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TBC3711 在野百合碱诱导的肺动脉高压中的治疗效果。

Therapeutic efficacy of TBC3711 in monocrotaline-induced pulmonary hypertension.

机构信息

University of Giessen Lung Center, Giessen, Germany.

出版信息

Respir Res. 2011 Jun 23;12(1):87. doi: 10.1186/1465-9921-12-87.

DOI:10.1186/1465-9921-12-87
PMID:21699729
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3141422/
Abstract

BACKGROUND

Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats.

METHODS

Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed.

RESULTS

The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling.

CONCLUSION

The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension.

摘要

背景

内皮素-1 信号在肺动脉高压的发病机制中起着重要作用。尽管已经开发出了不同的内皮素 A 受体拮抗剂，但仍需要一种新的治疗方法来治愈这种疾病。本研究旨在探讨选择性内皮素 A 受体拮抗剂 TBC3711 在野百合碱诱导的肺动脉高压大鼠中的治疗效果。

方法

雄性 Sprague-Dawley 大鼠注射野百合碱后，从第 21 天到第 35 天，随机口服给予 TBC3711（剂量：30mg/kg 体重/天）或安慰剂。进行不同血流动力学和右心肥厚参数的超声心动图测量。第 35 天后，对大鼠进行有创血流动力学和右心肥厚测量，然后处死。此外，还进行了肺血管和右心重构的组织学评估。

结果

新型内皮素 A 受体拮抗剂 TBC3711 显著减轻了野百合碱诱导的肺动脉高压，与安慰剂组相比，血流动力学和右心肥厚均有改善。此外，远端肺血管的肌化和中膜厚度也得到改善。右心室的组织学评估显示纤维化和心肌细胞大小明显减少，表明右心重构得到改善。

结论

本研究结果表明，选择性内皮素 A 受体拮抗剂 TBC3711 对已建立的肺动脉高压大鼠具有治疗益处，因此代表了一种治疗肺动脉高压的有用治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/7c5660bac1cc/1465-9921-12-87-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/b6cd7975a097/1465-9921-12-87-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/e140a1f40dec/1465-9921-12-87-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/33ec968a1bca/1465-9921-12-87-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/f0d060775c2b/1465-9921-12-87-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/d0b39dd57f4f/1465-9921-12-87-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/8e24ef9f7d0a/1465-9921-12-87-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/7c5660bac1cc/1465-9921-12-87-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/b6cd7975a097/1465-9921-12-87-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/e140a1f40dec/1465-9921-12-87-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/33ec968a1bca/1465-9921-12-87-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/f0d060775c2b/1465-9921-12-87-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/d0b39dd57f4f/1465-9921-12-87-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/8e24ef9f7d0a/1465-9921-12-87-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd37/3141422/7c5660bac1cc/1465-9921-12-87-7.jpg

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