Roles of anandamide in the hepatic microcirculation in cirrhotic rats.
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 A(2) 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 B(2) (TXB(2)) 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 TXB(2) and Cys-LT production in the perfusate. In response to anandamide administration, cirrhotic livers exhibited a significantly greater increase in IHR and production of TXB(2) 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 A(2)) production.
Yang
Ying-Ying
YY
Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
Lin
Han-Chieh
HC
Huang
Yi-Tsau
YT
Lee
Tzung-Yan
TY
Hou
Ming-Chih
MC
Wang
Ying-Wen
YW
Lee
Fa-Yauh
FY
Lee
Shou-Dong
SD
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001095:Arachidonic Acids / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003545:Cysteine / Q000378:metabolism; D015777:Eicosanoids / Q000096:biosynthesis; D063388:Endocannabinoids; D066298:In Vitro Techniques; D015289:Leukotrienes / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008102:Liver Circulation / Q000187:drug effects*; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D010477:Perfusion; D053284:Polyunsaturated Alkamides; D051381:Rats; D017207:Rats, Sprague-Dawley; D013929:Thromboxane B2 / Q000096:biosynthesis
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D063388:Endocannabinoids; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D053284:Polyunsaturated Alkamides; C112381:cysteinyl-leukotriene; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003545:Cysteine; C078814:anandamide