Instituto de Ciências Biomédicas, Programa de Desenvolvimento de Fármacos, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Eur J Pharmacol. 2013 Feb 28;702(1-3):316-22. doi: 10.1016/j.ejphar.2013.01.050. Epub 2013 Feb 8.
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.
本研究旨在探讨 LASSBio-1289（（E）-N-甲基-N'-(噻吩-3-亚甲基)苯并[d][1,3]二恶唑-5-甲脒）对野百合碱（MCT）诱导的大鼠肺动脉高压（PAH）的作用。在 MCT 注射后两周，LASSBio-1289（50 或 75mg/kg，po）或载体每天给药一次，共 14 天。与 MCT-载体组（52.74±6.19mmHg）相比，LASSBio-1289（75mg/kg）治疗可显著降低右心室收缩压（31.89±0.82mmHg；P<0.05）。通过超声心动图评估，LASSBio-1289（50 或 75mg/kg）的口服治疗可有效降低肺动脉直径和右心室（RV）面积。与 MCT-载体组（20.50±1.44mm2）相比，LASSBio-1289（75mg/kg）可降低 RV 面积（10.00±0.58mm2；P<0.05）。LASSBio-1289（75mg/kg）还可部分恢复 MCT 处理大鼠的肺动脉加速时间。LASSBio-1289（50mg/kg）的口服治疗可降低肺动脉小动脉壁厚度（68.57±2.21%），与 MCT-载体组（81.07±1.92%）相比，差异有统计学意义（P<0.05）。在离体肺动脉实验中，LASSBio-1289 引起苯肾上腺素或 KCl 诱导收缩的 50%松弛所需的浓度分别为 27.31±6.94μM 和 2.72±0.99μM，P<0.05。在 LASSBio-1289（50μM）存在的情况下，10mM CaCl2 诱导的最大收缩减少至对照曲线最大收缩的 36.00±8.28%（P<0.05）。LASSBio-1289 可有效减轻 MCT 诱导的大鼠 PAH，其有益作用可能是通过抑制肺动脉中 L 型电压门控 Ca2+通道的细胞外 Ca2+内流介导的。
