Desensitization of myocardial β-adrenergic receptors in cirrhotic rats

Abstract

Cardiac responses to catecholamines are known to be attenuated in chronic liver disease. To elucidate the role of beta-adrenergic receptor alteration in this phenomenon, we measured heart rate responsiveness to isoprenaline and myocardial beta-adrenergic receptor-binding characteristics in three groups of rats: those that were sham operated, those that had portal vein stenosis and those that were cirrhotic because of bile duct ligation. Responsiveness to isoprenaline was evaluated in conscious rats by the dose of isoprenaline needed to increase basal heart rate by 50 beats/min and by the maximal heart rate response. beta-Receptor characteristics in heart membranes were derived from 125I-iodocyanopindolol binding data. Compared with sham-operated controls, cirrhotic rats needed a significantly higher dose of isoprenaline to raise basal heart rate by 50 beats/min (102.3 +/- 19.1 vs. 28.3 +/- 11.3 ng/kg) and lower maximal heart rate response (104 +/- 29 vs. 158 +/- 61 beats/min). In addition, myocardial beta-receptor density was significantly lower in cirrhotic rats (26.5 +/- 4.6 vs. 37.5 +/- 10.3 fmol/mg protein) and the dissociation constant was higher (31.6 +/- 17.0 vs. 14.0 +/- 2.5 pmol/L). Analysis of beta 1/beta 2 subpopulations revealed that the decreased total beta-receptor density was entirely due to selective beta 1-receptor down-regulation. beta-Receptor affinity for agonist was not altered in cirrhotic rats. Rats with portal vein stenosis showed no significant differences in either isoprenaline responsiveness or beta-receptor characteristics when compared with controls. These results indicate that beta-adrenergic receptor down-regulation may be responsible for the myocardial hyporesponsiveness to catecholamines observed in cirrhosis.

Heart Function and Myocardial Tissue Characterization in Patients with HCV Related Cirrhosis: Diastolic Dysfunction and Cardiac Hypertrophy

“…Hyperdinamic circulation [3], QTc prolongation [4,5], beta-receptors desensitization [6,7], reduced systolic competence under strains [8][9][10][11] and diastolic dysfunction [12][13][14][15][16][17] are the key features of cirrhotic cardiomyopathy. Diastolic dysfunction, characterized by an altered pattern of transmitral flow due to impaired diastolic relaxation of left ventricle, can be easily assessed by echocardiography and accordingly can be considered as a marker of this condition.…”

Cardiac dysfunction in spontaneous bacterial peritonitis: A manifestation of cirrhotic cardiomyopathy?

“…5 In 1990, we documented down-regulation of ventricular ␤-adrenoceptors in rats with biliary cirrhosis. 6 Since then, a large number of studies have incontrovertibly demonstrated that both patients and animal models with nonalcoholic cirrhosis show blunted cardiac inotropic and chronotropic responses to diverse stimuli such as exercise, drugs, hemorrhage, surgery, or other stresses (reviewed [7][8][9] ). Thus was born the general definition of cirrhotic cardiomyopathy: depressed responsiveness to stimuli in the face of increased baseline contractility.…”

Hyperdynamic circulation in portal-hypertensive rats is dependent on central c-fos gene expression

“…3 In both cirrhosis and portal hypertension there is a decreased pressor sensitivity and impaired chronotropic responses to catecholamines. 4,5 Neural factors have been postulated to be involved in the genesis of the disturbed cardiovascular function in liver disease. Earlier studies have shown indirect evidence of sympathetic overactivity, as judged by elevated serum catecholamine levels in cirrhosis.…”