Programa de Pós-Graduação em Farmacologia e Química Medicinal, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Eur J Pharmacol. 2012 Sep 5;690(1-3):176-82. doi: 10.1016/j.ejphar.2012.05.043. Epub 2012 Jun 19.
In this study, we examined the effects of LASSBio-965 (N-[2-(3,4-dimethoxyphenyl) ethyl]-benzenesulfonamide), a compound designed as a simplified structure of a non-selective phosphodiesterase 4 inhibitor, on vascular smooth muscle in vitro as well as in a rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension. LASSBio-965 (50 mg/kg) treatment caused a significant decrease in right systolic ventricular pressure (32.47 ± 3.09 mmHg) compared to the MCT-vehicle group (51.88 ± 3.23 mmHg; P<0.05) and in the ratio of right ventricular weight to left ventricular weight plus septum (0.42 ± 0.03 g compared to 0.59 ± 0.06 g, respectively; MCT-vehicle group; P<0.05). LASSBio-965 induced a concentration-dependent relaxation of rat aortic rings, which was decreased by mechanical removal of the endothelium. Milrinone, rolipram, and sildenafil reduced the maximum relaxation (100%) to 22.4 ± 5.8, 69.5 ± 5.6 and 80.1 ± 10.7%, respectively (P<0.05). Maximum relaxation responses of aortic and pulmonary artery rings were decreased in the MCT-vehicle group (54.80 ± 5.69 and 35.87 ± 4.78, respectively) compared to the control (91.51 ± 4.79 and 54.32 ± 2.39, respectively) but improved with LASSBio-965 treatment (50mg/kg; 88.43 ± 4.54 and 59.36 ± 4.83, respectively). These results indicate that LASSBio-965 can attenuate the pulmonary arterial hypertension in an animal model most likely through the nonselective inhibition of phosphodiesterases 3, 4, and 5.
在这项研究中，我们考察了 LASSBio-965（N-[2-（3,4-二甲氧基苯基）乙基]苯磺酰胺）对体外血管平滑肌和野百合碱（MCT）诱导的肺动脉高压大鼠模型的影响。与 MCT-载体组（51.88±3.23mmHg）相比，LASSBio-965（50mg/kg）治疗可显著降低右心室收缩压（32.47±3.09mmHg；P<0.05），以及右心室重量与左心室重量加室间隔的比值（0.42±0.03g 与 0.59±0.06g，分别；MCT-载体组；P<0.05）。LASSBio-965 诱导大鼠主动脉环浓度依赖性舒张，该舒张作用被机械去除内皮后减弱。米力农、罗利普兰和西地那非将最大舒张率（100%）分别减少至 22.4±5.8%、69.5±5.6%和 80.1±10.7%（P<0.05）。与对照组（91.51±4.79和 54.32±2.39）相比，MCT-载体组主动脉和肺动脉环的最大舒张反应（分别为 54.80±5.69 和 35.87±4.78）降低，但用 LASSBio-965 治疗（50mg/kg）后有所改善（分别为 88.43±4.54 和 59.36±4.83）。这些结果表明，LASSBio-965 可能通过非选择性抑制磷酸二酯酶 3、4 和 5 来减轻动物模型中的肺动脉高压。
