Hemodynamic, renal, and endocrine effects of acute inhibition of nitric oxide synthase in compensated cirrhosis

To assess whether an increased production of nitric oxide is involved in th e circulatory and renal alterations of cirrhosis, we evaluated systemic hem odynamics (echocardiography), renal hemodynamics, and sodium handling (lith ium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 +/- 2 years) with compensa ted cirrhosis, portal hypertension, and hyperdynamic circulation during int ravenous N-G-monomethyl-L-arginine (L-NMMA) (3 mg/kg bolus plus 0.05 mg/kg min for 120 minutes) or placebo (the vehicle) in a randomized, placebo-cont rolled, crossover study. Administration of L-NMMA resulted in significant r eductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synth ase. L-NMMA also significantly reduced cardiac index (-13%) and increased s ystemic vascular resistance (+26%), arterial pressure (+9%), renal blood no w (+12%), glomerular filtration rate (+12%), and sodium excretion (+25%). C hanges in sodium excretion were caused by both enhanced filtered sodium loa d and reduced sodium reabsorption in the proximal tubule. Plasma norepineph rine significantly decreased in response to L-NMMA, and there was a trend f or reductions in PRA and PAC. Placebo had no appreciable effect on any of t he measured parameters. These results indicate that in patients with compen sated cirrhosis, portal hypertension and hyperdynamic circulation inhibitio n of nitric oxide synthase corrects the altered systemic hemodynamics and i mproves renal function and sodium excretion.