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Dual ECE/NEP inhibition improved diastolic function and ameliorated cardiac remodeling in rats with myocardial dysfunction secondary to pressure overload by aortic banding

Tan, M and Wu, B and Chen, I and Chai, C and Chou, S and Yeh, J and Chen, I and Wu, J and Jeng, AY and Dai, Z (2014) Dual ECE/NEP inhibition improved diastolic function and ameliorated cardiac remodeling in rats with myocardial dysfunction secondary to pressure overload by aortic banding. Experimental and Clinical Cardiology. pp. 358-368.

Abstract

Endothelin-1 (ET-1) substantially contributes to left ventricular remodeling and progression of heart failure. But, nonselective or selective ET-1 receptor antagonists exerts disappointing results. Sustained pressure overload can lead to left heart dysfunction through cardiac remodeling in patients with systemic hypertension. CGS 26393, an orally dual inhibitor of endothelin-converting enzyme (ECE) and neural endopeptidase (NEP). In this study, we investigated the effect of administration of CGS 26393, given immediately after aortic banding, on homodynamic functions, cardiac myocardial remodeling and cardiac expression of ET-1 and its receptors. The banded rats were randomized to receive saline or CGS 26393 from Days 1 to 28 (AOB <sub>28</sub>/CGS<sub>1-28</sub>). Compared with the AOB<sub>28</sub> group, administration of CGS 26393 resulted in significant decreases in both mean left atrial pressure and mean pulmonary arterial pressure, plasma ET-1 levels, and attenuated both fibrosis and hypertrophy in the left ventricle. In addition, CGS 26393 down-regulated the cardiac ET<sub>B</sub> receptor expression, but not ET<sub>A</sub>. These results suggest administration of CGS 26393 could improve diastolic function and ameliorate cardiac remodeling through decreasing ET-1 generation and down-regulating cardiac ET<sub>B</sub> receptors. The role of ET<sub>B</sub> in the development of cardiac dysfunction warrant further investigation

Item Type: Article
Additional Information: NIBR author: Jeng, A institute: NIBR contributor address: Z.-K. Dai, School of Medicine, College of Medicine Kaohsiung Medical University Hospital, Kaohsiung Medical University, 100, Shih-Chuan 1 st Rd, Kaohsiung, 807, Taiwan (Republic of China). E-mail: zenkong@kmu.edu.tw
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/23412

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