NTP42是一种血栓素受体拮抗剂,可减轻实验诱导的肺动脉高压

B. Kinsella, E. Mulvaney, H. Reid
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引用次数: 0

摘要

NTP42是一种新型的血栓素(TX)A2受体(TP)拮抗剂,正在开发用于治疗肺动脉高压(PAH)。PAH是一种具有多种病理生理特征的毁灭性疾病,包括肺血管过度收缩、血管重构、纤维化、炎症、血栓形成和右心室肥厚。通过TP信号传导,TXA2是一种有效的血管收缩剂,是血小板聚集的驱动因素,促有丝分裂和促炎症介质。从机制上讲,TP拮抗剂可以治疗PAH的许多特征,包括血管过度收缩、重构、原位血栓形成、纤维化和炎症。本研究探讨了NTP42在MCT诱导的PAH大鼠模型中的作用。皮下注射60 mg/kg MCT诱导PAH。将大鼠分为3组:1)No MCT, 2) Only MCT, 3) MCT+NTP42, 4) MCT+西地那非和5)MCT+Selexipag,在MCT 24小时后开始28天的治疗。从血流动力学测量来看,NTP42降低了mct诱导的PAH,包括平均肺动脉压(mPAP)和右收缩压(RSVP)。此外,NTP42在减少血管重构、炎症和纤维化方面优于标准护理(SoC)药物西地那非或Selexipag。mPAP、RVSP、Fulton指数、血管重构、炎症和纤维化等关键疾病指标的多参数评分显示,NTP42具有显著的治疗益处,优于所测试的soc。这些发现表明,NTP42和TP信号的拮抗作用可能减轻PAH的病理生理,代表了一种新的治疗靶点,比现有的治疗方法有明显的好处。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
NTP42, an antagonist of the thromboxane receptor, attenuates experimentally-induced pulmonary arterial hypertension
NTP42 is a novel antagonist of the thromboxane (TX)A2 receptor (TP), in development for treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, fibrosis, inflammation, thrombosis and right ventricular hypertrophy. Signalling through the TP, TXA2 is a potent vasoconstrictor, is a driver of platelet aggregation, a pro-mitogenic and a pro-inflammatory mediator. Mechanistically, TP antagonists should treat many of the hallmarks of PAH, including the excess vasoconstriction, remodelling, in situ thrombosis, fibrosis and inflammation. This study investigated the efficacy of NTP42 in a monocrotaline (MCT)-induced PAH rat model. PAH was induced by subcutaneous injection of 60 mg/kg MCT. Rats were assigned to the groups: 1) No MCT, 2) MCT Only, 3) MCT+NTP42, 4) MCT+Sildenafil and 5) MCT+Selexipag, where 28-day treatment was initiated 24hr post-MCT. From hemodynamic measurements, NTP42 reduced MCT-induced PAH including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP). Moreover, NTP42 was superior to standard-of-care (SoC) drugs Sildenafil or Selexipag in reducing vessel remodelling, inflammation and fibrosis. A multiparameter score of key disease indices, including mPAP, RVSP, Fulton’s index, vessel remodelling, inflammation and fibrosis, shows that NTP42 has significant treatment benefits and superior to the SoCs tested. These findings suggest that NTP42 and antagonism of TP signalling may alleviate PAH pathophysiology, representing a novel therapeutic target with marked benefits over existing therapies.
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