N -acylhydrazone derivative ameliorates monocrotaline-induced pulmonary hypertension through the modulation of adenosine AA2R activity

• Published in: International journal of cardiology Vol. 173; no. 2; pp. 154 - 162
• Main Authors: Alencar, Allan K.N, Pereira, Sharlene L, da Silva, Flavia E, Mendes, Luiza V.P, Cunha, Valéria do M.N, Lima, Lidia M, Montagnoli, Tadeu L, Caruso-Neves, 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, Zapata-Sudo, Gisele
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 01-05-2014; Elsevier
• Subjects: A2A adenosine agonist; Adenosine A2 Receptor Agonists - chemistry; Adenosine A2 Receptor Agonists - pharmacology; Animals; Benzamides - chemistry; Benzamides - pharmacology; Biological and medical sciences; Cardiology. Vascular system; Cardiovascular; Exercise Tolerance - drug effects; Heart; Hydrazones - chemistry; Hydrazones - pharmacology; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - diagnostic imaging; Hypertension, Pulmonary - drug therapy; Hypertrophy, Right Ventricular - chemically induced; Hypertrophy, Right Ventricular - diagnostic imaging; Hypertrophy, Right Ventricular - drug therapy; Male; Medical sciences; Monocrotaline; Monocrotaline - pharmacology; N-acylhydrazone derivative; Nitric Oxide Synthase Type III - metabolism; Pneumology; Pulmonary Artery - diagnostic imaging; Pulmonary Artery - drug effects; Pulmonary Artery - metabolism; Pulmonary hypertension; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Pulmonary vascular remodeling; Rats, Wistar; Receptor, Adenosine A2A - metabolism; Ultrasonography; Vasodilation - drug effects; Ventricular dysfunction; Pulmonary vascular remodeling; A2A adenosine agonist; Ventricular dysfunction; N-acylhydrazone derivative; Monocrotaline; Pulmonary hypertension; Purine nucleoside; Adenosine; Agonist; Respiratory disease; Lung; Activity; Cardiovascular disease; Respiratory system; Vascular remodeling; Dysfunction; Modulation; Cardiology
• ISSN: 0167-5273; 1874-1754
• DOI: 10.1016/j.ijcard.2014.02.022

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 (60 mg/kg, i.p.) of monocrotaline (MCT) and given LASSBio-1386 (50 mg/kg, p.o.) or vehicle for 14 days. The hemodynamic, exercise capacity (EC), endothelial nitric oxide synthase (eNOS), adenosine A2A receptor (A2A R), sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a), phospholamban (PLB) expression, Ca 2 + -ATPase activity and vascular activity of LASSBio-1386 were evaluated. Results and 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, A2A R, 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 A2A R agonists for the treatment of PAH.