53 The suppression of cardiac contractility by CB1 SCH 900776 nmr receptor activation may involve inhibition of L-type calcium channels54 and/or reductions in the myocardial cyclic adenosine

monophosphate content.55 Of the 2 major endocannabinoids, AEA is more likely to be involved, as suggested by a cirrhosis-related increase in myocardial AEA levels but not 2-AG levels.53 These findings raise the therapeutic potential of CB1 blockade in treating the hemodynamic abnormalities of patients with advanced liver cirrhosis. Because the increase in mesenteric blood flow may precipitate the rupture of varicosities and also contributes to ascites formation, CB1 blockade may avert these potentially fatal complications and thus keep patients alive until a liver transplant becomes available. CB2 receptors, which are normally undetectable in the liver, are prominently expressed in the cirrhotic human liver and are also detectable in nonparenchymal liver cells in the fibrotic mouse liver.9 THC suppresses the proliferation and induces the apoptosis of human hepatic myofibroblasts and stellate cells via CB2 receptors9 and thus may be antifibrotic and hepatoprotective.56

Accordingly, CB2−/− mice had an enhanced response to fibrogenic stimuli.9 CB2 receptor activation Cilomilast supplier by AEA also inhibits the hyperplastic proliferation of cholangiocytes, which is a frequent result of extrahepatic biliary obstruction, cholestasis, and toxic liver injury. This has been associated with the increased production of reactive oxygen species and cell death via the induction of the activator protein 4-Aminobutyrate aminotransferase 1 complex and thioredoxin 1.3 In cirrhotic rats, chronic treatment with the CB2-selective agonist JWH-133 attenuated cellular markers of fibrosis57 and enhanced the regenerative response to acute liver injury. Accordingly, CB2−/− mice had delayed liver regeneration in response to CCl4-induced injury, whereas JWH-133 treatment reduced the injury and accelerated liver regeneration.33 These

findings signal the therapeutic potential of nonpsychoactive CB2 agonists in the treatment of liver fibrosis. Paradoxically, in patients with hepatitis C virus infection, daily cannabis use increased fibrosis progression instead of protecting patients against it.58 Thus, endocannabinoids also exert a profibrotic effect that is possibly mediated by CB1 receptors. This is compatible with the finding of increased CB1 expression in stellate cells and hepatic myofibroblasts in the cirrhotic human liver and in the livers of mice with three different models of fibrosis.5 Genetic or pharmacological ablation of CB1 receptors protected mice against liver injury; this was reflected by the reduced expression of smooth muscle α-actin and transforming growth factor β.5 2-AG is the likely fibrogenic mediator because its hepatic level is preferentially increased by the CCl4 treatment of mice26 and rats.