MEMBRANE PHYSICAL-PROPERTIES DETERMINE CARDIAC BETA-ADRENERGIC-RECEPTOR FUNCTION IN CIRRHOTIC RATS

To elucidate the basic membrane mechanisms underlying cirrhotic cardiomyopathy, cardiac sarcolemmal plasma membrane physical properties, chemical composition, beta-adrenoceptor density, binding affinity, and isoproterenol-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) production were studied. Cirrhosis was induced by chronic bile duct ligation, while controls underwent a sham operation. The cardiac plasma membrane of cirrhotic rats was found to be more rigid than controls, primarily due to an increased cholesterol-to-phospholipid ratio. In cirrhotic animals, beta-adrenergic dysfunction was evident with a 21% decrease in beta-adrenoceptor density but no alteration in binding affinity. Despite the modest decrease in receptor number, beta-adrenoceptor-stimulated cAMP production was decreased by 37% in cirrhotic rats. When the membrane physical properties of the cirrhotic rats were restored to normal, by incubation with the fluidizing agent 2-(2-methoxyethoxy)ethyl 8-(cis-2-n-octylcyclopropyl)octanoate (A(2)C), isoproterenol-stimulated cAMP production also increased to levels indistinguishable from control animals. Restoration of membrane physical properties had no effect on either beta-adrenoceptor density or binding affinity. These results suggest that the increased rigidity of cardiomyocyte plasma membranes seen with cirrhosis is associated with decreased beta-adrenoceptor function. Moreover, restoring normal physical properties may result in restoration of beta-adrenoceptor-mediated contractile function.