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

Ana García‐Álvarez ,Jaume Agüero,Gonzalo Pizarro,Federico Sierra,José M García-Ruiz,Elena Sandoval,Paula Campelos,Manel Sabaté,Daniel Pereda,Mario Nuño-Ayala,Víctor I Peinado,Valentín Fuster,David Sanz-Rosa,Evelyn Santiago,Rodrigo Fernández‐Jiménez ,Joan Albert Barberà ,Manuel Castellà ,Jaime García‐Prieto ,Inés García‐Lunar ,Leticia Fernández‐Friera ,Borja Ibáñez

doi:10.1007/s00395-016-0567-0

Abstract

Beta-3 adrenergic receptor (β3AR) 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 β3AR 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 β3AR agonists on hemodynamics, vascular remodeling and RV performance in chronic PH. Ex vivo human experiments were performed to explore the expression of β3AR mRNA and the vasodilator response of β3AR agonists in pulmonary arteries. Single intravenous administration of the β3AR agonist BRL37344 produced a significant acute reduction in PVR, and two-weeks treatment with two different β3AR selective agonists, intravenous BRL37344 or oral mirabegron, resulted in a significant reduction in PVR (median of −2.0 Wood units/m2 for BRL37344 vs. +1.5 for vehicle, p = 0.04; and −1.8 Wood units/m2 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 β3AR agonists-treated pigs. β3AR was expressed in human pulmonary arteries and β3AR agonists produced vasodilatation. β3AR 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.

Highlights

Pulmonary hypertension (PH) comprises a group of diseases characterized by a chronic increase in pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), and progressive right ventricular (RV) dysfunction [16]
Proof of concept study In chronic pulmonary hypertension (PH) [n = 8, mean PAP 37.5 (17.0), PVRI 7.6 (7.7)], a single bolus of BRL37344 (5 lg/kg) caused, 20 min after intervention, a significant reduction in PAP and PVRI associated with an increase in CI (Table 1)
Long-term studies In the first experiment [n = 8, mean PAP 32.5 (8.8), PVRI 5.7 (4.0)], animals randomized to long-term intravenous therapy with the Beta-3 adrenergic receptor (b3AR) agonist BRL37344 (10 lg/kg/day for 14 days) showed a significant reduction in PVRI and an increase in CI compared with vehicle (Table 2; Fig. 1a)

Summary

Introduction

Pulmonary hypertension (PH) comprises a group of diseases characterized by a chronic increase in pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR), and progressive right ventricular (RV) dysfunction [16]. Few therapies are currently available for pulmonary arterial hypertension (group 1 in the current PH classification), but no pharmacological therapy has been demonstrated to have a consistent effect in PH due to left heart disease (group 2), which is the most frequent cause of PH [15, 37]. Impairment of nitric oxide synthesis and signaling through the soluble guanylate cyclase-cyclic guanylate monophosphate pathway [17, 24] are implicated in the pathogenesis of PH causing vasoconstriction and structural remodeling. Therapies that increase nitric oxide release and guanylate cyclase-cyclic guanylate monophosphate availability, in addition to their vasodilator effect, have an antiproliferative effect on the pulmonary vasculature [35, 38]

Objectives

Methods

Results

Conclusion