CONTROL OF NO BY EXERCISE & INSULIN IN DIABETIC HEART

通过运动控制“不”

• 批准号: 6044504
• 负责人: Thomas H HINTZE
• 金额: $ 28.87万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6044504
• 关键词: antihypercholesterolemic agent; cardiovascular disorder chemotherapy; cardiovascular disorder therapy; coronary vasodilator; coronary vessels; diabetes mellitus; diabetes mellitus therapy; diabetic angiopathy; dogs; exercise; heart metabolism; insulin; nitric oxide; nitric oxide synthase; nonhuman therapy evaluation; vasodilation

Diabetes is one of the leading causes of cardiovascular death and disability in the United States and despite the treatment with insulin, patients with diabetes still have severe coronary vascular disease and altered cardiac metabolism. The goal of our studies is to better understand the mechanism responsible for diabetic cardiac disease especially the consequences of reduced production of NO on cardiac metabolism. Our approach will combine physiologic studies quantifying NO production and changes in cardiac metabolism over an extended period of time (5 weeks) after alloxan induced diabetes in chronically instrumented conscious dogs with in vitro studies of tissues from those dogs to determine microvessel NO production, ecNOS gene expression and the control of cardiac metabolism by NO. We will examine the potential consequences of alterations in NOS gene expression in the reduced NO production which we have already documented. A major focus of our studies both in vivo and in vitro will be the potential role of NO in the control of cardiac oxygen consumption and myocardial substrate utilization. We hypothesize that the loss of NO production during the development of diabetes contributes to the metabolic consequences of this disease. Since we have previously shown that exercise can upregulate NO production and mild regular exercise is beneficial in patients with diabetes we will test the hypothesis that regular exercise training will at least partially restore NO dependent control of tissue metabolism by increasing ecNOS. Furthermore, we will test the hypothesis that administration of Simvastatin (since "statins" increase the message half life for ecNOS and since our preliminary data suggest that NO production in vivo and in vitro is increased by statins) to correct the decrease in ecNOS enzyme, restores the cardiac metabolic dysfunction associated with diabetes. Thus, our aims will provide for an integrated approach to study: 1) the mechanism of the reduction in NO production we have found in diabetes, 2) the potential that this results in a cardiac metabolic defect, and, 3) the treatment of the cardiovascular complications of diabetes with exercise or Simvastatin corrects the cardiac metabolic defect.

糖尿病是美国心血管死亡和残疾的主要原因之一，尽管使用胰岛素治疗，但糖尿病患者仍患有严重的冠状动脉疾病和心脏代谢改变。 我们的研究目的是更好地了解糖尿病心脏疾病的机制，特别是减少NO的产生对心脏代谢的影响。 我们的方法将联合收割机生理学研究与体外研究相结合，所述生理学研究在长期使用仪器的清醒狗中在四氧嘧啶诱导糖尿病后的较长时间（5周）内定量NO产生和心脏代谢的变化，所述体外研究来自这些狗的组织以确定微血管NO产生，ecNOS基因表达和NO对心脏代谢的控制。我们将研究NOS基因表达改变的潜在后果。我们已经记录了NO产量的减少。 我们在体内和体外研究的一个主要焦点是NO在控制心脏耗氧量和心肌底物利用率中的潜在作用。 我们推测，在糖尿病的发展过程中，NO产生的损失有助于这种疾病的代谢后果。 由于我们以前已经表明，运动可以上调NO的产生和温和的定期运动是有益的糖尿病患者，我们将测试的假设，定期运动训练将至少部分恢复NO依赖的组织代谢的控制，通过增加ecNOS。 此外，我们将检验这样的假设，即施用辛伐他汀（因为“他汀类药物”增加了ecNOS的信息半衰期，并且因为我们的初步数据表明他汀类药物增加了体内和体外NO的产生）以纠正ecNOS酶的降低，恢复了与糖尿病相关的心脏代谢功能障碍。 因此，我们的目标将提供一种综合方法来研究：1）我们在糖尿病中发现的NO产生减少的机制，2）这导致心脏代谢缺陷的可能性，以及3）运动或辛伐他汀纠正心脏代谢缺陷治疗糖尿病的心血管并发症。