Contribution of nitric oxide to the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats

Gastroenterology. 2000 May;118(5):937-44. doi: 10.1016/s0016-5085(00)70180-6.


Background & aims: Decreased cardiac contractility and beta-adrenergic responsiveness have been observed in cirrhosis, but the etiology remains unclear. We aimed to test the role of nitric oxide (NO), a negative inotropic agent, in the pathogenesis of cirrhotic cardiomyopathy in a rat model.

Methods: Cirrhosis was induced by bile duct ligation. Four weeks after ligation or sham operation, cardiac levels of tumor necrosis factor (TNF)-alpha, guanosine 3,5'-cyclic monophosphate (cGMP), inducible NOS (NOS2), and endothelial constitutive NOS (NOS3) messenger RNA (mRNA) and protein were determined. Serum nitrite/nitrate level was measured. Cardiac contractile function was evaluated in isolated left ventricular papillary muscles in the absence and presence of the NOS inhibitor nitro-L-arginine methyl ester (L-NAME).

Results: Cardiac TNF-alpha, NOS2 mRNA and protein, cGMP, and serum interleukin (IL)-1beta and nitrite/nitrate levels were significantly higher in cirrhotic rats than sham controls. No significant differences in NOS3 mRNA or protein were found between cirrhotic and sham control rats. Baseline isoproterenol-stimulated papillary muscle contractile force was significantly lower in the cirrhotic group; with L-NAME incubation, contractile force increased significantly in cirrhotic rats but was unaffected in the controls. In normal papillary muscles, IL-1beta attenuated the contractility, but coincubation with L-NAME again reversed this attenuation. Incubation with the exogenous NO donor S-nitroso-N-acetyl-penicillamine also blunted papillary muscle contractility.

Conclusions: These results suggest that cytokine-induced stimulation of NOS2 plays a significant role in the pathogenesis of cirrhotic cardiomyopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Ducts
  • Blotting, Western
  • Cardiomyopathies / etiology
  • Cardiomyopathies / metabolism*
  • Cardiomyopathies / physiopathology
  • Constriction, Pathologic
  • Cyclic GMP / metabolism
  • Cytokines / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Heart Ventricles / metabolism
  • Immunohistochemistry
  • Ligation
  • Liver Cirrhosis, Experimental / complications
  • Liver Cirrhosis, Experimental / metabolism*
  • Liver Cirrhosis, Experimental / physiopathology
  • Male
  • Myocardial Contraction / drug effects
  • Myocardium / metabolism
  • Nitrates / blood
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nitric Oxide*
  • Nitrites / blood
  • Rats
  • Rats, Sprague-Dawley
  • Ventricular Function, Left


  • Cytokines
  • Enzyme Inhibitors
  • Nitrates
  • Nitric Oxide Donors
  • Nitrites
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos2 protein, rat
  • Nos3 protein, rat
  • Cyclic GMP