Differential effects of jaundice and cirrhosis on beta-adrenoceptor signaling in three rat models of cirrhotic cardiomyopathy

Background/Aims: Attenuated cardiac function has been reported in cirrhosis as well as in jaundice, but the mechanisms remain unclear. This study aime d to explore the differential effects of jaundice and cirrhosis on the hear t. Methods: Three rat models of cirrhosis were studied: chronic bile duct liga tion, bile duct ligation followed by choledochojejunostomy to relieve jaund ice, and a less jaundiced model induced by thioacetamide administration. Co ntrols underwent a sham operation. Cardiac function was assessed by measuri ng isolated ventricular papillary muscle contractility. Cardiac beta-adrene rgic receptor signaling was studied by measuring cAMP production stimulated at the receptor, G-protein, and adenylyl cyclase levels in the signaling p athway, using isoproterenol, aluminum fluoride and forskolin, respectively. Results: Serum bilirubin and bile salt levels were markedly elevated in the bile duct-ligated group, moderately increased in the thioacetamide rats, a nd normal in the choledochojejunostomy and sham-operated controls. Papillar y muscle contractile force after maximal beta-adrenergic receptor stimulati on was decreased to a similar extent in all three cirrhotic models. In the bile duct-ligated and thioacetamide-induced cirrhotic rats, production of c AMP by all three drugs was significantly attenuated. However, the cAMP prod uction in the choledochojejunostomy group was blunted only with isoproteren ol and fluoride, and remained intact with forskolin stimulation. Conclusions: These results demonstrate that cirrhosis per se impairs cardia c function by attenuating the portion of the beta-adrenergic receptor signa ling pathway upstream of adenylyl cyclase. Furthermore, significant jaundic e and/or cholemia can inhibit adenylyl cyclase, which may contribute to blu nted cardiac contractility in jaundiced patients.