Clinical Science (2007) 112, 533-542 - Y.-Y. Yang and others - Effects of cannabinoid receptor inhibition in cirrhotic rats

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Clinical Science (2007) 112, (533–542) (Printed in Great Britain)

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

Ying-Ying YANG * †, Han-Chieh LIN ‡ §, Yi-Tsau HUANG

, Tzung-Yan LEE ¶, Ming-Chih HOU ‡ §, Ying-Wen WANG ‡ §, Fa-Yauh LEE † § and Shou-Dong LEE ‡ §

*Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan, †Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan, ‡Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan, §Department of Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan,

Institute of Traditional Medicine, National Yang-Ming University School of Medicine, Taipei 11217, Taiwan, and ¶Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Taipei 33302, Taiwan

Key words: cannabinoid receptor, cirrhosis, eicosanoid, increased intrahepatic resistance.

Abbreviations: AA, arachidonic acid; BF, blood flow; BW, body weight; CB₁, cannabinoid 1; CBL, common bile-duct ligation; COX, cyclo-oxygenase; HRP, horseradish peroxidase; IHR, intrahepatic resistance; LOX, lipoxygenase; LT, leukotriene; Cys-LT, cysteinyl LT; LW, liver weight; MAP, mean arterial pressure; PG, prostaglandin; PLA₂, phospholipase A₂; cPLA₂, cytosolic PLA₂; PPP, portal perfusion pressure; sPLA₂, secreted PLA₂; PVP, portal venous pressure; RI, resistance index; SMA superior mesenteric artery; TGF-b₁, transforming growth factor-b₁; TX, thromboxane.

Correspondence: Dr Han-Chieh Lin, at the Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan (email hclin@vghtpe.gov.tw).

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_1a (prostaglandin F_1a) and Cys-LTs (cysteinyl leukotrienes)] were measured. Additionally, the protein levels of hepatic COX (cyclo-oxygenase) isoforms, 5-LOX (5-lipoxygenase), CB₁ receptor, TGF-b₁ (transforming growth factor b₁), 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-b₁, 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-b₁ activity, which was associated with decreased hepatic collagen deposition and the activated PLA₂/eicosanoid cascade in cirrhotic livers.