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

European Journal of Pharmacology 702 (2013) 316–322.

Sharlene L. Pereiraa, Arthur E. Kummerleb, Carlos A. M. Fragaa,c, Eliezer J. Barreiroa,c, Nazareth N. Rochad, Emanuelle B. Ferraze, José H. M. Nascimentoe, Roberto T. Sudoa,c, Gisele Zapata-Sudoa,c

aInstituto de Ciências Biomédicas, Programa de Desenvolvimento de Fármacos, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

bInstituto de Ciências Exatas,Universidade Federal Rural do Rio de Janeiro, Seropédica, RJ, Brazil

cInstituto de Ciências Biomédicas, Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

dDepartamento de Fisiologia e Farmacologia, Universidade Federal Fluminense, Instituto Biomédico, Niterói, RJ, Brazil

eInstituto de Biofísica Carlos Chagas Filho, Laboratório de Eletrofisiologia Cardíaca, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

 

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 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; 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 mm2) compared to the MCT-vehicle group (20.50 ± 1.44 mm2; 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 (50 mg/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 IC50 of LASSBio-1289 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 10 mM 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 Ca2+ influx through L-type voltage-gated Ca2+ channels in the pulmonary artery.

PMID: 23399770

 

Supplement

In Figure 1A, we show the tridimensional structure of (E)-N-methyl-N0-(thiophen-3- methylene)benzo[d][1,3]dioxole-5-carbohydrazide (LASSBio-1289): a novel L-type voltage-gated Ca2+ channel blocker, which was evaluated in experimental pulmonary hypertension. In Figure 1B, we show transthoracic echocardiograph images of control rats, MCT-injected rats (pulmonary hypertension) and MCT-injected rats treated with LASSBio-1289. This substance decreased endothelial dysfunction of pulmonary arteries, pulmonary vascular remodeling and right ventricular hypertrophy in rats with pulmonary hypertension.

Sharlene Lopes Pereira-1

Figure 1: Panel A: Tridimensional structure of LASSBio-1289. Panel B: Representative images of transthoracic echocardiograph in control rats, monocrotaline (MCT)-injected rats and MCT-injected rats treated orally with LASSBio-1289 (50 mg/kg/day) for 14 days.

Acknowledgements

This work was supported by grants of Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação Universitária Jose Bonifácio (FUJB), PRONEX, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Instituto Nacional de Ciência e Tecnologia (INCT).

 

Contact

Dr. Sharlene Lopes Pereira

sharlene.pereira@yahoo.com.br

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