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

Abstract

Objective: In human heart failure downregulation of β-adrenoceptors and upregulation of G_i-protein α-subunits (G_iα) 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 G_iα levels in patients suffering from congestive heart failure.

Methods:

Total G_iα 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, G_iα 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 G_iα-upregulation and β-adrenoceptor downregulation in heart failure, which might contribute to the clinical improvement of patients treated with β-blockers.