow. Normalization of arterial pressure may enhance the renal physiological effects of ANF, in this portal hypertensive model.