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

• Published in: European journal of pharmacology Vol. 702; no. 1-3; pp. 316 - 322
• Main Authors: Pereira, Sharlene Lopes, Kummerle, Arthur Eugen, Fraga, Carlos Alberto Manssour, Barreiro, Eliezer Jesus, Rocha, Nazareth de Novaes, Ferraz, Emanuelle Baptista, Nascimento, José Hamilton Matheus do, Sudo, Roberto Takashi, Zapata-Sudo, Gisele
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 28.02.2013
• Subjects: Acetylcholine - pharmacology; Animals; antagonists; Benzodioxoles - pharmacology; Benzodioxoles - therapeutic use; calcium; Calcium Channel Blockers - pharmacology; Calcium Channel Blockers - therapeutic use; calcium chloride; Calcium Chloride - pharmacology; Cardiomegaly - drug therapy; Cardiomegaly - pathology; Cardiomegaly - physiopathology; echocardiography; Familial Primary Pulmonary Hypertension; Hemodynamics; Hydrazones - pharmacology; Hydrazones - therapeutic use; hypertension; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - physiopathology; hypertrophy; In Vitro Techniques; L-type Ca2+ channel blocker; Male; Monocrotaline; N-acylhydrazone; oral administration; pharmacology; Phenylephrine - pharmacology; Pulmonary arterial hypertension; pulmonary artery; Pulmonary Artery - drug effects; Pulmonary Artery - pathology; Pulmonary Artery - physiopathology; Pulmonary vascular remodeling; Rat monocrotaline model; Rats; Rats, Wistar; Vasoconstrictor Agents - pharmacology; Vasodilator Agents - pharmacology; Pulmonary vascular remodeling; Pulmonary arterial hypertension; Hemodynamics; N-acylhydrazone; Rat monocrotaline model; L-type Ca2+ channel blocker
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2013.01.050

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 (75mg/kg) treatment caused a significant decrease in right ventricular systolic pressure (31.89±0.82mmHg) compared to the MCT-vehicle group (52.74±6.19mmHg; P<0.05). Oral treatment with LASSBio-1289 (50 or 75mg/kg) effectively decreased pulmonary artery diameter and right ventricle (RV) area, assessed by echocardiography. LASSBio-1289 (75mg/kg) reduced RV area (10.00±0.58mm2) compared to the MCT-vehicle group (20.50±1.44mm2; P<0.05). LASSBio-1289 (75mg/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±0.99μM, respectively, P<0.05. In the presence of LASSBio-1289 (50μM), 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 Ca2+ influx through L-type voltage-gated Ca2+ channels in the pulmonary artery.