In the present study we tested the hypothesis that inhibition of renal phosphodiesterase type 5 (PDE5) in patients with liver cirrhosis and ascites increases sodium excretion. The effect of sildenafil citrate was studied in a randomized double-blind placebo-controlled cross-over study. Diuretics were withdrawn and a fixed sodium diet (100 mmol/day) was given to the patients for five days prior to both study days. After a 60-min basal period, eight patients received either oral sildenafil (50 mg) or placebo. Glomerular filtration rate (GFR) and renal blood flow (RBF) were determined by ^99mTc-diethylenetriamine-pentaacetate and ¹³¹I-hippuran clearances. In human nephrectomy specimens PDE5 mRNA was expressed at similar levels in cortex (n=6) and inner medulla (n=4). Histochemical staining showed PDE5 immunoreactivity in collecting ducts and vascular smooth muscle. At baseline, cirrhotic patients exhibited elevated plasma concentrations of ANP, renin, ANG II and aldosterone that did not differ on the two study days. Basal sodium excretion was similar at the two study days (median 17 and 18 mmol, respectively) and patients were in positive sodium balance. Sildenafil increased heart rate, plasma renin activity, plasma angiotensin II and aldosterone concentrations significantly after 60 min. Plasma cGMP concentration was increased after 120 and 180 min and urinary sodium excretion and mean arterial blood pressure were decreased significantly at 120 min and 180 min. Plasma ANP concentration, GFR and RBF did not change after sildenafil. In patients with ascites and cirrhosis, inhibition of PDE5 did not promote natriuresis but led to increased plasma levels of the renin-angiotensin-aldosterone system.