Objective: Treatment with the β-blocker carvedilol leads to an improvement of outcome and ejection fraction in heart failure. These effects occur without affecting the number of β-adrenergic receptors, as determined in right ventricular biopsies from patients with heart failure. This study was aimed at investigating the effects of carvedilol on β-adrenergic signal transduction alterations in a model of left ventricular pressure overload, which is characterized by sympathetic activation and a desensitized β-adrenergic signal transduction. Methods: Transgenic rats with overexpression of renin [TG(mREN2)27] were treated with carvedilol (30 μg/kg) or held under control conditions and were compared with Sprague-Dawley rats. Myocardial β-adrenoceptors (125I-labeled iodocyanopindolol binding), Giα (pertussis toxin labeling), Gsα-activity (reconstitution into cyc−S49 membranes) and adenylyl cyclase activity were measured. Blood pressure and heart rate, increase in heart rate during sacrifice and pressure rate products were determined. Results: β-Adrenoceptors were downregulated and Giα-protein levels were significantly increased, producing a desensitization of basal, isoprenaline- and guanine nucleotide-stimulated adenylyl cyclase activity compared to controls. Carvedilol reduced heart rate, blood pressure and pressure rate product in TG(mREN2)27. Carvedilol did not restore biochemical alterations, but even further reduced β-adrenoceptor numbers and adenylyl cyclase. It exhibited a two affinity state, guanine nucleotide-sensitive binding to cardiac β-adrenergic receptors similar to isoprenaline but different from metoprolol. Conclusions: Carvedilol did not restore β-adrenergic signal transduction at concentrations producing antiadrenergic effects in vivo. This effect might be due to an atypical guanine nucleotide-dependent interaction with β-adrenergic receptors. Thus, ancillary properties could explain the recently reported beneficial effects in patients with heart failure independent from an upregulation of β-adrenergic receptors.