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 CB(1) (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 CB(1) receptor antagonist, IHR, SMA (superior mesenteric artery) blood flow and hepatic production of eicosanoids [TXB(2) (thromboxane B(2)), 6-keto PGF(1alpha) (prostaglandin F(1alpha)) and Cys-LTs (cysteinyl leukotrienes)] were measured. Additionally, the protein levels of hepatic COX (cyclo-oxygenase) isoforms, 5-LOX (5-lipoxygenase), CB(1) receptor, TGF-beta(1) (transforming growth factor beta(1)), cPLA(2) [cytosolic PLA(2) (phospholipase A(2))], sPLA(2) (secreted PLA(2)) 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 CB(1) receptor, TGF-beta(1), cPLA(2) and hepatic collagen deposition, and the hepatic levels of 5-LOX and COX-2 and the corresponding production of TXB(2) 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-beta(1) activity, which was associated with decreased hepatic collagen deposition and the activated PLA(2)/eicosanoid cascade in cirrhotic livers.
Yang
Ying-Ying
YY
Institute of Clinical Medicine, National Yang-Ming University School of Medicine, 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 / Q000032:analysis; D003094:Collagen / Q000032:analysis; D017998:Leukotriene D4 / Q000096:biosynthesis; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000503:physiopathology; D008833:Microcirculation; D010741:Phospholipases A / Q000032:analysis; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D012039:Regional Blood Flow / Q000187:drug effects; D013929:Thromboxane B2 / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000032:analysis; D014655:Vascular Resistance / Q000187:drug effects
D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D016212:Transforming Growth Factor beta; C103505:AM 251; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D017998:Leukotriene D4; D003094:Collagen; D001094:Arachidonate 5-Lipoxygenase; D010741:Phospholipases A