Metformin reduces hepatic resistance and portal pressure in cirrhotic rats

Abstract

Objective: Increased hepatic vascular resistance is the primary factor in the development of portal hypertension (PH). Metformin ameliorates vascular cells function in several vascular beds. Our study was aimed at evaluating the effects, and the underlying mechanisms, of metformin on hepatic and systemic hemodynamics in cirrhotic rats and its possible interaction with the effects of propranolol (Prop), the current standard treatment for PH. Methods: CCl₄-cirrhotic rats received by gavage metformin 300mg/kg or its vehicle once a day for 1 week, before measuring Mean Arterial Pressure (MAP), Portal Pressure (PP), Portal Blood Flow (PBF), Hepatic Vascular Resistance (HVR), and putative molecular/cellular mechanisms. In a subgroup of cirrhotic rats, the hemodynamic response to acute Prop (5mg/kg i.v.) was assessed. Effects of metformin±Prop on PP and MAP were validated in common bile duct ligated (CBDL)-cirrhotic rats. Results: Metformin-treated CCl₄-cirrhotic rats had lower PP and HVR than vehicle-treated rats, without significant changes in MAP or PBF. Metformin caused a significant reduction in liver fibrosis (Sirius red), HSC-activation (alpha-SMA, PDGFRB, TGFβR1 and RhoK), hepatic inflammation (CD68 and CD163), superoxide (dihydroethidium staining) and NO-scavenging (protein nitrotyrosination). Propranolol, by decreasing PBF, further reduced PP. Similar findings were observed in CBDL-cirrhotic rats. Conclusion: Metformin administration reduces PP by decreasing the structural and functional components of the elevated hepatic resistance of cirrhosis. This effect is additive to that of propranolol. The potential impact of this pharmacological combination, otherwise commonly used in patients with cirrhosis and diabetes, needs clinical evaluation.