Effects of metoprolol on myocardial β-adrenoceptors and G iα -proteins in patients with congestive heart failure

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Abstract
Objective: In human heart failure downregulation of β-adrenoceptors and upregulation of Gi-protein α-subunits (Giα) results desensitization of the myocardial β-adrenergic signal transduction pathway and reduced positive inotropic effects of catecholamines. Metoprolol treatment has been shown to restore the reduced β-adrenoceptor density in dilated cardiomyopathy. The main objective of the present study was to investigate whether metoprolol also decreases the elevated inhibitory Giα levels in patients suffering from congestive heart failure. Methods: Total Giα was determined by pertussis toxin-catalysed ADP ribosylation and β1- and β2-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 β1-selective blocker metoprolol in addition (mean 98 ± 12 mg daily). Results: In biopsies from patients treated with metoprolol, Giα significantly decreased to 74% of predrug value and total β-adrenoceptor increased by a selective increase in β1- 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 Giα-upregulation and β-adrenoceptor downregulation in heart failure, which might contribute to the clinical improvement of patients treated with β-blockers.

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