CONTROL OF NO BY EXERCISE & INSULIN IN DIABETIC HEART

通过运动控制“不”

• 批准号: 6629007
• 负责人: Thomas H HINTZE
• 金额: $ 30.85万
• 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/6629007
• 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，尽管接受了胰岛素治疗，但糖尿病患者仍然患有严重的冠状动脉血管疾病和心脏代谢改变。 我们研究的目的是更好地了解导致糖尿病心脏病的机制，尤其是降低心脏代谢的NO产生的后果。 我们的方法将结合生理研究，在长期（5周）中，在长期（5周）中量化了无生产和心脏代谢的变化，此前Alloxan诱导了慢性仪器有意识的犬的糖尿病，并在这些狗的体外研究中对这些狗的组织进行体外研究，以确定微型固定剂，ecnos基因的表达和无用的心脏代谢的控制。 我们将研究NOS基因表达变化的潜在后果，在我们已经记录的NO产生的降低中。 我们研究的主要重点在体内和体外都将是NO在控制心脏氧气消耗和心肌底物利用率中的潜在作用。 我们假设在糖尿病发展过程中NO产生的损失会导致该疾病的代谢后果。 由于我们以前已经表明，运动可以上调任何生产，而轻度的定期运动对糖尿病患者有益，因此我们将检验以下假设：定期运动训练至少会通过增加ecnos来部分恢复对组织代谢的依赖性控制。 此外，我们将检验以下假设：辛伐他汀的给药（由于“汀类药物”增加了eCNOS的信息半寿命，并且由于我们的初步数据表明，汀类药物中的体内和体外的产生没有增加）以纠正ECNOS酶的减少，因此恢复了与糖尿病相关的心脏代谢功能障碍。 因此，我们的目的将提供一种综合研究方法：1）我们在糖尿病中发现的NO生产的减少机制，2）这可能导致心脏代谢缺陷的潜力，以及3）治疗糖尿病的心血管并发症，通过运动或辛伐他汀纠正心脏代谢缺陷。