title: 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/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 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.
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. agarciaa@cnic.es.|Hospital Clínic, IDIBAPS, Barcelona, Spain. agarciaa@cnic.es.
authors.forename: Ana
authors.initials: A
authors.lastname: García-Álvarez
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.|Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pereda
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.|Hospital Universitario Quirón Madrid, UEM, Madrid, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: García-Lunar
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Sanz-Rosa
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.|Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Fernández-Jiménez
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: García-Prieto
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Nuño-Ayala
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Sierra
authors.affiliation: Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Santiago
authors.affiliation: Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Sandoval
authors.affiliation: Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Campelos
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Agüero
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.|Hospital Universitario Quirón Madrid, UEM, Madrid, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Pizarro
authors.affiliation: Hospital Clínic, IDIBAPS, Barcelona, Spain.|Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias, Barcelona, Spain.
authors.forename: Víctor I
authors.initials: VI
authors.lastname: Peinado
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.|Hospital Universitario Montepríncipe, Madrid, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Fernández-Friera
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.|Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: García-Ruiz
authors.affiliation: Hospital Clínic, IDIBAPS, Barcelona, Spain.|Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias, Barcelona, Spain.
authors.forename: Joan A
authors.initials: JA
authors.lastname: Barberá
authors.affiliation: Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Castellá
authors.affiliation: Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Sabaté
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.|Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, USA.
authors.forename: Valentín
authors.initials: V
authors.lastname: Fuster
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. bibanez@cnic.es.|Department of Cardiology, IIS-Fundación Jiménez Díaz, Madrid, Spain. bibanez@cnic.es.
authors.forename: Borja
authors.initials: B
authors.lastname: Ibañez
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D000068577:Nebivolol / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D013552:Swine; D013844:Thiazoles / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D022702:Receptors, Adrenergic, beta-3; D013844:Thiazoles; D000068577:Nebivolol; C520025:mirabegron
keywords: Beta-3 adrenergic receptor; Pulmonary hypertension; Pulmonary vascular resistance; Therapy