Effects of altered cardiac membrane fluidity on beta-adrenergic receptor signalling in rats with cirrhotic cardiomyopathy.
OBJECTIVE
The relationship between cardiac plasma membrane physical properties and beta-adrenergic receptor signalling function in cirrhotic cardiomyopathy remains unclear. We aimed to clarify this issue by examining the effect of altering membrane fluidity on beta-adrenergic receptor signalling in cirrhotic rats.


METHODS
Cirrhosis was induced by chronic bile duct ligation, while controls were sham-operated. Left ventricular papillary muscle contractility was measured in an organ bath containing 95% oxygen saturated Tyrode's buffer. Cardiac plasma membrane physical properties, represented by membrane fluidity, were evaluated by fluorescent depolarization, using 1,6-diphenyl-1,3,5,-hexatriene as a probe. Membrane cAMP levels were measured after stimulation at the beta-adrenoceptor level by isoproterenol (10(-4) mol/l), the G-protein level with AIF(-4) (10 mmol/l) and the adenylyl cyclase level with forskolin (100 micromol/l) before and after membrane fluidization with 2-(2-methoxyethoxy)ethyl 8-(cis-2-n-octylcyclopropyl)octanoate (A2C).


RESULTS
Maximum papillary muscle contractile force under isoproterenol stimulation was 0.48+/-0.05 and 0.34+/-0.03 N/cm2 in sham-operated and bile duct ligated rats, respectively (p<0.05). Cardiac membranes from cirrhosis were rigid and this was associated with diminished cAMP generation. After the fluidity of membranes from cirrhotic rats was restored to control values with A2C, cAMP production stimulated with isoproterenol was significantly increased. However, cAMP production stimulated by AIF(-4) and forskolin did not differ before and after membrane fluidization.


CONCLUSIONS
The blunted cardiac contractility of cirrhosis was associated with decreased membrane fluidity and diminished beta-adrenergic receptor signalling. The results suggest that in cirrhotic cardiomyopathy, the rigid plasma membrane interferes with the beta-adrenoceptor and G-protein coupling process.
Ma
Z
Z
Liver Unit, University of Calgary, Canada.
Lee
S S
SS
Meddings
J B
JB
D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000150:complications*; D008297:Male; D008560:Membrane Fluidity; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010210:Papillary Muscles / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction
D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP