title: Beneficial effects of a novel agonist of the adenosine A2A receptor on monocrotaline-induced pulmonary hypertension in rats.
abstract: OBJECTIVE
  Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, right ventricular hypertrophy and increased right ventricular systolic pressure. Here, we investigated the effects of a N-acylhydrazone derivative, 3,4-dimethoxyphenyl-N-methyl-benzoylhydrazide (LASSBio-1359), on monocrotaline (MCT)-induced pulmonary hypertension in rats.
  
  
  METHODS
  PAH was induced in male Wistar rats by a single i.p. injection of MCT (60 mg·kg(-1)) and 2 weeks later, oral LASSBio-1359 (50 mg·kg(-1)) or vehicle was given once daily for 14 days. Echocardiography was used to measure cardiac function and pulmonary artery dimensions, with histological assay of vascular collagen. Studies of binding to human recombinant adenosine receptors (A1, A2A, A3) and of docking with A2A receptors were also performed.
  
  
  RESULTS
  MCT administration induced changes in vascular and ventricular structure and function, characteristic of PAH. These changes were reversed by treatment with LASSBio-1359. MCT also induced endothelial dysfunction in pulmonary artery, as measured by diminished relaxation of pre-contracted arterial rings, and this dysfunction was reversed by LASSBio-1359. In pulmonary artery rings from normal Wistar rats, LASSBio-1359 induced relaxation, which was decreased by the adenosine A2A receptor antagonist, ZM 241385. In adenosine receptor binding studies, LASSBio-1359 showed most affinity for the A2A receptor and in the docking analyses, binding modes of LASSBio-1359 and the A2A receptor agonist, CGS21680, were very similar.
  
  
  CONCLUSIONS
  In rats with MCT-induced PAH, structural and functional changes in heart and pulmonary artery were reversed by treatment with oral LASSBio-1359, most probably through the activation of adenosine A2A receptors.
authors.affiliation: Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Allan K N
authors.initials: AK
authors.lastname: Alencar
authors.forename: Sharlene L
authors.initials: SL
authors.lastname: Pereira
authors.forename: Tadeu L
authors.initials: TL
authors.lastname: Montagnoli
authors.forename: Rodolfo C
authors.initials: RC
authors.lastname: Maia
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Kümmerle
authors.forename: Sharon S
authors.initials: SS
authors.lastname: Landgraf
authors.forename: Celso
authors.initials: C
authors.lastname: Caruso-Neves
authors.forename: Emanuelle B
authors.initials: EB
authors.lastname: Ferraz
authors.forename: Roberta
authors.initials: R
authors.lastname: Tesch
authors.forename: José H M
authors.initials: JH
authors.lastname: Nascimento
authors.forename: Carlos M R
authors.initials: CM
authors.lastname: de Sant'Anna
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Roberto T
authors.initials: RT
authors.lastname: Sudo
authors.forename: Gisele
authors.initials: G
authors.lastname: Zapata-Sudo
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D003094:Collagen / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics; D006835:Hydrazones / Q000494:pharmacology / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D062105:Molecular Docking Simulation; D016686:Monocrotaline; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D017208:Rats, Wistar; D043683:Receptors, Adenosine A2
chemical_list: C000596271:3,4-dimethoxyphenyl-N-methylbenzoylhydrazide; D058908:Adenosine A2 Receptor Agonists; D001549:Benzamides; D006835:Hydrazones; D043683:Receptors, Adenosine A2; D016686:Monocrotaline; D003094:Collagen