Alpha-2A Adrenoceptor Agonist Guanfacine Restores Diuretic Efficiency in Experimental Cirrhotic Ascites: Comparison with Clonidine

BACKGROUND: In human cirrhosis, adrenergic hyperfunction causes proximal tubular fluid retention and contributes to diuretic-resistant ascites, and clonidine, a sympatholytic drug, improves natriuresis in difficult-to-treat ascites. AIM: To compare clonidine (aspecific α(2)-adrenoceptor agonist) to SSP-002021R (prodrug of guanfacine, specific α(2A)-receptor agonist), both associated with diuretics, in experimental cirrhotic ascites. METHODS AND RESULTS: Six groups of 12 rats were studied: controls (G1); controls receiving furosemide and potassium canrenoate (G2); rats with ascitic cirrhosis due to 14-week CCl(4) treatment (G3); cirrhotic rats treated (over the 11(th)-14(th) CCl(4) weeks) with furosemide and canrenoate (G4), furosemide, canrenoate and clonidine (G5), or diuretics and SSP002021R (G6). Three rats of each group had their hormonal status and renal function assessed at the end of 11(th), 12(th), 13(th), and 14(th) weeks of respective treatments.Cirrhotic rats in G3 and G4 gained weight over the 12(th)-14(th) CCl(4) weeks. In G4, brief increase in sodium excretion over the 11(th)-12(th) weeks preceded worsening of inulin clearance and natriuresis (diuretic resistance). In comparison with G4, the addition of clonidine (G5) or guanfacine (G6) to diuretics improved, respectively, sodium excretion over the 11(th)-12(th) CCl(4) weeks, or GFR and electrolytes excretion over the 13(th)-14(th) CCl(4) weeks. Natriuretic responses in G5 and G6 were accompanied by reduced catecholamine serum levels. CONCLUSIONS: α(2A)-receptor agonists restore glomerular filtration rate and natriuresis, and delay diuretic-resistant ascites in experimental advanced cirrhosis. Clonidine ameliorates diuretic-dependent natriuresis just for a short time.