title: N-acylhydrazone derivative ameliorates monocrotaline-induced pulmonary hypertension through the modulation of adenosine AA2R activity.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) is a disease that results in right ventricular (RV) dysfunction. While pulmonary vascular disease is the primary pathological focus, RV hypertrophy and RV dysfunction are the major determinants of prognosis in PAH. The aim of this study was to investigate the effects of (E)-N'-(3,4-dimethoxybenzylidene)-4-methoxybenzohydrazide (LASSBio-1386), an N-acylhydrazone derivative, on the lung vasculature and RV dysfunction induced by experimental PAH.
  
  
  METHODS
  Male Wistar rats were injected with a single dose (60mg/kg, i.p.) of monocrotaline (MCT) and given LASSBio-1386 (50mg/kg, p.o.) or vehicle for 14 days. The hemodynamic, exercise capacity (EC), endothelial nitric oxide synthase (eNOS), adenosine A2A receptor (A2AR), sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a), phospholamban (PLB) expression, Ca(2+)-ATPase activity and vascular activity of LASSBio-1386 were evaluated.
  
  
  CONCLUSIONS
  The RV systolic pressure was elevated in the PAH model and reduced from 49.6 ± 5.0 mm Hg (MCT group) to 27.2 ± 2.1 mm Hg (MCT+LASSBio-1386 group; P<0.05). MCT administration also impaired the EC, increased the RV and pulmonary arteriole size, and promoted endothelial dysfunction of the pulmonary artery rings. In the PAH group, the eNOS, A2AR, SERCA2a, and PLB levels were changed compared with the control; in addition, the Ca(2+)-ATPase activity was reduced. These alterations were related with MCT-injected rats, and LASSBio-1386 had favorable effects that prevented the development of PAH. LASSBio-1386 is effective at preventing endothelial and RV dysfunction in PAH, a finding that may have important implications for ongoing clinical evaluation of A2AR agonists for the treatment of PAH.
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Allan K N
authors.initials: AK
authors.lastname: Alencar
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Sharlene L
authors.initials: SL
authors.lastname: Pereira
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Flavia E
authors.initials: FE
authors.lastname: da Silva
authors.affiliation: Programa de Farmacologia e Inflamação, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Luiza V P
authors.initials: LV
authors.lastname: Mendes
authors.affiliation: Programa de Farmacologia e Inflamação, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Valéria do M N
authors.initials: Vdo M
authors.lastname: Cunha
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Lidia M
authors.initials: LM
authors.lastname: Lima
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Tadeu L
authors.initials: TL
authors.lastname: Montagnoli
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Celso
authors.initials: C
authors.lastname: Caruso-Neves
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Emanuelle B
authors.initials: EB
authors.lastname: Ferraz
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Roberta
authors.initials: R
authors.lastname: Tesch
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: José H M
authors.initials: JH
authors.lastname: Nascimento
authors.affiliation: Departamento de Química, Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil.
authors.forename: Carlos M R
authors.initials: CM
authors.lastname: Sant'anna
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Roberto T
authors.initials: RT
authors.lastname: Sudo
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Electronic address: gsudo@farmaco.ufrj.br.
authors.forename: Gisele
authors.initials: G
authors.lastname: Zapata-Sudo
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D017079:Exercise Tolerance / Q000187:drug effects; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000188:drug therapy*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000188:drug therapy; D008297:Male; D016686:Monocrotaline / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011651:Pulmonary Artery / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D014463:Ultrasonography; D014664:Vasodilation / Q000187:drug effects
chemical_list: D058908:Adenosine A2 Receptor Agonists; D001549:Benzamides; D006835:Hydrazones; C000593725:N'-(3,4-dimethoxybenzylidene)-4-methoxybenzohydrazide; D043705:Receptor, Adenosine A2A; D016686:Monocrotaline; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat
keywords: A2A adenosine agonist; Monocrotaline; N-acylhydrazone derivative; Pulmonary hypertension; Pulmonary vascular remodeling; Ventricular dysfunction