title: Pathogenesis of solute-free water retention in experimental ascitic cirrhosis: is vasopressin the only culprit?
abstract: Catecholamines trigger proximal tubular fluid retention and reduce renal excretion of solute-free water. In advanced cirrhosis, non-osmotic hypersecretion of vasopressin (antidiuretic hormone or ADH) is considered the cause of dilutional hyponatraemia, but ADH V2 receptor antagonists are not beneficial in long-term treatment of ascites. To test the hypothesis that water retention in experimental ascitic cirrhosis might depend primarily on adrenergic hyper-function, hormonal status, renal function and tubular free-water reabsorption (TFWR) were assessed in six groups of rats with ascitic cirrhosis: rats with cirrhosis due to 13-week CCl4 (carbon tetrachloride) administration (group G1); cirrhotic rats receiving daily diuretics (0.5 mg/kg furosemide plus 2 mg/kg K(+)-canrenoate) from the 11th to the 13th week of CCl4 (G2), diuretics associated with guanfacine oral prodrug (α2A-adrenergic receptor agonist and sympatholytic agent) at 2 (G3), 7 (G4) or 10 (G5) mg/kg, or with SSP-004240F1 (V2 receptor antagonist) at 1 mg/kg (G6). Natriuresis was lower in G1 than in G2, G4 and G6 (all P<0.05). Guanfacine, added to diuretics (i.e. G3 compared with G2), reduced serum noradrenaline from 423±22 to 211±41 ng/l (P<0.05), plasma renin activity (PRA) from 35±8 to 9±2 ng/ml/h (P<0.05) and TFWR from 45±8 to 20±6 μl/min (P<0.01). TFWR correlated with plasma aldosterone (r=0.51, P<0.01) and urinary potassium excretion (r=0.90, P<0.001). In ascitic cirrhosis, reduced volaemia, use of diuretics (especially furosemide) and adrenergic hyper-function cause tubular retention of water. Suitable doses of sympatholytic agents are effective aquaretics.
authors.affiliation: Division of Gastroenterology, Gradenigo Hospital, 10135 Torino, Italy giovannisan@iol.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sansoè
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, 10125 Torino, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Aragno
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, 10125 Torino, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mastrocola
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, 10125 Torino, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Parola
mesh_terms: D000818:Animals; D001201:Ascites / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D002191:Canrenoic Acid / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology; D005665:Furosemide / Q000494:pharmacology; D016316:Guanfacine / Q000494:pharmacology; D007010:Hyponatremia / Q000209:etiology / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000150:complications / Q000503:physiopathology*; D008297:Male; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D014667:Vasopressins / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D004232:Diuretics; D014667:Vasopressins; D016316:Guanfacine; D005665:Furosemide; D002191:Canrenoic Acid; D009638:Norepinephrine
keywords: ascites; cirrhosis complications; dilutional hyponatraemia; experimental cirrhosis; α2-adrenoceptor agonists