Anandamide mediates hyperdynamic circulation in cirrhotic rats via CB(1) and VR(1) receptors.
OBJECTIVE
Hyperdynamic circulation and mesenteric hyperaemia are found in cirrhosis. To delineate the role of endocannabinoids in these changes, we examined the cardiovascular effects of anandamide, AM251 (CB(1) antagonist), AM630 (CB(2) antagonist) and capsazepine (VR1 antagonist), in a rat model of cirrhosis.


METHODS
Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, diameters of mesenteric arteriole and venule (intravital microscopy), arterial pressure, cardiac output, systemic vascular resistance and superior mesenteric artery (SMA) flow were measured after anandamide, AM251 (with or without anandamide), AM630 and capsazepine administration. CB(1), CB(2) and VR1 receptor expression in SMA was assessed by western blot and RT-PCR.


RESULTS
Anandamide increased mesenteric vessel diameter and flow, and cardiac output in cirrhotic rats, but did not affect controls. Anandamide induced a triphasic arterial pressure response in controls, but this pattern differed markedly in cirrhotic rats. Pre-administration of AM251 blocked the effects of anandamide. AM251 (without anandamide) increased arterial pressure and systemic vascular resistance, constricted mesenteric arterioles, decreased SMA flow and changed cardiac output in a time-dependent fashion in cirrhotic rats. Capsazepine decreased cardiac output and mesenteric arteriolar diameter and flow, and increased systemic vascular resistance in cirrhotic rats, but lacked effect in controls. Expression of CB(1) and VR1 receptor proteins were increased in cirrhotic rats. AM630 did not affect any cardiovascular parameter in either group.


CONCLUSIONS
These data suggest that endocannabinoids contribute to hyperdynamic circulation and mesenteric hyperaemia in cirrhosis, via CB(1)- and VR1-mediated mechanisms.
Moezi
L
L
Liver Unit, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
Gaskari
S A
SA
Liu
H
H
Baik
S K
SK
Dehpour
A R
AR
Lee
S S
SS
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001652:Bile Ducts / Q000601:surgery; D001783:Blood Flow Velocity; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002302:Cardiac Output / Q000187:drug effects; D004195:Disease Models, Animal; D063388:Endocannabinoids; D006940:Hyperemia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D008102:Liver Circulation / Q000187:drug effects; D008105:Liver Cirrhosis, Biliary / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D017538:Mesenteric Artery, Superior / Q000737:chemistry / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013152:Splanchnic Circulation / Q000187:drug effects*; D050916:TRPV Cation Channels / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D001095:Arachidonic Acids; D063388:Endocannabinoids; D007211:Indoles; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014665:Vasodilator Agents; C103505:AM 251; C071423:capsazepine; D002211:Capsaicin; C094023:iodopravadoline; C078814:anandamide