title: 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.
authors: Instituto de Ciências Biomédicas, Programa de Desenvolvimento de Fármacos, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. sharlene.pereira@yahoo.com.br
authors: Sharlene Lopes
authors: SL
authors: Pereira
authors: Arthur Eugen
authors: AE
authors: Kummerle
authors: Carlos Alberto Manssour
authors: CA
authors: Fraga
authors: Eliezer Jesus
authors: EJ
authors: Barreiro
authors: Nazareth de Novaes
authors: Nde N
authors: Rocha
authors: Emanuelle Baptista
authors: EB
authors: Ferraz
authors: José Hamilton Matheus
authors: JH
authors: do Nascimento
authors: Roberto Takashi
authors: RT
authors: Sudo
authors: Gisele
authors: G
authors: Zapata-Sudo
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D002122:Calcium Chloride / Q000494:pharmacology; D006332:Cardiomegaly / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D065627:Familial Primary Pulmonary Hypertension; D006835:Hydrazones / Q000494:pharmacology / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D016686:Monocrotaline; D010656:Phenylephrine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D052117:Benzodioxoles; D002121:Calcium Channel Blockers; D006835:Hydrazones; C586082:N-methyl-N'-(thiophen-3-methylene)benzo(d)(1,3)dioxole-5-carbohydrazide; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D016686:Monocrotaline; D002122:Calcium Chloride; D000109:Acetylcholine