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

Abstract

Background/Aims: Attenuated cardiac function has been reported in cirrhosis as well as in jaundice, but the mechanisms remain unclear. This study aimed to explore the differential effects of jaundice and cirrhosis on the heart. Methods: Three rat models of cirrhosis were studied: chronic bile duct ligation, bile duct ligation followed by choledochojejunostomy torelieve jaundice, and a less jaundiced model induced by thioacetamide administration. Controls underwent a sham operation. Cardiac function was assessed by measuring isolated ventricular papillary muscle contractility. Cardiac β-adrenergic receptor signaling was studied by measuring cAMP production stimulated at the receptor, G-protein, and adenylyl cyclase levels in the signaling pathway, 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, and normal in the choledochojejunostomy and sham-operated controls. Papillary muscle contractile force after maximal β-adrenergic receptor stimulation was decreased to a similar extent in all three cirrhotic models. In the bile duct-ligated and thioacetamide-in-duced cirrhotic rats, production of cAMP by all three drugs was significantly attenuated. However, the cAMP production in the choledochojejunostomy group was blunted only with isoproterenol and fluoride, and remained intact with forskolin stimulation. Conclusions: These results demonstrate that cirrhosis per se impairs cardiac function by attenuating the portion of the β-adrenergic receptor signaling pathway upstream of adenylyl cyclase. Furthermore, significant jaundice and/or cholemia can inhibit adenylyl cyclase, which may contribute to blunted cardiac contractility in jaundiced patients.