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

Abstract：

: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 75mg/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; P<0.05). 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 mm(2)) compared to the MCT-vehicle group (20.50±1.44 mm(2); P<0.05). LASSBio-1289 (75 mg/kg) also partially recovered the pulmonary artery acceleration time in MCT-treated rats. Oral treatment with LASSBio-1289 (50mg/kg) decreased the pulmonary arteriolar wall thickness (68.57±2.21%) compared to the MCT-vehicle group (81.07±1.92%; P<0.05). 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 μM, respectively, P<0.05. In the presence of LASSBio-1289 (50 μM), the maximal contraction induced by 10mM CaCl2 was reduced to 36.00±8.28% of the maximal contraction of the control curve (P<0.05). LASSBio-1289 was effective in attenuating MCT-induced PAH in rats, and its beneficial effects were likely mediated by the inhibition of extracellular Ca(2+) influx through L-type voltage-gated Ca(2+) channels in the pulmonary artery.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Pereira SL,Kummerle AE,Fraga CA,Barreiro EJ,Rocha Nde N,Ferraz EB,do Nascimento JH,Sudo RT,Zapata-Sudo G

doi

10.1016/j.ejphar.2013.01.050

subject

Has Abstract

pub_date

2013-02-28 00:00:00

pages

316-22

issue

1-3

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(13)00070-8

journal_volume

702

pub_type

杂志文章

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