Pharmacological Stimulation of β ₂-adrenergic Receptors (β ₂AR) Enhances Therapeutic Effectiveness of β ₁AR Blockade in Rodent Dilated Ischemic Cardiomyopathy

Abstract

Background. We have reported that β ₂ adrenoreceptor (β ₂AR) 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 β ₂AR stimulation enhances the therapeutic effects of β ₁AR blockade on cardiac remodeling in the same model. Methods and Results. Metoprolol, a β ₁AR blocker, given alone (β ₁) or in combination with β ₂AR agonist, fenoterol (β ₁β ₂) 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. β ₁β ₂ prevented LV remodeling, MI expansion and cardiomyocytes hypertrophy to a greater degree than β ₁, due, in large part, to a vasodilatory effect of β ₂AR stimulation and thus improvement of arterio-ventricular mismatch. The abnormal diastolic performance improved only in β ₁β ₂. β ₁β ₂ treatment reduced myocardial apoptosis throughout myocardium, but β ₁ reduced apoptopsis only in the areas remote from MI. Conclusion. The therapeutic effects of chronic β ₁AR blockade on cardiac remodeling of heart failure are enhanced and extended when supplemented with β ₂AR stimulation.