Effects of metoprolol on myocardial beta-adrenoceptors and Gi alpha-proteins in patients with congestive heart failure.

OBJECTIVE: In human heart failure downregulation of beta-adrenoceptors and upregulation of Gi-protein alpha-subunits (Gi alpha) results desensitization of the myocardial beta-adrenergic signal transduction pathway and reduced positive inotropic effects of catecholamines. Metoprolol treatment has been shown to restore the reduced beta-adrenoceptor density in dilated cardiomyopathy. The main objective of the present study was to investigate whether metoprolol also decreases the elevated inhibitory Gi alpha levels in patients suffering from congestive heart failure.
METHODS: Total Gi alpha was determined by pertussis toxin-catalysed ADP ribosylation and beta 1- and beta 2-adrenoceptor densities by radioligand binding in right ventricular myocardial biopsies of 18 patients with dilated or ischaemic cardiomyopathy (NYHA II-IV) before and after 3 months of therapy. Nine controls were treated with conventional therapy only [diuretics, digitalis, nitrates, angiotensin-converting enzyme (ACE) inhibitors], and nine received the beta 1-selective blocker metoprolol in addition (mean 98 +/- 12 mg daily).
RESULTS: In biopsies from patients treated with metoprolol, Gi alpha significantly decreased to 74% of predrug value and total beta-adrenoceptor increased by a selective increase in beta 1-adrenoceptors (44.7 vs 34.0 fmol mg-1 protein). These effects were accompanied by significantly increased oxygen uptake at the anaerobic threshold (8.65 vs 6.95 ml . kg-1 . min-1). In the control group no significant changes in biochemical and clinical parameters occurred.
CONCLUSION: Metoprolol partly reverses Gi alpha-upregulation and beta-adrenoceptor downregulation in heart failure, which might contribute to the clinical improvement of patients treated with beta-blockers.