Effect of chronic CB₁ cannabinoid receptor antagonism on livers of rats with biliary cirrhosis

Recent studies have shown that the activated endocannabinoid system participates in the increase in IHR (intrahepatic resistance) in cirrhosis. The increased hepatic production of vasoconstrictive eicosanoids is involved in the effect of endocannabinoids on the hepatic microcirculation in cirrhosis; however, the mechanisms of these effects are still unknown. The aim of the present study was to investigate the effects of chronic CB₁ (cannabinoid 1) receptor blockade in the hepatic microcirculation of CBL (common bile-duct-ligated) cirrhotic rats. After 1 week of treatment with AM251, a specific CB₁ receptor antagonist, IHR, SMA (superior mesenteric artery) blood flow and hepatic production of eicosanoids [TXB₂ (thromboxane B₂), 6-keto PGF_1α (prostaglandin F_1α) and Cys-LTs (cysteinyl leukotrienes)] were measured. Additionally, the protein levels of hepatic COX (cyclo-oxygenase) isoforms, 5-LOX (5-lipoxygenase), CB₁ receptor, TGF-β₁ (transforming growth factor β₁), cPLA₂ [cytosolic PLA₂ (phospholipase A₂)], sPLA₂ (secreted PLA₂) and collagen deposition were also measured. In AM251-treated cirrhotic rats, a decrease in portal venous pressure was associated with the decrease in IHR and SMA blood flow. Additionally, the protein levels of hepatic CB₁ receptor, TGF-β₁, cPLA₂ and hepatic collagen deposition, and the hepatic levels of 5-LOX and COX-2 and the corresponding production of TXB₂ and Cys-LTs in perfusates, were significantly decreased after 1 week of AM251 treatment in cirrhotic rats. Furthermore, acute infusion of AM251 resulted in a decrease in SMA blood flow and an increase in SMA resistance in CBL rats. In conclusion, the chronic effects of AM251 treatment on the intrahepatic microcirculation were, at least partly, mediated by the inhibition of hepatic TGF-β₁ activity, which was associated with decreased hepatic collagen deposition and the activated PLA₂/eicosanoid cascade in cirrhotic livers.