Aquaretic effects of α2A adrenergic receptor agonists (sympatholytic agents) vs. vasopressin V2 receptor antagonists in Experimental Ascitic Cirrhosis.
AASLD LiverLearning®. Sansoe' G. Nov 14, 2016; 144992
Label: Portal Hypertension: Experimental
Dr. Giovanni Sansoe'
Dr. Giovanni Sansoe'
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TITLE: Aquaretic effects of α2A adrenergic receptor agonists (sympatholytic agents) vs. vasopressin V2 receptor antagonists in Experimental Ascitic Cirrhosis.

This study was funded in 2012 by the Department of Research and Development, Shire, Basingstoke, Hampshire, U.K.

Background. Catecholamines trigger proximal tubular fluid retention and decrease Na+ and water delivery to the diluting segment of the Henle’s loop, thereby reducing renal excretion of solute-free water. In advanced cirrhosis, non-osmotic hypersecretion of vasopressin (ADH) is considered the main cause of dilutional hyponatremia, but ADH V2 receptor antagonists are not beneficial in the long-term treatment of ascites. Aim. To test the hypothesis that adrenergic hyperfunction might contribute to water retention in experimental ascitic cirrhosis. Methods. Hormonal status, renal function and tubular solute free-water reabsorption (TFWR) were assessed in six groups of rats with ascitic cirrhosis: rats with cirrhosis due to 13-week CCl4 administration (group G1); cirrhotic rats receiving daily diuretics (0.5 mg/kg furosemide plus 2 mg/kg K+-canrenoate) from 11th to 13th weeks of CCl4 (G2), diuretics associated with guanfacine oral prodrug (α2A adrenergic receptor agonist and sympatholytic agent) 2 (G3), 7 (G4), or 10 mg/kg (G5), or with SSP-004240F1 (V2 receptor antagonist) 1 mg/kg (G6), from 11th to 13th weeks of CCl4. Results. Natriuresis was lower in G1 than in G2, G4 and G6 (all P<0.05). Low-dose guanfacine, added to diuretics (in G3), reduced serum norepinephrine from 423 ± 22 (in G2) to 211 ± 41 ng/L (in G3) (P<0.05), plasma renin activity from 35 ± 8 to 9 ± 2 ng/mL/h (G2 vs. G3) (P<0.05), and TFWR from 45 ± 8 to 20 ± 6 microL/min (G2 vs. G3) (P<0.01). Compared to G1 (untreated ascitic cirrhosis) or G2 (ascitic cirrhosis treated with sole diuretics), TFWR was reduced to a very similar extent in groups G3 (low-dose guanfacine plus diuretics) and G6 (V2 antagonist plus diuretics). TFWR correlated only with plasma aldosterone (r=0.51, P<0.01) and urinary potassium excretion (r=0.90, P<0.001). Conclusion. In ascitic cirrhosis, reduced volaemia, use of diuretics (especially furosemide), and adrenergic hyperfunction contribute to tubular retention of water and dilutional hyponatremia. Suitable doses of sympatholytic agents are as effective as V2 antagonists when the aquaretic effect is needed.
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