Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha.
Transgenic (TG) mice with cardiac-specific overexpression of tumor necrosis factor (TNF)-alpha 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 beta-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.
Funakoshi
Hajime
H
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan 812-8582.
Kubota
Toru
T
Machida
Yoji
Y
Kawamura
Natsumi
N
Feldman
Arthur M
AM
Tsutsui
Hiroyuki
H
Shimokawa
Hiroaki
H
Takeshita
Akira
A
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D004452:Echocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006439:Hemodynamics / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology; D007150:Immunohistochemistry; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009205:Myocarditis / Q000235:genetics; D009206:Myocardium / Q000201:enzymology; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000318:Adrenergic beta-Agonists; D000578:Amidines; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D007545:Isoproterenol