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 β‐adrenergic receptor alteration in this phenomenon, we measured heart rate responsiveness to isoprenaline and myocardial β‐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. β‐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 β‐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 β₁/β₂ subpopulations revealed that the decreased total β‐receptor density was entirely due to selective β₁‐receptor down‐regulation. β‐Receptor affinity for agonist was not altered in cirrhotic rats. Rats with portal vein stenosis showed no significant differences in either isoprenaline responsiveness or β‐receptor characteristics when compared with controls. These results indicate that β‐adrenergic receptor down‐regulation may be responsible for the myocardial hyporesponsiveness to catecholamines observed in cirrhosis. (HEPATOLOGY 1990;12:481–485).