Portal hypertension and the hyperdynamic circulation: Nitric oxide in a haze of cannabinoid smoke (Reprinted from Nat Med, vol 7, 827-832)

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 i n endotoxin-induced hypotension. Here we show that rats with biliary cirrho sis have low blood pressure, which is elevated by the CB1 receptor antagoni st SR141716A. The low blood pressure of rats with CC14-induced cirrhosis wa s similarly reversed by SR141716A, which also reduced the elevated mesenter ic blood flow and portal pressure. Monocytes from cirrhotic but not control patients or rats elicited SR141716A-sensitive hypotension in normal recipi ent rats and showed significantly elevated levels of anandamide. Compared w ith non-cirrhotic controls, in cirrhotic human livers there was a three-fol d increase in CB1 receptors on isolated vascular endothelial cells. These r esults implicate anandamide and vascular CB1 receptors in the vasodilated s tate in advanced cirrhosis and indicate a novel approach for its management .