Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis.
Advanced cirrhosis is associated with generalized vasodilation of unknown origin, which contributes to mortality. Cirrhotic patients are endotoxemic, and activation of vascular cannabinoid CB1 receptors has been implicated in endotoxin-induced hypotension. Here we show that rats with biliary cirrhosis have low blood pressure, which is elevated by the CB1 receptor antagonist SR141716A. The low blood pressure of rats with CCl4-induced cirrhosis was similarly reversed by SR141716A, which also reduced the elevated mesenteric blood flow and portal pressure. Monocytes from cirrhotic but not control patients or rats elicited SR141716A-sensitive hypotension in normal recipient rats and showed significantly elevated levels of anandamide. Compared with non-cirrhotic controls, in cirrhotic human livers there was a three-fold increase in CB1 receptors on isolated vascular endothelial cells. These results implicate anandamide and vascular CB1 receptors in the vasodilated state in advanced cirrhosis and indicate a novel approach for its management.
Bátkai
S
S
National Institute on Alcohol Abuse & Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
Járai
Z
Z
Wagner
J A
JA
Goparaju
S K
SK
Varga
K
K
Liu
J
J
Wang
L
L
Mirshahi
F
F
Khanolkar
A D
AD
Makriyannis
A
A
Urbaschek
R
R
Garcia
N
N
Sanyal
A J
AJ
Kunos
G
G
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators; D002851:Chromatography, High Pressure Liquid; D063388:Endocannabinoids; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D007022:Hypotension / Q000209:etiology; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D013058:Mass Spectrometry; D009000:Monocytes / Q000378:metabolism; D053284:Polyunsaturated Alkamides; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism*; D014664:Vasodilation / Q000502:physiology*
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C078814:anandamide