The optimal dose of spironolactone to reduce portal vein pressure, alone or in combination with isosorbide-5-mononitrate (IsMn), has not been identified. We studied the effects of 8 days oral treatment with spironolactone, IsMn or both on portal pressure, plasma volume and renal sodium handling in rats with partial portal vein ligation. At daily doses of 0.33; 0.50; 1, and 1.50 mg/kg, spironolactone reduced portal pressure (all P < .05) as compared with placebo. Only the highest dose significantly lowered plasma volume (10.1 ± 0.7 vs. 13.0 ± 0.3 mL; P < .03) and enhanced urinary fractional sodium excretion (0.73 ± 0.04 vs. 0.58 ± 0.03%; P < .03) and the (Na+)/(K+) ratio in urine (0.43 ± 0.04 vs. 0.30 ± 0.03; P < .02). IsMn at doses of 0.25; 0.50, and 1 mg/kg decreased portal pressure (all P < .05) without a change in plasma volume but with a tendency (not significant) to lower fractional sodium excretion. IsMn impaired free water clearance at doses of 0.5 and 1 mg/kg (P < .05). Combinations of spironolactone 1 mg/kg with IsMn 0.5 or 1 mg/kg have no additive effect on portal pressure compared with spironolactone or IsMn alone. The higher the dose of IsMn in the combination, the more the natriuretic effect of spironolactone is opposed. Low doses of spironolactone are as effective as a higher dose to reduce portal pressure. This reduced portal pressure was independent of changes in plasma volume and diuretic effect, which suggests that spironolactone might have a direct vasoactive effect on the splanchnic circulation. To counteract sodium retention of nitrovasodilators, combination with high doses of spironolactone seems advantageous.