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(Circulation Research. 2002;90:959.)
© 2002 American Heart Association, Inc.

Integrative Physiology

Disruption of Inducible Nitric Oxide Synthase Improves ß-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

From the Department of Cardiovascular Medicine (H.F., T.K., N.K., Y.M., H.T., H.S., A.T.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; the Cardiovascular Institute (A.M.F.), University of Pittsburgh Medical Center, Pittsburgh, Pa.

Correspondence to Toru Kubota, MD, PhD, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan 812-8582. E-mail kubotat{at}cardiol.med.kyushu-u.ac.jp

Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor- develop congestive heart failure. We have previously reported that short-term inhibition of inducible nitric oxide synthase (iNOS) ameliorates ß-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/dt_max was significantly suppressed, and its ß-adrenergic responsiveness was blunted. As in the case with short-term inhibition of iNOS, the disruption of iNOS gene improved ß-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 ß-adrenergic inotropic responsiveness, NO-independent mechanisms might be more important in the development of congestive heart failure.

Key Words: cytokines • nitric oxide synthase • heart failure • tumor necrosis factor • transgenic mice

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