OPIATE RECEPTOR INHIBITION IN CONGESTIVE HEART FAILURE

充血性心力衰竭中的阿片受体抑制

基本信息

批准号：
3348863
负责人：
Chang-Seng Liang
金额：
$ 18.2万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-09-30 至 1993-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3348863
关键词：
adenylate cyclase adrenocorticotropic hormone baroreceptors beta antiadrenergic agent catecholamines congestive heart failure dogs endorphins exercise guanine nucleotide binding protein heart circulation heart contraction heart pharmacology hemodynamics isolation perfusion naltrexone opioid receptor

项目摘要

We have recently shown that plasma beta-endorphin and adrenocorticotropic hormone (ACTH) are increased in experimental right heart failure, and that acute administration of opiate receptor antagonists increases cardiac output, aortic pressure, left ventricular dP/dt and dP/dt/P, and blood flow to the skeletal muscle, myocardium, and kidneys. We have further shown that the acute salutary hemodynamic effects are mediated via delta-receptor mediated sympathetic stimulation. These results indicate that endogenous opioid peptides may play an important role in the regulation of circulations in chronic heart failure and that their actions depend on the functional integrity of the beta-adrenoceptor-coupled adenylate cyclase activity. We propose to study the effects of chronic opiate receptor inhibition in heart failure. We speculate that since excessive sympathetic stimulation in heart failure reduces myocardial beta-receptor number and adenylate cyclase activity (probably secondary to alterations in guanine nucleotide-binding proteins) the adrenergically-mediated stimulatory effects associated with the initial administrations of opiate receptor blockers may be lost with time during chronic opiate receptor inhibition, and a worsening of myocardial function ensues. We will administer naltrexone, an orally active long-acting opiate receptor blocking agent, or placebo, for 6 weeks either during the development of heart failure or after stable heart failure has developed, to determine whether chronic opiate receptor inhibition enhances the onset or the degree of beta- adrenoceptor down-regulation, beta-adrenergic sensitivity, guanine nucleotide-binding proteins, and myocardial failure. We will measure the resting and exercise hemodynamics, plasma beta-endorphin, ACTH and catecholamines, baroreflex sensitivity, and inotropic left ventricular responses to adrenergic agents at the start and end of treatment. WE will measure myocardial norepinephrine, beta-adrenoceptor density, adenylate cyclase activity, levels of guanine nucleotide-binding proteins, and right ventricular contractile function using an isolated trabeculate muscle preparation. Results of the study will further our understanding of the role of endogenous opioids in the circulation of heart failure, and may potentially lead to new treatments for heart failure.

我们最近表明，血浆β-内啡肽和肾上腺皮质激素激素（ACTH）在实验右心力衰竭中增加，并且阿片受体拮抗剂的急性给药增加心脏输出，主动脉压力，左心室DP/DT和DP/DT/P以及血流到骨骼肌，心肌和肾脏。我们进一步显示了急性抗血液动力学作用是通过增量受体介导的介导的交感神经刺激。这些结果表明内源性阿片类肽可能在调节中起重要作用慢性心力衰竭的流通，他们的行为取决于 β-肾上腺素耦合的腺苷酸环化酶的功能完整性活动。我们建议研究慢性鸦片受体的影响抑制心力衰竭。我们推测这是因为过度同情心力衰竭刺激会减少心肌β受体数量和腺苷酸环化酶活性（可能继发于鸟嘌呤的改变核苷酸结合蛋白）肾上腺素介导的刺激性与鸦片受体的初始管理相关的效果在慢性鸦片受体抑制期间，阻滞剂可能会随着时间而丢失，随之而来的心肌功能恶化。我们将管理 Naltrexone，一种口服活跃的长效阿片受体阻滞剂，或安慰剂，在心力衰竭发展期间持续6周稳定心力衰竭后，确定是否慢性鸦片受体抑制增强了β-的发作或程度肾上腺素受体下调，β-肾上腺素能敏感性，鸟嘌呤核苷酸结合蛋白和心肌衰竭。我们将衡量休息和运动血液动力学，血浆β-内啡肽，ACTH和儿茶酚胺，压力反射敏感性和肌力左心室在治疗开始和结束时对肾上腺素能剂的反应。我们将测量心肌去甲肾上腺素，β-肾上腺素受体密度，腺苷酸盐环化酶活性，鸟嘌呤核苷酸结合蛋白的水平，右使用孤立的小梁肌肉的心室收缩功能准备。该研究的结果将进一步了解我们对内源性阿片类药物在心力衰竭循环中的作用，可能有可能导致心力衰竭的新治疗方法。