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CLINICAL STUDIES

Upregulated expression of cardiac endothelin-1 participates in myocardial cell growth in Bio14.6 Syrian cardiomyopathic hamsters

Tsukasa Inada, MD^*, Hisayoshi Fujiwara, MD^*, Koji Hasegawa, MD^*, Makoto Araki, MD^*, Rikako Yamauchi-Kohno, MS, Hideo Yabana, PhD, Takako Fujiwara, MD, Masaru Tanaka, MD^* and Shigetake Sasayama, MD, FACC^*

^* Department of Cardiovascular Medicine, Kyoto University, Graduate School of Medicine, Kyoto 606-8507, Japan
Lead Optimization Research Laboratory, Tanabe Seiyaku, Saitama, Japan
Department of Food Science, Kyoto Women’s University, Kyoto, Japan

Manuscript received March 20, 1998; revised manuscript received August 24, 1998, accepted October 2, 1998.

Reprint requests and correspondence: Koji Hasegawa, MD, Department of Cardiovascular Medicine, Kyoto University, Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
koj{at}kuhp.kyoto-u.ac.jp

Objectives

The purpose of this study is to investigate the role of endogenous endothelin-1 (ET-1) in myocardial growth in Bio 14.6 Syrian cardiomyopathic hamsters (Bio).

Background

While ET-1, as a growth-promoting peptide, has been implicated in the development of secondary cardiac hypertrophy, the role of endogenous ET-1 in cardiac growth in primary myocardial disease is unknown.

Methods

We measured left ventricular ET-1 levels by a specific sandwich enzyme-linked immunosorbent assay. Furthermore, we examined the chronic effect of T0201, an ET type A receptor-specific antagonist.

Results

The ET-1 levels in the left ventricles were 1.8-fold higher (p < 0.0005) at 20 weeks and 6.4-fold higher (p < 0.0001) at 35 weeks in the Bio compared to age-matched control F1B hamsters (F1B). The Bio ET-1 levels in the lungs exhibited an only 1.3-fold elevation at 35 weeks. Immunohistochemistry demonstrated the localization of ET-1 mainly in the cardiac myocytes. The treatment with T0201 significantly reduced the heart weight/body weight ratio in the Bio, but did not affect the heart weight/body weight ratio in the F1B. Histologically, T0201 reduced the myocyte diameter of Bio to a level similar with that of F1B. However, T0201 did not affect the extent of fibrosis in Bio or F1B.

Conclusions

The ET-1 level in the heart of cardiomyopathic hamsters increases in stage-dependent and organ-specific manners. Though myocyte degeneration and subsequent replacement fibrosis do not require an ET-1 pathway, the accelerated synthesis of ET-1 in the heart may contribute to the pathological growth of remaining myocytes in this animal model.

Abbreviations and Acronyms   Bio = Bio 14.6 Syrian cardiomyopathic hamsters   ET-1 = endothelin-1   EIA = enzyme-linked immunosorbent assay   F1B = F1B hamsters

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