NITRIC OXIDE, CARDIAC CONTRACTILITY, AND HEART FAILURE

一氧化氮、心脏收缩和心力衰竭

• 批准号: 2211398
• 负责人: Joshua M Hare
• 金额: $ 2.48万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 1995-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2211398
• 关键词: G protein; adenylate cyclase; adrenergic receptor; autonomic reflex; biological signal transduction; dogs; guanine nucleotide binding protein; heart contraction; heart failure; human subject; muscarinic receptor; myocardium disorder; nitric oxide

The overall goal of this project is to examine the role of nitric oxide (NO) as a modulator of autonomic cardiac regulation, and to test the general hypothesis that abnormalities of NO regulation contribute to the autonomic abnormalities characteristic of heart failure. beta-adrenergic hyporesponsiveness and decreased parasympathetic tone are hallmarks of heart failure, and NO has properties that could contribute to these autonomic derangements. The heart expresses both constitutive and inducible forms of nitric oxide synthase (cNOS and iNOS, respectively). Whereas cNOS activity appears to be involved in both beta-adrenergic and cholinergic contractile responses, the induction of iNOS by cytokines or endotoxin depresses the beta-adrenergic contractile response. Intracoronary infusions of a specific NOS inhibitor will be used to assess the contribution of NO to beta-adrenergic and cholinergic contractile responses in conscious dogs before and after the induction of heart failure by rapid pacing and in patients with and without heart failure. The intracoronary infusion technique isolates the cardiac effects of NOS inhibition by reducing systemic responses. Specific aim 1 proposes to test the hypotheses that NO accounts for the development within the heart of 1) beta-adrenergic receptor pathway, 2) muscarinic receptor pathway, and 3) myocardial adenylyl cyclase abnormalities associated with the development of dilated cardiomyopathy in the dog. Specific aim 2 proposes to test the hypothesis that the NO pathway acts independently of the guanine-nucleotide binding protein signal transduction systems in influencing cardiac sympathetic-parasympathetic interactions. Specific aim 3 proposes to test in humans the hypotheses that NO may l) modulate parasympathetic-sympathetic interactions, 2) account, in part, for the adrenergic and 3) muscarinic abnormalities characteristic of human heart failure. The studies contained in this application should provide important new insights into the control of myocardial inotropic state in the normal and failing ventricle.

该项目的总体目标是检查一氧化氮的作用 （否）作为自主心脏调节的调节剂，并测试 一般假设，没有任何调节的异常有助于 心力衰竭的自主异常特征。 β-肾上腺素能 低调和副交感的降低是标志 心力衰竭，没有可能有助于这些的特性 自主神经。心脏既表达构成和 一氧化氮合酶的诱导形式（分别为CNOS和INOS）。 而CNO的活动似乎参与了β-肾上腺素能和 胆碱能收缩反应，细胞因子诱导iNOS或 内毒素降低β-肾上腺素能收缩反应。 特定NOS抑制剂的冠状内输注将用于评估 NO对β-肾上腺素能和胆碱能收缩的贡献 诱导心脏前后有意识的狗的反应 快速起搏和患有和没有心力衰竭的患者失败。 冠状动脉内输注技术分离了NOS的心脏效应 通过减少系统性反应来抑制。 特定目标1提议 检验没有说明心脏发展的假设 1）β-肾上腺素能受体途径，2）毒蕈碱受体途径， 3）心肌腺苷酸环化酶异常 发育狗的心肌病扩张。特定目标2提出 测试NO​​途径独立起作用的假设 鸟嘌呤核苷酸结合蛋白信号转导系统 影响心脏交感神经 - 交感神经相互作用。具体目标 3提议在人类中测试任何假设，即不可调节 副交感神交往，2）部分说明 肾上腺素能和3）毒蕈碱异常的特征 失败。本应用程序中包含的研究应提供 重要的新见解，可以控制心肌肌力状态 正常和失败的心室。