LONG-TERM TREATMENT WITH ANGIOTENSIN I-CONVERTING ENZYME-INHIBITORS ATTENUATES THE LOSS OF CARDIAC BETA-ADRENOCEPTOR RESPONSES IN RATS WITH CHRONIC HEART-FAILURE

Background Cardiac contractile force in response to beta-adrenoceptor agonists and beta-adrenergic receptor density are decreased in failing human hearts. The effects of angiotensin I-converting enzyme (ACE) inhibitor on cardiac responsiveness to beta-adrenergic stimulation in failing hearts are not established. The present study was undertaken to determine whether ACE inhibitor may improve cardiac beta-adrenergic responsiveness in animals with chronic heart failure (CHF). Methods and Results CHF was induced by left coronary artery ligation in rats. Cardiac output and stroke volume indices decreased 12 weeks after the operation. Tn sham-operated rats, dobutamine and isoprenaline increased cardiac output and stroke volume indices. In contrast, cardiac output and stroke Volume responses to dobutamine and isoprenaline were severely blunted in the CHF rat Cardiac beta(1)-adrenergic receptor density was decreased while its dissociation constant (K-d) was not altered in the viable tissue of the left ventricle of the CHF rat, which is consistent with beta-adrenergic receptor downregulation. Cardiac norepinephrine content decreased in the CHF rats. Rats were treated orally with ACE inhibitors, 3 mg/kg trandolapril or 10 mg/kg enalapril once daily, or 5 mg/kg captopril twice daily from the 2nd to the 12th weeks after the operation. Treatment with ACE inhibitors attenuated the reduction in cardiac output and stroke volume indices and improved the inotropic response to dobutamine and isoprenaline and reversed partially the cardiac norepinephrine content in the CHF rat. ACE inhibitor treatment also attenuated the reduction in beta(1)-adrenergic receptor density in the viable tissue of the left ventricle of the CHF rat. Conclusions The results suggest that ACE inhibitor treatment attenuates the blunting of cardiac responses to beta-adrenergic agonists in the CHF rat and that one of the mechanisms underlying this effect is prevention of cardiac beta(1)-adrenergic receptor downregulation.