Advanced cirrhosis of the liver, a longterm consequence of viral hepatitis or chronic alcohol abuse, is associated with generalized vasodilation of unknown origin, which contributes to potentially letjhal complications such as ascites and variceal hemorrhage. Cirrhotic patients are endotoxemic, and we have previously shown that activation of vascular cannabinoid CB1 receptors is involved in endotoxin-induced hypotension (FASEB J. 12:1035-1044, 1998). In the present reporting period we have demonstrated that rats with biliary cirrhosis, induced by ligation of the common bile duct, have low blood pressure, which can be ioncreased by the administration of 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 venous pressure. Monocytes from cirrhotic but not control patients or rats elicited SR141716A-sensitive hypotension when injected into normal recipient rats, and were found to contain elevated levels of the endocannabinoid anandamide. Vascular endothelial cells isolated from cirrhotic human livers removed at transplantation had a 3-fold increase in CB1 receptors as compared to endothelial cells isolated from non-cirrhotic human liver tissue. These results implicate anandamide and vascular CB1 receptors in the vasodilated state of advanced liver cirrhosis and suggest a novel approach for its pharmacological management. In another study using the radiolabeled microsphere technique, we found that cannabinoids elicit profound cerebral and coronary vasodilation in vivo by direct activation of vascular cannabinoid CB1 receptors, rather than via autoregulation, a decrease in sympathetic tone or, in the case of anandamide, via the action of a non-cannabinoid metabolite.
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