CONTROL OF NO BY EXERCISE & INSULIN IN DIABETIC HEART

通过运动控制“不”

• 批准号: 6498973
• 负责人: Thomas H HINTZE
• 金额: $ 30.07万
• 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/6498973
• 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疾病死亡和残疾的主要原因之一，尽管接受了胰岛素治疗，糖尿病患者仍有严重的冠状动脉疾病和心脏代谢改变。我们研究的目的是为了更好地了解糖尿病心脏病的发病机制，特别是NO产生减少对心脏代谢的影响。我们的方法将结合生理学研究，量化四氧嘧啶诱导的慢性仪器清醒犬糖尿病后较长时间(5周)内NO的产生和心脏代谢的变化，并对这些狗的组织进行体外研究，以确定微血管NO的产生、ecNOS基因的表达和NO对心脏代谢的控制。我们将研究一氧化氮合酶基因表达的改变在我们已经记录的NO产生减少中的潜在后果。我们在体内和体外研究的一个主要焦点将是NO在控制心肌耗氧量和心肌底物利用方面的潜在作用。我们假设，糖尿病发展过程中NO产生的损失导致了这种疾病的代谢后果。由于我们之前已经证明，运动可以上调NO的产生，并且轻微的定期运动对糖尿病患者是有益的，我们将检验这样的假设，即定期运动训练至少可以通过增加ecNOS来部分恢复对组织代谢的NO依赖控制。此外，我们将测试给予辛伐他汀的假说(因为他汀类药物增加了ecNOS的消息半衰期，而且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酶的减少，恢复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的方法来研究：1)我们在糖尿病中发现的NO产生减少的机制，2)这可能导致心脏代谢缺陷，以及3)运动或辛伐他汀治疗糖尿病心血管并发症纠正心脏代谢缺陷。