Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-α

Hajime Funakoshi, Toru Kubota, Yoji Machida, Natsumi Kawamura, Arthur M. Feldman, Hiroyuki Tsutsui, Hiroaki Shimokawa, Akira Takeshita

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51 Citations (Scopus)

Abstract

Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor (TNF)-α develop dilated cardiomyopathy with myocardial inflammation. The purpose of this study was to investigate the role of nitric oxide (NO) in this mouse model of cardiomyopathy. Female TG and wild-type mice at the age of 10 wk were studied. The expression and activity of inducible NO synthase (iNOS) were significantly increased in the TG myocardium, whereas those of endothelial NOS were not altered. The majority of the iNOS protein was isolated in the interstitial cells. The selective iNOS inhibitor (1S,5S,6R,7R)7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0]heptane hydrochloride (ONO-1714) was used to examine the effects of iNOS induction on myocardial contractility. Echocardiography and left ventricular pressure measurements were performed. Both fractional shortening and the maximum rate of rise of left ventricular pressure were significantly suppressed in TG mice. Although ONO-1714 did not change hemodynamic parameters or contractility at baseline, it significantly improved β-adrenergic inotropic responsiveness in TG mice. These results indicate that induction of iNOS may play an important role in the pathogenesis of cardiac dysfunction in this mouse model of cytokine-induced cardiomyopathy.

Original languageEnglish
Pages (from-to)H2159-H2166
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume282
Issue number6 51-6
DOIs
Publication statusPublished - 2002 Jan 1

Keywords

  • Cytokine
  • Heart failure
  • Transgenic mice

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Funakoshi, H., Kubota, T., Machida, Y., Kawamura, N., Feldman, A. M., Tsutsui, H., Shimokawa, H., & Takeshita, A. (2002). Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-α. American Journal of Physiology - Heart and Circulatory Physiology, 282(6 51-6), H2159-H2166. https://doi.org/10.1152/ajpheart.00872.2001