Endocannabinoids acting at vascular CB, receptors mediate the vasodilated state in advanced liver cirrhosis

Advanced cirrhosis is associated with generalized vasodilation of unknown o rigin, 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 cirrhos is have low blood pressure, which is elevated by the CB1 receptor antagonis t SR141716A. The low blood pressure of rats with CCl4-induced cirrhosis was similarly reversed by SR141716A, which also reduced the elevated mesenteri c blood flow and portal pressure. Monocytes from cirrhotic but not control patients or rats elicited SR141716A-sensitive hypotension in normal recipie nt rats and showed significantly elevated levels of anandamide. Compared wi th non-cirrhotic controls, in cirrhotic human livers there was a three-fold increase in CB1 receptors on isolated vascular endothelial cells. These re sults implicate anandamide and vascular CB1 receptors in the vasodilated st ate in advanced cirrhosis and indicate a novel approach for its management.