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 (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.

β3 adrenergic receptor antagonist SR59230A exerts beneficial effects on right ventricular performance in monocrotaline‑induced pulmonary arterial hypertension

“…Also, right ventricular EF was recovered and the E/A ratio, a recommended parameter to evaluate RV diastolic function (30), was revealed to approach the normal level following SR59230A therapy. These results contradict previous reports, which revealed the beneficial effects of the β3-AR agonist in a number of pulmonary hypertension models (20,21). These controversies may be partly due to the differences between experimental models; one study used pigs with chronic PH established by the surgical banding of the main pulmonary vein (20), whilst another established a rat PAH model using a lower dose of MCT (60 mg/kg) (21).…”

“…These results contradict previous reports, which revealed the beneficial effects of the β3-AR agonist in a number of pulmonary hypertension models (20,21). These controversies may be partly due to the differences between experimental models; one study used pigs with chronic PH established by the surgical banding of the main pulmonary vein (20), whilst another established a rat PAH model using a lower dose of MCT (60 mg/kg) (21). In addition, it should be noted that the majority of previous studies used non-selective β3-AR agonists; therefore the possibility that the observed beneficial effects may be caused by other β-adrenergic functions (including β2-AR stimulation) should not be excluded (20,22).…”

“…These controversies may be partly due to the differences between experimental models; one study used pigs with chronic PH established by the surgical banding of the main pulmonary vein (20), whilst another established a rat PAH model using a lower dose of MCT (60 mg/kg) (21). In addition, it should be noted that the majority of previous studies used non-selective β3-AR agonists; therefore the possibility that the observed beneficial effects may be caused by other β-adrenergic functions (including β2-AR stimulation) should not be excluded (20,22). Conversely, one other study identified the involvement of β1/β2-AR in the development of PAH, and that the α1/β1/β2-AR blocker carvedilol improved RV function and prevented maladaptive myocardial remodeling in rats with severe experimentally-induced PAH.…”

“…Indeed, emerging technologies were at the forefront of this research area when a rat RNA-Seq transcriptomic BodyMap across 11 organs confirmed the expression of β3-AR in rat adrenal, thymus, heart and lung tissues (19). An additional study revealed that β3-AR was expressed in the human pulmonary artery (20), and that the β3-AR agonist BRL37344 reduced pulmonary vascular resistance and improved RV performance in a porcine chronic pulmonary hypertension model. A further study indicated that nebivolol, a β3-adrenergic agonist, reduced the overexpression of growth and inflammatory mediators in pulmonary vascular cells harvested from patients with PAH (21).…”

Mirabegron, A Selective β3-Adrenoceptor Agonist Causes an Improvement in Erectile Dysfunction in Diabetic Rats

“…It would seem that oral, venous or intraperitoneal administration could be more physiological and therefore lead to more relevant practical conclusions. In different animal models, mirabegron was given oral, intravenous and intraperitoneal routes [20][21][22][23][24][25]. Considering that the oral administration of mirabegron, rather than intracavernous injection, may be more tolerable, a clinical study evaluating the potential benefit of oral mirabegron in a subset of patients with lower urinary tract symptoms or overactive bladder and concomitant ED is necessary to assess its potential for improving erectile function.…”