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LIVER AND BILIARY TRACT

Roles of anandamide in the hepatic microcirculation in cirrhotic rats

¹Institute of Clinical Medicine, National Yang-Ming University School of Medicine, and ²Division of General Medicine and ³Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital; ⁴Department of Medicine and ⁵Institute of Traditional Medicine, National Yang-Ming University School of Medicine, and ⁶Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Taipei, Taiwan

Submitted 8 August 2005 ; accepted in final form 10 October 2005

Cannabinoids have been reported to participate in the pathogenesis of peripheral vasodilatation in cirrhosis. However, their roles in increased intrahepatic resistance (IHR) in cirrhotic livers are unknown. We aimed to investigate the effects of cannabinoids in the hepatic microcirculation of cirrhotic rats produced by bile duct ligation. In isolated liver perfusion, portal perfusion pressure (PPP) and the production of eicosanoids in the perfusate were measured. In addition, various hepatic protein levels [cyclooxygenase (COX) isoform and 5-lipoxygenase (5-LOX)] were also determined. Finally, concentration-response curves for PPP and the corresponding production of eicosanoids in response to anandamide (1.44 x 10^–10–1.44 x 10^–3 M) after indomethacin (COX inhibitor), piriprost (5-LOX inhibitor), or furegrelate (thromboxane A₂ synthase inhibitor) preincubation were obtained. The study showed that cirrhotic livers had significantly higher levels of PPP, COX-2 and 5-LOX protein expression, and production of thromboxane B₂ (TXB₂) and cysteinyl leukotrienes (Cys-LTs) than normal livers. Anandamide induced a dose-dependent increase in PPP in both normal and cirrhotic livers. The anandamide-induced increase in PPP was found concomitantly with a significant increase in TXB₂ and Cys-LT production in the perfusate. In response to anandamide administration, cirrhotic livers exhibited a significantly greater increase in IHR and production of TXB₂ and Cys-LTs than normal livers. Indomethacin and furegrelate, but not piriprost, significantly ameliorated the anandamide-induced increase in IHR in cirrhotic livers. In conclusion, anandamide plays, in part, an important role in increased IHR of cirrhotic livers. The anandamide-induced increase in IHR in cirrhotic livers may be mediated by increased COX-derived eicosanoid (mainly thromboxane A₂) production.

liver perfusion; portal hypertension; eicosanoids; vasoconstriction

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