Abstract 767: Carvedilol Sensitizes Beta1- And Beta2-Adrenergic Receptors In Human Myocardium By Inhbiting A Phosphatidylinositol-3 Kinase- And Phosphodiesterase 4-Mediated Pathway
Background: In response to sympathetic activation during chronic heart failure (CHF), myocardial β-adrenergic receptors (β-ARs) are downregulated, blunting the response to catecholamines. Metoprolol (METO), but not carvedilol (CARV), upregulates downregulated β-ARs in failing myocardium. Nevertheless, in patients treated with CARV or METO, dobutamine increases cardiac output to similar extents. Thus, we hypothesized that CARV sensitizes β-ARs by improving post-receptor signaling events.
Methods and Results: Isometric force of contraction was determined on atrial trabeculae of 54 patients undergoing cardiac surgery. Patients were divided along the median of the in vitro EC50-value for isoprenaline (ISO; −6.8 logM) into those with normal (EC50< −6.8 logM) and desensitized β-ARs (EC50> −6.8 logM). Both METO (1 μM) and CARV (10 nM) antagonized the effect of ISO in trabeculae of patients with normal β-AR affinity. In desensitized tissue, however, preincubation with CARV for 5–10 min led to a leftward shift of the ISO response (EC50: Control, −5.5 ±0.2 logM; CARV, −7.5 ±0.3 logM; p<0.001, n=11/9), while METO produced a rightward shift (−4.5 ±0.3 logM). In a second protocol, the β1-AR mediated positive inotropic effect of norepinephrine was followed by a negative inotropic effect in 51% of patients. This secondary negative inotropic effect was eliminated by inhibiting phospatidylinositol-3 kinase (PI3K) with LY294002 or phosphodiesterase- (PDE-) 4 with rolipram. A similar PI3K- and PDE-4-mediated negative inotropic component was observed in 40% of the patients after β2-AR stimulation with epinephrine. CARV completely inhibited the negative inotropic effect after β1- or β2-AR stimulation, without affecting the initial positive inotropic effect. In contrast, METO competitively antagonized the positive inotropic effect without affecting the negative inotropic component after β1- or β2-AR stimulation.
Conclusions: In human myocardium, desensitization of β-ARs is associated with coupling of both β1- and β2-ARs to PI3K and PDE-4. CARV sensitizes β1- and β2-ARs by blocking this pathway. This may explain the restored in vivo response to dobutamine in patients with CHF during CARV treatment despite a lack of upregulation of myocardial β-AR density.