Inhibition of hepatic tumour necrosis factor-α attenuates the anandamide-induced vasoconstrictive response in cirrhotic rat livers

Background: Increased anandamide, an endocannabinoid that interacts with both cannabinoid CB1 and CB2 receptors, can induce hepatic vasoconstrictive responses that contribute to the increased intrahepatic resistance (IHR) in cirrhotic rats. Chronic endotoxaemia and the subsequent release of tumour necrosis factor-alpha (TNF-alpha) are suggested to result in increased anandamide in cirrhotic livers. Thalidomide, which inhibited TNF-alpha effectively, has been used clinically in states of chronic TNF-alpha elevation with encouraging results. Aims: This study explores the possible effects of thalidomide on hepatic endocannabinoids and microcirculation of cirrhotic rats. Methods: Portal venous pressure (PVP), superior mesenteric arterial blood flow (SMA BF), hepatic TNF-alpha, interleukin (IL-6), protein expression of CB1 and CB2 receptor and thromboxane synthase (TXS) were measured in bile duct-ligated (BDL) rats receiving 1-month of vehicle (BDL-V) or thalidomide (BDL-thalido). The degree of hepatic fibrosis was also assessed. In the liver perfusion system, IHR and concentration-response curves of the portal perfusion pressure to anandamide were evaluated. Results: In BDL-thalido rats, PVP, IHR and hepatic levels of TNF-alpha and IL-6, protein expression of CB1 receptors, TXS and hepatic fibrosis were lower than in BDL-V rats. In BDL-thalido rat livers, the attenuation of the vasoconstrictive response to anandamide was associated with an upregulation of the CB2 receptor and a downregulation of the CB1 receptor. Nevertheless, SMA BF was not different between BDL-thalido and BDL-V rats. Conclusions: Thalidomide decreased the PVP and IHR through the attenuation of anandamide-induced constrictive response, decreasing the production of TNF-alpha, IL-6 and TXA(2) in the liver and the suppression of hepatic fibrogenesis of rats with biliary cirrhosis of this study.