The relationship between endotoxemia and hepatic endocannabinoids in cirrhotic rats with portal hypertension

Background & Aims: Cirrhosis is characterized by endotoxemia and increased intrahepatic resistance, which is caused by hepatic fibrosis and endothelial dysfunction, as well as the activated endocannabinoids system, including cannabinoid (CB1 and CB2) receptors. Besides accelerating hepatic fibrogenesis, endotoxins induce the release of circulating endocannabinoids and portal hypertension in cirrhosis. This study examines how suppression of endotoxemia by antibiotics affects intrahepatic resistance and the hepatic endocannabinoid system in bile-duct-ligated (BDL) rats. Methods: Measurements were performed that included: mean arterial pressure, cardiac index (Cl), systemic vascular resistance, superior mesenteric arterial blood flow and resistance, PVP, plasma endotoxin and hepatic tumor necrosis factor-alpha (TNF alpha), anandamide and 2-arachidonylglycerol, hepatic expression of cannabinoid receptors, endothelial nitric oxide synthase (eNOS), phospho-eNOS, Akt, phospho-Akt and thromboxane synthase (TXS), matrix metalloproteinase-2 (MMP-2), tissue inhibitor of metalloproteinase-2 (TIMP-2), hepatic fibrosis, and leukocyte infiltration. Hepatic endothelial dysfunction was evaluated in BDL rats receiving vehicle (BDL-V) or 2-weeks of ciprofloxacin (BDL-cipro). Results: Plasma endotoxin and hepatic TNF alpha, anandamide and 2-arachidonylglycerol, expression of TXS, MMP-2, TIMP-2, hepatic fibrosis and infiltration of hepatic leukocytes, Cl, PVP and intrahepatic resistance were significantly lower in BDL-cipro than in BDL-V rats. Conversely, systemic vascular resistance, eNOS and Akt phosphorylation were significantly higher in BDL-cipro than in BDL-V rats. Improvement of hepatic endothelial dysfunction was associated with lower expression of hepatic CB(1)and a higher expression of hepatic CB2 in BDL-cipro rats. Conclusions: In cirrhotic rats, ciprofloxacin suppressed endotoxemia and the hepatic endocannabinoid system thus ameliorating hyperdynamic circulation and decreased intrahepatic resistance by preventing hepatic fibrogenesis and endothelial dysfunction. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.