A novel Ca2+ channel antagonist reverses cardiac hypertrophy and pulmonary arteriolar remodeling in experimental pulmonary hypertension

摘要

This work investigates the actions of LASSBio-1289, (E)-N-methyl-N??- (thiophen-3-methylene)benzo[d][1,3]dioxole-5-carbohydrazide, on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats. Two weeks following the MCT injection, LASSBio-1289 (50 or 75 mg/kg, p.o.) or vehicle was administrated once daily for 14 days. LASSBio-1289 (75 mg/kg) treatment caused a significant decrease in right ventricular systolic pressure (31.89??0.82 mmHg) compared to the MCT-vehicle group (52.74??6.19 mmHg; P0.05). Oral treatment with LASSBio-1289 (50 or 75 mg/kg) effectively decreased pulmonary artery diameter and right ventricle (RV) area, assessed by echocardiography. LASSBio-1289 (75 mg/kg) reduced RV area (10.00??0.58 mm2) compared to the MCT-vehicle group (20.50??1.44 mm 2; P0.05). LASSBio-1289 (75 mg/kg) also partially recovered the pulmonary artery acceleration time in MCT-treated rats. Oral treatment with LASSBio-1289 (50 mg/kg) decreased the pulmonary arteriolar wall thickness (68.57??2.21%) compared to the MCT-vehicle group (81.07??1.92%; P0.05). In experiments with isolated pulmonary arteries, the concentration of LASSBio-1289 necessary to produce 50% relaxation in the phenylephrine- or KCl-induced contraction was 27.31??6.94 and 2.72??0.99 ??M, respectively, P0.05. In the presence of LASSBio-1289 (50 ??M), the maximal contraction induced by 10 mM CaCl2 was reduced to 36.00??8.28% of the maximal contraction of the control curve (P0.05). LASSBio-1289 was effective in attenuating MCT-induced PAH in rats, and its beneficial effects were likely mediated by the inhibition of extracellular Ca2+ influx through L-type voltage-gated Ca2+ channels in the pulmonary artery. ? 2013 Elsevier B.V.