Disruption of inducible nitric oxide synthase improves β-adrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy

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

研究成果: ジャーナルへの寄稿学術誌査読

55 被引用数 (Scopus)


Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor-a develop congestive heart failure. We have previously reported that short-term inhibition of inducible nitric oxide synthase (iNOS) ameliorates β-adrenergic hyporesponsiveness in TG mice. To examine whether long-term inhibition of iNOS may rescue TG mice from developing congestive heart failure, we disrupted iNOS gene by crossing TG mice with iNOS knockout mice. Myocardial levels of iNOS protein were significantly increased in TG mice compared with age- and sex-matched wild-type (WT) mice. No iNOS protein was detected in TG mice with the disruption of iNOS. Myocardial levels of endothelial NOS were not different among these mice. To examine the effects of iNOS disruption on myocardial contractility, left ventricular pressure was measured. In TG mice, +dP/dtmax was significantly suppressed, and its β-adrenergic responsiveness was blunted. As in the case with short-term inhibition of iNOS, the disruption of iNOS gene improved β-adrenergic inotropic responsiveness in TG mice but not in WT mice. However, the iNOS disruption did not alter myocardial inflammation, ventricular hypertrophy, or the survival of these mice. These results indicate that although myocardial expression of iNOS plays a key role in the attenuation of β-adrenergic inotropic responsiveness, NO-independent mechanisms might be more important in the development of congestive heart failure.

ジャーナルCirculation research
出版ステータス出版済み - 5月 17 2002

!!!All Science Journal Classification (ASJC) codes

  • 生理学
  • 循環器および心血管医学