Pulmonary arterial hypertension (PAH) is a chronic progressive disease which leads to elevated pulmonary arterial pressure and right heart failure. 3,7-Bis(2-hydroxyethyl)icaritin (ICT), an icariin derivatives, was reported to have potent inhibitory activity on phosphodiesterase type 5 (PDE5) which plays a crucial role in the pathogenesis of PAH. The present study was designed to investigate the effects of ICT on monocrotaline (MCT)-induced PAH rat model and reveal the underlying mechanism. MCT-induced PAH rat models were established with intragastric administration of ICT (10, 20, 40 mg/kg/d), Icariin (ICA) (40 mg/kg/d) and Sildenafil (25 mg/kg/d). The mean pulmonary arterial pressure (mPAP) and right ventricle hypertrophy index (RVHI) were measured. Pulmonary artery remodeling was assessed by H&E staining. Blood and lung tissue were collected to evaluate the level of endothelin 1 (ET-1), nitric oxide (NO), and cyclic guanosine monophosphate (cGMP). The expressions endothelial nitric oxide synthase (eNOS) and PDE5A in lung tissues were determined by Western blot analysis. The results showed that ICT reduced RVHI and mPAP, and reversed lung vascular remodeling in rats with MCT-induced PAH. ICT also reversed MCT-induced ET-1 elevation, NO and cGMP reduction in serum or lung tissue. Moreover, ICT administration significantly induced eNOS activation and PDE5A inhibition. ICT with lower dose had better effects than ICA. In summary, ICT is more effective in preventing MCT-induced PAH in rats via NO/cGMP activation compared with ICA. These findings demonstrate a novel mechanism of the action of ICT that may have value in prevention of PAH.

中文翻译：

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3,7-双（2-羟乙基）二十碳四烯酸，一种磷酸二酯酶-5的有效抑制剂，可通过NO / cGMP激活来防止一克来克林诱导的肺动脉高压。

肺动脉高压（PAH）是一种慢性进行性疾病，可导致肺动脉压升高和右心衰竭。据报道，3,7-双（2-羟乙基）二十碳四烯酸（ICT）是一种大麻素衍生物，对5型磷酸二酯酶（PDE5）具有有效的抑制活性，而磷酸二酯酶5型在PAH的发病机理中起着至关重要的作用。本研究旨在调查信息通讯技术对Monocrotaline（MCT）诱导的PAH大鼠模型的影响，并揭示其潜在机制。通过胃内施用ICT（10、20、40 mg / kg / d），伊卡林（ICA）（40 mg / kg / d）和西地那非（25 mg / kg / d）建立MCT诱导的PAH大鼠模型。测量平均肺动脉压（mPAP）和右室肥大指数（RVHI）。通过H＆E染色评估肺动脉重塑。收集血液和肺组织以评估内皮素1（ET-1），一氧化氮（NO）和环状鸟苷单磷酸（cGMP）的水平。通过Western blot分析确定肺组织中内皮型一氧化氮合酶（eNOS）和PDE5A的表达。结果表明，ICT降低了MCT诱导的PAH大鼠的RVHI和mPAP，并逆转了肺血管重构。ICT还逆转了MCT诱导的血清或肺组织中ET-1升高，NO和cGMP降低。此外，ICT管理显着诱导了eNOS激活和PDE5A抑制。较低剂量的ICT具有比ICA更好的效果。总之，与ICA相比，ICT通过NO / cGMP激活在预防MCT诱导的大鼠PAH中更有效。这些发现证明了ICT行动的新机制可能对预防PAH具有价值。