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NITRIC OXIDE SUPPRESSION OF DIABETIC HEART CONTRACTION

一氧化氮抑制糖尿病心脏收缩

基本信息

批准号：
2234917
负责人：
JACQUELYN M SMITH
金额：
$ 9.49万
依托单位：
MIDWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-06-01 至 2000-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2234917
关键词：
beta adrenergic receptor calcium channel calcium flux cardiac myocytes cyclic AMP cyclic GMP disease /disorder model enzyme induction /repression heart contraction insulin dependent diabetes mellitus isoproterenol laboratory rat myocardium nitric oxide nitric oxide synthase norepinephrine voltage /patch clamp

项目摘要

The overall hypothesis of this proposal is that inducible nitric oxide synthase (iNOS) is elevated in cardiac myocytes during the development of insulin-deficient diabetes mellitus and the subsequent production of nitric oxide (NO) and cGMP suppress the response of the cardiac myocyte to beta-adrenergic stimulation. The specific aims to address this hypothesis are as follows: (A) To determine if NO production in the diabetic cardiac myocyte modulates the beta-adrenergic stimulation of contraction. It is hypothesized that the production of NO by iNOS decreases the beta-adrenergic stimulation of contraction in diabetic cardiac myocytes. Moreover, it is hypothesized that inhibition of iNOS will enhance beta-adrenergic stimulation of contraction in diabetic cardiac myocytes. (B) To determine if NO production in the diabetic cardiac myocyte modulates the beta-adrenergic stimulation of calcium current. It is hypothesized that production of NO by iNOS decreases the beta-adrenergic stimulation of calcium current (ICa) in the diabetic cardiac myocyte and that inhibition of iNOS will enhance B-adrenergic stimulation of ICa. (C) To determine if cGMP production mediates the suppression of beta-adrenergic-stimulated calcium current and contraction in the diabetic cardiac myocyte. It is hypothesized that increased production of cGMP in the diabetic cardiac myocyte suppresses Beta- adrenergic stimulation of ICa and contraction. It is further hypothesized that an increased production of NO by iNOS results in an increased production of cGMP in the cardiac myocyte. Therefore, inhibition of cGMP production will enhance the beta-adrenergic stimulation of both ICa and contraction in diabetic cardiac myocyte. Diabetes will be induced by intravenous streptozotocin injection (60 mg/Kg). Isolated cardiac myocytes will be used to measure nitric oxide, cGMP and cAMP production. These parameters will be correlated with measurements of cardiac myocyte contraction and calcium currents using whole cell voltage clamp techniques. Measurements will be determined under basal conditions, in response to isoproterenol, and in the presence of selective nitric oxide synthase inhibitors.

这项提议的总体假设是，诱导型一氧化氮在发育过程中，心肌细胞中的诱导型一氧化氮合酶（iNOS）水平升高，胰岛素缺乏型糖尿病和随后产生的一氧化氮（NO）和环鸟苷酸（cGMP）抑制心肌细胞的反应 β肾上腺素能刺激。解决这一问题的具体目标假设如下：（A）为了确定是否在糖尿病心肌细胞调节β-肾上腺素能刺激收缩。据推测，通过iNOS产生的NO 降低糖尿病患者β-肾上腺素能收缩刺激心肌细胞此外，据推测，抑制iNOS 将增强β-肾上腺素能刺激收缩糖尿病心肌细胞 (B)为了确定糖尿病患者体内NO的产生，心肌细胞调节β-肾上腺素能刺激钙电流据推测，iNOS产生的NO降低了细胞内的NO水平。 β-肾上腺素能刺激钙电流（伊卡）在糖尿病抑制iNOS可增强B-肾上腺素能刺激伊卡。 (C)为了确定cGMP的产生是否介导了抑制β-肾上腺素能刺激的钙电流和收缩在糖尿病心肌细胞中。据推测，糖尿病心肌细胞中cGMP的产生抑制β- 肾上腺素能刺激伊卡和收缩。进一步假设iNOS产生的NO增加导致增加心肌细胞中cGMP的产生。因此，我们认为， cGMP产生的抑制将增强β-肾上腺素能糖尿病心肌细胞伊卡和收缩刺激。糖尿病将通过静脉注射链脲佐菌素诱发（60 mg/Kg）。分离的心肌细胞将用于测量一氧化氮， cGMP和cAMP产生。这些参数将与心肌细胞收缩和钙电流的测量，全电池电压箝位技术。将确定测量值在基础条件下，在异丙肾上腺素的作用下，选择性一氧化氮合酶抑制剂。