First evidence that albumin can directly improve cardiac contractility in cirrhotic rats

A low cardiac output due to cirrhotic cardiomyopathy could be a critical factor in the pathogenesis of hepatorenal syndrome (HRS) in cirrhosis. Albumin together with vasoconstrictor drugs is widely used in the management of HRS however the mechanisms are still unclear. Aim of our study was to verify whether albumin infusion may restore a normal cardiac contractile response to betaadrenergic agonists and to improve betaadrenergic signal transduction in an animal model of cirrhosis with ascites. 12 Wistar Kyoto rats were treated for 15 weeks by inhalation with carbon tetrachloride (CCl4 ) to induce cirrhosis and 12 rats were used as control animals. Three days and one day before the sacrifice, albumin was administered as saline solution at a dose of 3g/kg B.W. i.v. to 8 cirrhotic and to 8 control rats. In 4 cirrhotic rats the same amount of saline solution was administered at the same times. Left ventricular contractility was determined in isolated hearts with a beta-agonist, isoproterenol. Cardiac gene expression of betaadrenergic signalling was performed by Real-Time PCR. Plasma antioxidant capacity was evaluated with Electron Spin Resonance spectroscopy. The maximal response of cardiac contractility induced by isoproterenol (10-8 mol and 10-6 mol) was significantly reduced in the left ventricular tissue of cirrhotic rats in comparison to controls (p<0.01). In albumin-treated cirrhotic rats, isoproterenolinduced cardiac contractility was stronger in comparison to saline-treated cirrhotic rats (p<0.01) and it was not significant different than controls. In hearts from saline-treated cirrhotic rats, gene expression analysis showed a significant overexpression of G protein alpha inhibiting subunit 2 (Galphai2) (p<0.01), of regulator of G-protein signalling (RGS-2) (p<0.01) and of phosphodiesterase-2a (PDE), as compared to control rats. In albumin-treated cirrhotic rats, gene expression of RGS2 and PDE2a was lower in comparison to saline-treated cirrhotic rats alone (p<0.01) and was similar to control animals. No difference was observed for Galphai2 expression between salinetreated and albumin-treated cirrhotic rats. Plasma antioxidant capacity was decreased in cirrhotic rats compared to the control rats (to 57% +-8%, p<0.01). The administration of albumin almost completely restored the antioxidant level in cirrhotic rats.These results demonstrate for the first time that the administration of albumin improve cardiac contractility and beta adrenergic signal transduction by modulating the expression of RGS2 and PDE2a in cirrhotic rats. All these effects were accompanied by an increase of the level of antioxidant status in these animals