Inhibition of hepatic tumour necrosis factor-alpha attenuates the anandamide-induced vasoconstrictive response in cirrhotic rat livers.
BACKGROUND
Increased anandamide, an endocannabinoid that interacts with both cannabinoid CB(1) and CB(2) receptors, can induce hepatic vasoconstrictive responses that contribute to the increased intrahepatic resistance (IHR) in cirrhotic rats. Chronic endotoxaemia and the subsequent release of tumour necrosis factor-alpha (TNF-alpha) are suggested to result in increased anandamide in cirrhotic livers. Thalidomide, which inhibited TNF-alpha effectively, has been used clinically in states of chronic TNF-alpha elevation with encouraging results.


OBJECTIVE
This study explores the possible effects of thalidomide on hepatic endocannabinoids and microcirculation of cirrhotic rats.


METHODS
Portal venous pressure (PVP), superior mesenteric arterial blood flow (SMA BF), hepatic TNF-alpha, interleukin (IL-6), protein expression of CB(1) and CB(2) receptor and thromboxane synthase (TXS) were measured in bile duct-ligated (BDL) rats receiving 1-month of vehicle (BDL-V) or thalidomide (BDL-thalido). The degree of hepatic fibrosis was also assessed. In the liver perfusion system, IHR and concentration-response curves of the portal perfusion pressure to anandamide were evaluated.


RESULTS
In BDL-thalido rats, PVP, IHR and hepatic levels of TNF-alpha and IL-6, protein expression of CB(1) receptors, TXS and hepatic fibrosis were lower than in BDL-V rats. In BDL-thalido rat livers, the attenuation of the vasoconstrictive response to anandamide was associated with an upregulation of the CB(2) receptor and a downregulation of the CB(1) receptor. Nevertheless, SMA BF was not different between BDL-thalido and BDL-V rats.


CONCLUSIONS
Thalidomide decreased the PVP and IHR through the attenuation of anandamide-induced constrictive response, decreasing the production of TNF-alpha, IL-6 and TXA(2) in the liver and the suppression of hepatic fibrogenesis of rats with biliary cirrhosis of this study.
Department of Medicine, Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Ying-Ying
YY
Yang
Kuei-Chuan
KC
Lee
Yi-Tsau
YT
Huang
Fa-Yauh
FY
Lee
Ga-Yang
GY
Chau
Che-Chuan
CC
Loong
Han-Chieh
HC
Lin
Shou-Dong
SD
Lee
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D063388:Endocannabinoids; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000098:blood supply / Q000378:metabolism*; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism*; D008833:Microcirculation / Q000187:drug effects; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013792:Thalidomide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*
D001095:Arachidonic Acids; D017931:DNA Primers; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; C078814:anandamide