34 This and the similar effects of synthetic CB analogues and endocannabinoids are mediated by CB1 receptors located, in part, in the peripheral cardiovascular system,35 and they play a pathogenic role in various forms of shock,36, 37 including endotoxic shock.38-40 Advanced liver cirrhosis Maraviroc in vitro is associated with endotoxemia and hypotension,

and this suggests endocannabinoid involvement. Indeed, cirrhosis in rats is accompanied by progressive hypotension reversible by CB1 blockade,27 which also reduces the elevated portal venous pressure and mesenteric blood flow. The likely source of endocannabinoids is activated macrophages, in which lipopolysaccharide induces the CD14-dependent synthesis of AEA.38, 41 AEA Selleck CHIR99021 levels are elevated in circulating macrophages of cirrhotic rats or patients, and such macrophages injected into normal rats elicit CB1-mediated hypotension.27, 42 Cirrhosis increases CB1 expression in vascular endothelial cells27 or in mesenteric arteries29, 43 and increases the vasodilator potency of AEA.29, 43, 44 In patients with cirrhosis, circulating AEA levels, but not 2-AG levels, are increased in peripheral blood but not in hepatic

veins or liver tissue, and this suggests that the liver is not its source.45 These findings implicate AEA as a mediator of the vasodilated state in cirrhosis. Although in one study of patients with cirrhosis the increase in circulating AEA did not correlate with the degree of hepatic and renal dysfunction,46 in another study of patients with primary biliary cirrhosis, the CB1 expression in hepatocytes and biliary epithelial cells and the CB2 expression in hepatocytes and cholangiocytes were positively correlated with the severity of the histological stage.8 Cirrhosis is associated with renal sodium retention, which has been attributed, in part, to portal hypertension secondary to liver parenchymal damage and fibrosis.47 In cirrhotic rats, rimonabant dose-dependently reduced ascites by ensuring a less positive sodium balance.48 AEA

induces CB1-mediated mesenteric vasodilation independently of nitric oxide.49 Avelestat (AZD9668) However, the effect of higher doses of AEA is resistant to CB1 blockade49 and may be mediated via putative AEA receptors implicated in the mesenteric vasorelaxant effect of AEA observed in CB1/CB2 double-knockout mice,11, 50 which may also contribute to mesenteric vasodilation in cirrhosis. The hyperdynamic circulation of advanced cirrhosis is associated with increased cardiac output and tachycardia. However, the cirrhotic heart has an underlying decrease in contractility and β-adrenergic hyposensitivity called cirrhotic cardiomyopathy,51 and this has been attributed to endocannabinoid activation of cardiac CB1 receptors on the basis of pharmacological studies using isolated myocardial preparations from bile duct–ligated rats.