Elsevier

Journal of Hepatology

Volume 30, Issue 3, March 1999, Pages 485-491
Journal of Hepatology

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

https://doi.org/10.1016/S0168-8278(99)80109-3Get rights and content

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.

Section snippets

Chemical reagents and isotopes

cAMP protein binding assay kits were purchased from Amersham Canada Ltd. (Montreal, QC, Canada). Adenosine 5′-triphosphate (ATP), Guanosine 5′-triphosphate (GTP), (−)-isoproterenol (−)-bitartrate salt, sodium fluoride, aluminum chloride, and forskolin were purchased from Sigma Chemical Company (St. Louis, MO, USA). Other reagents were obtained either from Sigma or Fisher Scientific (Pittsburgh, PA, USA) and were the highest grade available.

Animal models

Male Sprague-Dawley rats (Bioscience Ltd, Calgary, AB

Histological and biochemical characteristics of the cirrhotic models

The liver architecture was severely deranged at 4 weeks after bile duct ligation surgery. Tremendous bile ductular proliferation was observed in portal areas. Fibrosis and hepatocyte necrosis were evident. Similar changes were observed in rats 10 days after undergoing choledochojejunostomy. In addition, after choledochojejunostomy, the liver and spleen weights were similar to the BDL rats, although the degree of ascites was decreased. Also, hepatocyte necrosis was less severe in the

Discussion

Over the past decade, we and others have been investigating the pathogenesis of cirrhotic cardiomyopathy 14., 16., 19., 20., 21. using the chronic bile duct-ligated rat, a model notable for deep jaundice. Because jaundice per se can induce blunted cardiac function 22., 23., this approach has been subject to the criticism that any observed changes could be due to the jaundice rather than cirrhosis. Accordingly, we felt that clarification of the roles and possible interaction between jaundice and

Acknowledgements

This study was funded by operating research grants from the Medical Research Council of Canada. Dr Ma was supported by a Canadian Liver Foundation Fellowship award and Dr Lee by an Alberta Heritage Foundation for Medical Research Scholarship award.

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