RP5063, a novel, multimodal, serotonin receptor modulator, prevents monocrotaline-induced pulmonary arterial hypertension in rats
RP5063, a novel, multimodal, serotonin receptor modulator, prevents monocrotaline-induced pulmonary arterial hypertension in rats
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DOI：
10.1016/j.ejphar.2017.05.048
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发表时间：
2017-09-05
影响因子：
5
通讯作者：
Salvail, Dany
中科院分区：
文献类型：
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作者：
Bhat, Laxminarayan;Hawkinson, Jon;Salvail, Dany
肺动脉高压（PAH）是一种以肺血管收缩和重塑为特征的疾病，涉及5-羟色胺（5-HT）受体5-HT 2A和5-HT 2B的失调。使用野百合碱（MCT）诱导的PAH大鼠模型来检查RP 5063（一种5-HT受体调节剂）的潜在有益作用。单次给予60 mg/kg MCT后，每天两次（b.i.d.）给予溶媒、RP 5063（1、3或10 mg/kg）或西地那非（50 mg/kg）28天。RP 5063，剂量低至1 mg/kg，b.i.d.降低肺阻力和增加全身血氧饱和度。RP 5063的最高剂量（10 mg/kg，b.i.d.）降低舒张压、收缩压和平均肺压、右心室收缩压、舒张压和富尔顿指数（右心室重量与左心室重量的比值）。低至3 mg/kg RP 5063的剂量，每日两次也增加了体重增加和体温，表明MCT给药动物的总体健康状况改善。在接受较高剂量（50 mg/kg，b.i.d.）参比药物西地那非给药的动物中，观察到肺动脉压、右心室压和舒张压、肺阻力和富尔顿指数相似降低以及全身血氧饱和度增加。组织学检查显示，RP 5063产生肺血管壁厚度和肌肉血管比例的剂量依赖性降低，类似于西地那非。在所有剂量下，RP 5063完全阻断MCT诱导的血浆细胞因子TNF α、IL-1 β和IL-6升高。总之，RP 5063改善了MCT处理大鼠的肺血管病理学和血液动力学、右心室压力和肥大、全身氧饱和度和总体健康状况。
Pulmonary arterial hypertension (PAH), a condition characterized by pulmonary vasculature constriction and remodeling, involves dysregulation of the serotonin (5-HT) receptors 5-HT2A and 5-HT2B. A rat model of monocrotaline (MCT)-induced PAH was used to examine the potential beneficial effects of RP5063, a 5-HT receptor modulator. After a single 60 mg/kg dose of MCT, rats were gavaged twice-daily (b.i.d.) with vehicle, RP5063 (1, 3, or 10 mg/kg), or sildenafil (50 mg/kg) for 28 days. RP5063 at a dose as low as 1 mg/kg, b.i.d. reduced pulmonary resistance and increased systemic blood oxygen saturation. The highest dose of RP5063 (10 mg/kg, b.i.d.) reduced diastolic, systolic, and mean pulmonary pressure, right systolic ventricular pressure, ventilatory pressure, and Fulton's index (ratio of right to left ventricular weight). Doses as low as 3 mg/kg RP5063, b.i.d. also increased weight gain and body temperature, suggesting an improvement in overall health of MCT-treated animals. Similar reductions in pulmonary, right ventricular, and ventilatory pressure, pulmonary resistance, and Fulton's index as well as increased systemic blood oxygen saturation were observed in animals treated with the reference agent sildenafil at a higher dose (50 mg/kg, b.i.d.). Histological examination revealed that RP5063 produced dose-dependent reductions in pulmonary blood vessel wall thickness and proportion of muscular vessels, similar to sildenafil. RP5063 completely blocked MCT-induced increases in the plasma cytoldnes TNF alpha, IL-1 beta, and IL-6 at all doses. In summary, RP5063 improved pulmonary vascular pathology and hemodynamics, right ventricular pressure and hypertrophy, systemic oxygen saturation, and overall health of rats treated with MCT.