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

Abstract

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

• Authors: Hajime Funakoshi, Toru Kubota, Natsumi Kawamura, Yoji Machida, Arthur M Feldman, Hiroyuki Tsutsui, Hiroaki Shimokawa, Akira Takeshita
• Journal: Circulation research (Circ Res) Vol. 90 Issue 9 Pg. 959-65 (May 17 2002) ISSN: 1524-4571 [Electronic] United States
• PMID: 12016261 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Agonists
• Tumor Necrosis Factor-alpha
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Nos2 protein, mouse
• Nos3 protein, mouse
• Isoproterenol

Topics

• Adrenergic beta-Agonists (pharmacology)
• Animals
• Blood Pressure (drug effects)
• Blotting, Western
• Cardiomyopathies (genetics, pathology, physiopathology)
• Enzyme Induction
• Female
• Genotype
• Heart Rate (drug effects)
• Isoproterenol (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Mutation
• Myocardial Contraction (drug effects)
• Myocardium (enzymology, pathology)
• Nitric Oxide Synthase (biosynthesis, genetics)
• Nitric Oxide Synthase Type II
• Nitric Oxide Synthase Type III
• Organ Size (drug effects)
• Survival Analysis
• Tumor Necrosis Factor-alpha (genetics, physiology)