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.

该提议的总体假设是诱导型一氧化氮在发育过程中，合成酶（iNOS）的心肌细胞升高缺乏胰岛素的糖尿病和随后产生一氧化氮（NO）和CGMP抑制心肌细胞的反应进行β-肾上腺素能刺激。具体目的是解决这个问题假设如下：（a）确定是否没有生产糖尿病心肌细胞调节β-肾上腺素能刺激收缩。假设Inos的NO生产减少糖尿病患者收缩的β-肾上腺素能刺激心肌细胞。此外，假设抑制iNOS 将增强糖尿病患者收缩的β-肾上腺素能刺激心肌细胞。（b）确定糖尿病患者是否没有产生心肌细胞调节钙的β-肾上腺素能刺激当前的。假设INOS的NO生产降低了糖尿病患者钙电流（ICA）的β-肾上腺素能刺激心肌细胞和对iNOS的抑制作用将增强B-肾上腺素能刺激ICA。（c）确定CGMP生产是否介导抑制β-肾上腺素能刺激的钙电流和收缩在糖尿病性心肌细胞中。假设增加糖尿病心肌细胞中CGMP的产生抑制β- 肾上腺素能刺激ICA和收缩。进一步假设INOS的NO产生增加导致心肌细胞中CGMP的产生增加。所以， CGMP产生的抑制作用将增强β-肾上腺素能糖尿病心肌细胞的ICA刺激和收缩。糖尿病将由静脉注射链二唑菌素诱导（60 mg/kg）。孤立的心肌细胞将用于测量一氧化氮， CGMP和营地生产。这些参数将与使用心肌细胞收缩和钙电流的测量全细胞电压夹技术。将确定测量值在基础条件下，响应异丙肾上腺素，在存在下选择性一氧化氮合酶抑制剂。