Marijuana-like substances (endocannabinoids) intrinsic in animals and humans act at specific receptors on the blood vessel wall to produce vasodilation, the generalized blood vessel dilation seen in many patients with advanced liver cirrhosis, according to an article by George Kunos, M.D., Ph.D., and colleagues in the July 1 issue of Nature Medicine (Volume 7, Number 7; Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis). Dr. Kunos, who serves as Scientific Director, Division of Intramural Biological and Clinical Research, NIAAA, performed some of the research under an NIH grant from his previous position on the faculty of the Department of Medicine at Virginia Commonwealth University.
In advanced cirrhosis, vasodilation lowers blood pressure and increases blood flow to the liver and gut. Due to liver scarring, this increased blood flow meets with resistance, resulting in elevated portal pressure (portal hypertension) that can cause fluid to accumulate in the abdomen (a condition known as ascites) and dilated blood vessels to rupture—both life-threatening complications. Prevailing theory has held that an unknown endogenous vasodilator contributes to the maintenance of portal hypertension and the development of ascites.
In the series of experiments reported July 1, Dr. Kunos and his colleagues demonstrate that the elusive mediator is most likely an endocannabinoid acting at vascular CB1 receptors. "Our findings raise the promising possibility that CB1 receptor-blocking drugs can reverse the vasodilated state and reduce the risk of death in patients who are awaiting liver transplants," Dr. Kunos said.
The research team led by Dr. Kunos found elevated levels of the endocannabinoid anandamide and low blood pressure in two distinct animal models of cirrhosis. Using the CB1 antagonist SR141716A, they succeeded in raising blood pressure and reducing portal pressure and blood flow to the liver.
A separate experiment demonstrated that macrophages, a special type of white blood cell isolated from the blood of cirrhotic humans and rats, contained elevated levels of the endocannabinoid anandamide. When the researchers injected such macrophages into healthy animals, they decreased blood pressure—an effect that they also found could be prevented by pretreatment with SR141719A.
In addition to elevated levels of anandamide, the researchers found elevated cellular levels of its receptor; in human cirrhotic liver samples, they identified a threefold increase in CB1 receptors in cells lining the blood vessel walls. "Taken together, these findings strongly implicate anandamide and vascular CB1 receptors in the vasodilated state in advanced cirrhosis and indicate a novel approach for its management," the authors conclude.
An estimated three and a half million Americans have liver cirrhosis—a progressive disease that develops as a long-term consequence of chronic alcoholism or viral hepatitis and produces scarring and eventual loss of liver function. Cirrhosis is second only to traffic crashes as the leading cause of alcohol-related deaths. At present, the only definitive treatment is transplantation.
"New understandings of the mechanisms of cirrhosis recently have emerged, providing hope that soon we may have medications that can interrupt or reverse the disease process," said NIAAA Director Enoch Gordis, M.D. "The work by Dr. Kunos and his colleagues extends that hope even to treatments for end-stage cirrhosis."
For interviews with Dr. Kunos, please telephone 514/878-2332 through June 26, and 34-91-896-7000 June 28 and 29; after July 1, telephone his office (301/443-2069). For interviews with Dr. Gordis, please telephone the NIAAA press office.
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The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of U.S. research on the causes, consequences, prevention and treatment of alcohol abuse, alcoholism, and alcohol problems and disseminates research findings to science, practitioner, policy making, and general audiences.