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Beneficial effects of a novel agonist of the adenosine A 2A receptor on monocrotaline‐induced pulmonary hypertension in rats
Author(s) -
Alencar Allan K N,
Pereira Sharlene L,
Montagnoli Tadeu L,
Maia Rodolfo C,
Kümmerle Arthur E,
Landgraf Sharon S,
CarusoNeves Celso,
Ferraz Emanuelle B,
Tesch Roberta,
Nascimento José H M,
Sant'Anna Carlos M R,
Fraga Carlos A M,
Barreiro Eliezer J,
Sudo Roberto T,
ZapataSudo Gisele
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12193
Subject(s) - right ventricular hypertrophy , pulmonary artery , pulmonary hypertension , agonist , medicine , receptor , antagonist , adenosine , endocrinology , vascular resistance , chemistry , pharmacology , blood pressure
Background and Purpose 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. Experimental Approach PAH was induced in male W istar 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 (A 1 , A 2A , A 3 ) and of docking with A 2A receptors were also performed. Key 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 A 2A receptor antagonist, ZM 241385. In adenosine receptor binding studies, LASSBio ‐1359 showed most affinity for the A 2A receptor and in the docking analyses, binding modes of LASSBio ‐1359 and the A 2A receptor agonist, CGS21680, were very similar. Conclusion and Implications 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 A 2A receptors.