In other vascular beds, metformin has been shown to ameliorate vascular cells phenotype and function. Our study evaluated the effects of metformin on hepatic and

systemic hemodynamics and the underlying mechanisms in cirrhotic rats. In addition, we studied the possible interaction between metformin and propranolol (Prop), the current standard treatment of PH. Methods: CCl4-cirrhotic rats received by gavage metformin 300mg/kg or its vehicle (n=12 per group) once a day for 1 week, before measuring hemodynamic parameters (MAP, Portal Pressure-PP, Portal Blood Flow-PBF, Hepatic Y-27632 clinical trial Vascular Resistance-HVR), and molecular/cellular potential mechanisms (liver fibrosis, HSC activation, Rho-Kinase activity, oxidative Decitabine cost stress, eN〇S and AMPK pathways). In 10 rats per group, the PP and MAP response to acute Prop (5mg/kg i. v.) was assessed. Effects of metformin±Prop on PP and MAP were further evaluated in BDLcirrhotic rats (n=8 per group). Results: Metformin-treated CCl4 cirrhotic rats had lower PP (10.2±0.8

vs 13.9±0.8 mmHg; 27%; p<0.01) and HVR (0.8±0.1 vs 1.3±0.2 mmHg*mL- 1*min; −40%; p<0.01) than vehicle-treated rats, without significant changes in MAP or PBF. Prop further reduced PP in metformin (−26%) and vehicle treated rats (−14%), being the additional effect greater in the metformin group (p<0.01). As a result,

the final PP was much lower in the metformin group (38%; p<0.01) with no significant differences in MAP (79±7 vs 80±7 mmHg). Metformin treatment caused a significant reduction in liver fibrosis (−41%), HSC-activation (a-SMA −72% and desmin −46%) and Rho-kinase activity (−55%) (all p<0.01). In addition, hepatic oxidative stress (O2-: −76%) and oxidative stress-mediated N〇-scavenging (nitrotyrosine: −43%) was also reduced in livers from metformin rats. No significant changes in AMPK or eN〇S pathways were observed. CBDL-cirrhosis: Metformin-treated Rebamipide rats also had significantly lower PP than vehicle (17.2±2.3 vs 19.1±2.7 mmHg; p<0.01) without changes in MAP. Prop further reduced PP in both groups of BDL rats, resulting in significantly lower PP in the metformin group (14, 8±1, 7 vs 17, 5±1, 4; p<0.01). Conclusions: Our study demonstrates that in cirrhotic rats metformin administration reduces PP by decreasing HVR; probably due to an amelioration of the structural and functional components of the elevated hepatic resistance of cirrhosis. This effect is additive to that obtained with propranolol. The potential impact of this pharmacological combination, otherwise commonly used in patients with cirrhosis and diabetes, needs further clinical evaluation.