Pharmacological stimulation of β₂-adrenergic receptors (β₂AR) enhances therapeutic effectiveness of β₁AR blockade in rodent dilated ischemic cardiomyopathy

Background. We have reported that β₂ adrenoreceptor (β₂AR) stimulation is anti-apoptotic, and has strong beneficial effect on cardiac remodeling in an experimental model of post myocardial infarction chronic heart failure (CHF) in rats. Here we investigate whether the addition of chronic pharmacological β₂AR stimulation enhances the therapeutic effects of β₁AR blockade on cardiac remodeling in the same model. Methods and results. Metoprolol, β₁AR blocker, given alone (β₁) or in combination with β₂AR agonist, fenoterol (β₁β₂) were administered to rats via drinking water for 6 weeks, beginning 2 weeks following permanent coronary ligation. Progressive left ventricular (LV) remodeling of untreated animals, assessed by repeated echocardiography, occurred during the observation time, i.e., 42% and 25% increases in end-systolic and end-diastolic LV volumes respectively, 27% fall in ejection fraction, and 35% infarct expansion. Pressure-volume loop analyses at 2d and 8th post infarction weeks showed continuous deterioration of systolic and diastolic functions and arterio-ventricular mismatch. Histological evaluation at the end of 8 weeks revealed the MI expansion and hypertrophy of cardiomyocytes. β₁β₂ prevented LV emodeling, MI expansion and cardiomyocytes hypertrophy to a greater degree than β₁, due, in large part, to a vasodilatory effect of β₂AR stimulation and thus improvement of arterio-ventricular mismatch. The abnormal diastolic performance improved only in β₁ β₂. β₁ β₂ treatment reduced myocardial apoptosis throughout myocardium, but β₁ reduced apoptopsis only in the areas remote from MI. Conclusion. The therapeutic effects of chronic β₁AR blockade on cardiac remodeling of heart failure are enhanced and extended when supplemented with β₂AR stimulation.