Pharmacological stimulation of beta2-adrenergic receptors (beta2AR) enhances therapeutic effectiveness of beta1AR blockade in rodent dilated ischemic cardiomyopathy

Abstract

Background: We have reported that beta2 adrenoreceptor (beta2AR) 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 beta2AR stimulation enhances the therapeutic effects of beta1AR blockade on cardiac remodeling in the same model.

Methods and results: Metoprolol, a beta1AR blocker, given alone (beta1) or in combination with beta2AR agonist, fenoterol (beta1beta2) 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. beta1beta2 prevented LV remodeling, MI expansion and cardiomyocytes hypertrophy to a greater degree than beta1, due, in large part, to a vasodilatory effect of beta2AR stimulation and thus improvement of arterio-ventricular mismatch. The abnormal diastolic performance improved only in beta1beta2. beta1beta2 treatment reduced myocardial apoptosis throughout myocardium, but beta1 reduced apoptosis only in the areas remote from MI.

Conclusion: The therapeutic effects of chronic beta1AR blockade on cardiac remodeling of heart failure are enhanced and extended when supplemented with beta2AR stimulation.