A possible defect of guanosine 3Ј-5Ј-cyclic monophosphate (cGMP) content in the renal tissue caused by an increased activity of cGMP phosphodiesterase (PDE) has, so far, not been evaluated in the pathogenesis of renal resistance to endogenous natriuretic peptides (ENP) in cirrhosis with ascites. To test this hypothesis the activity of cGMP-PDE and the concentration of cGMP were evaluated in vitro in the renal tissue of 10 control rats and 10 cirrhotic rats with ascites before and after the intravenous (IV) administration of Zaprinast (Sigma, St. Louis, MO), a specific cGMP-PDE inhibitor (30 g/kg/min). Moreover, the effects of the intravenous administration of Zaprinast (15 g/kg/min and 30 g/kg/min) on renal plasma flow (RPF), glomerular filtration rate (GFR), and urinary sodium excretion (U Na V) were evaluated in 10 conscious control rats and 10 conscious cirrhotic rats with ascites. The effects of Zaprinast on plasma renin activity (PRA) was also evaluated in 10 control rats and in 10 cirrhotic rats with ascites. Finally, the effect of Zaprinast on RPF, GFR, and U Na V were evaluated in 10 cirrhotic rats after the IV administration of the ENP-receptor antagonist, HS-142-1. The renal content of cGMP was reduced in cirrhotic rats because of increased activity of cGMP-PDE. Zaprinast inhibited cGMP-PDE activity and increased the renal content of cGMP in these animals. The inhibition of cGMP-PDE was associated with an increase in RPF, GFR, and U Na V and a reduction in PRA. HS-142-1 prevented any renal effect of Zaprinast in cirrhotic rats. In conclusion, an increased activity of the cGMP-PDE in renal tissue contributes to the renal resistance to ENP in cirrhosis with ascites. (HEPATOLOGY 2000;31;
304-310.)Increased circulating levels of endogenous natriuretic peptides (ENP), a family of 4 distinct, but related substances 1 : atrial natriuretic peptide (ANP), 2 brain natriuretic peptide, 3 C-type natriuretic peptide, 4 and urodilatin 5 are hallmarks of patients with cirrhosis and ascites. 6-11 Although ENP were found to play an important role in the preservation of renal hemodynamics and sodium excretion in cirrhotic rats with ascites, 12 advanced stages of cirrhosis and ascites are characterized in animal models, as well as in patients with cirrhosis and ascites, by a reduced natriuretic and glomerular responsiveness to exogenous administration of ANP, brain natriuretic peptide, and C-type natriuretic peptide. [12][13][14][15][16] Several biological effects of ENP, including increased glomerular filtration and natriuresis, are mediated via 2 biologically active types of receptors, namely NPR-A and NPR-B receptors. [17][18][19][20] The downstream activation of a membrane guanylyl cyclase results in increased guanosine 3-Ј5Ј-cyclic monophosphate (cGMP) generation. [17][18][19][20][21] The mechanisms that mediate the renal hyporesponsiveness to ENP in cirrhosis with ascites remain poorly defined. They may be multifactorial and include the activation of renal vasoconstrictors and antinatriuretic factors, i.e., renin-...