Contribution of nitric oxide to the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats.
OBJECTIVE
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.
Liu
H
H
Liver Unit, Gastroenterology Research Group, University of Calgary, Calgary, Alberta, Canada.
Ma
Z
Z
Lee
S S
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D000818:Animals; D001652:Bile Ducts; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D003251:Constriction, Pathologic; D006152:Cyclic GMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles / Q000378:metabolism; D007150:Immunohistochemistry; D008026:Ligation; D008106:Liver Cirrhosis, Experimental / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left
D016207:Cytokines; D004791:Enzyme Inhibitors; D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D006152:Cyclic GMP