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-methoxy-ethoxy)ethyl 8-(cis-2-n-octylcyclopropyl)octanoate (A2C), 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.
Ma
Z
Z
Gastroenterology Research Group, University of Calgary, Alberta, Canada.
Meddings
J B
JB
Lee
S S
SS
D000818:Animals; D002462:Cell Membrane / Q000502:physiology; D000242:Cyclic AMP / Q000096:biosynthesis; D007700:Kinetics; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism*; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D008563:Membrane Lipids; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP