CONTROL OF NO BY EXERCISE & INSULIN IN DIABETIC HEART

通过运动控制“不”

• 批准号: 6351541
• 负责人: Thomas H HINTZE
• 金额: $ 29.1万
• 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/6351541
• 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，糖尿病患者仍然患有严重的冠状血管疾病和心脏代谢改变。 我们研究的目的是更好地了解糖尿病性心脏病的机制，特别是一氧化氮生成减少对心脏代谢的影响。 我们的方法将结合生理学研究，在长期使用仪器的清醒狗中，在四氧嘧啶诱发糖尿病后，在较长一段时间内（5周）量化NO产生和心脏代谢的变化，与对这些狗的组织进行体外研究，以确定微血管NO产生、ecNOS基因NO 的表达及其对心脏代谢的控制。 我们将研究 NOS 基因表达改变对 NO 产生减少的潜在影响，这一点我们已经记录在案。 我们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中的潜在作用。 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有益，因此我们将检验以下假设：定期运动训练将通过增加 ecNOS 至少部分恢复组织代谢的 NO 依赖性控制。 此外，我们将测试以下假设：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研究方法：1）我们在糖尿病中发现的一氧化氮生成减少的机制，2）这可能导致心脏代谢缺陷，以及，3）治疗糖尿病心血管并发症可通过运动或辛伐他汀纠正心脏代谢缺陷。