Beta-3 adrenergic agonists reduce pulmonary vascular resistance and improve right ventricular performance in a porcine model of chronic pulmonary hypertension

Abstract

Beta-3 adrenergic receptor (beta 3AR) agonists have been shown to produce vasodilation and prevention of ventricular remodeling in different conditions. Given that these biological functions are critical in pulmonary hypertension (PH), we aimed to demonstrate a beneficial effect of beta 3AR agonists in PH. An experimental study in pigs (n = 34) with chronic PH created by pulmonary vein banding was designed to evaluate the acute hemodynamic effect and the long-term effect of beta 3AR agonists on hemodynamics, vascular remodeling and RV performance in chronic PH. Ex vivo human experiments were performed to explore the expression of beta 3AR mRNA and the vasodilator response of beta 3AR agonists in pulmonary arteries. Single intravenous administration of the beta 3AR agonist BRL37344 produced a significant acute reduction in PVR, and two-weeks treatment with two different beta 3AR selective agonists, intravenous BRL37344 or oral mirabegron, resulted in a significant reduction in PVR (median of -2.0 Wood units/m(2) for BRL37344 vs. + 1.5 for vehicle, p = 0.04; and -1.8 Wood units/m(2) for mirabegron vs. + 1.6 for vehicle, p = 0.002) associated with a significant improvement in magnetic resonance-measured RV performance. Histological markers of pulmonary vascular proliferation (p27 and Ki67) were significantly attenuated in beta 3AR agonists-treated pigs. beta 3AR was expressed in human pulmonary arteries and beta 3AR agonists produced vasodilatation. beta 3AR agonists produced a significant reduction in PVR and improved RV performance in experimental PH, emerging as a potential novel approach for treating patients with chronic PH.