title: Metformin reduces hepatic resistance and portal pressure in cirrhotic rats.
abstract: Increased hepatic vascular resistance is the primary factor in the development of portal hypertension. 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 portal hypertension. CCl4-cirrhotic rats received by gavage metformin 300 mg/kg or its vehicle once a day for 1 wk, before mean arterial pressure (MAP), portal pressure (PP), portal blood flow (PBF), hepatic vascular resistance, and putative molecular/cellular mechanisms were measured. In a subgroup of cirrhotic rats, the hemodynamic response to acute Prop (5 mg/kg iv) was assessed. Effects of metformin ± Prop on PP and MAP were validated in common bile duct ligated-cirrhotic rats. Metformin-treated CCl4-cirrhotic rats had lower PP and hepatic vascular resistance than vehicle-treated rats, without significant changes in MAP or PBF. Metformin caused a significant reduction in liver fibrosis (Sirius red), hepatic stellate cell activation (α-smooth muscle actin, platelet-derived growth factor receptor β polypeptide, transforming growth factor-βR1, and Rho kinase), hepatic inflammation (CD68 and CD163), superoxide (dihydroethidium staining), and nitric oxide scavenging (protein nitrotyrosination). Prop, by decreasing PBF, further reduced PP. Similar findings were observed in common bile duct ligated-cirrhotic rats. 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 Prop. The potential impact of this pharmacological combination, otherwise commonly used in patients with cirrhosis and diabetes, needs clinical evaluation.
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; and Institute of Liver and Biliary Sciences, New Delhi, India.
authors.forename: Dinesh M
authors.initials: DM
authors.lastname: Tripathi
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; and.
authors.forename: Eva
authors.initials: E
authors.lastname: Erice
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; and.
authors.forename: Erica
authors.initials: E
authors.lastname: Lafoz
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; and.
authors.forename: Héctor
authors.initials: H
authors.lastname: García-Calderó
authors.affiliation: Institute of Liver and Biliary Sciences, New Delhi, India.
authors.forename: Shiv K
authors.initials: SK
authors.lastname: Sarin
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; and.
authors.forename: Jaime
authors.initials: J
authors.lastname: Bosch
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; and.
authors.forename: Jordi
authors.initials: J
authors.lastname: Gracia-Sancho
authors.affiliation: Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain; and jcgarcia@clinic.cat.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: García-Pagán
mesh_terms: D000818:Animals; D001794:Blood Pressure; D006975:Hypertension, Portal / Q000188:drug therapy; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000188:drug therapy*; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011169:Portal Vein / Q000187:drug effects* / Q000503:physiopathology; D011433:Propranolol / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014655:Vascular Resistance
chemical_list: D008687:Metformin; D011433:Propranolol
keywords: LSEC; cirrhosis; fibrosis; liver; portal hypertension