OPIATE RECEPTOR INHIBITION IN CONGESTIVE HEART FAILURE

我们最近发现，血浆中的β-内啡肽和促肾上腺皮质激素 实验性右心衰竭时激素(ACTH)升高， 阿片受体拮抗剂的急性给药增加心脏 心输出量、主动脉压、左心室dp/dt和dp/dt/P以及血流量 骨骼肌、心肌和肾脏。我们已经进一步证明 急性有益的血流动力学效应是通过三角洲受体介导的 介导的交感神经刺激。这些结果表明，内生性 阿片肽可能在调节血管紧张素转换酶活性中发挥重要作用 慢性心力衰竭患者的血液循环和他们的行为取决于 β-肾上腺素能受体偶联腺苷环化酶的功能完整性 活动。我们建议研究慢性阿片受体的作用 心力衰竭时的抑制作用。我们推测由于过度的同情 心力衰竭时的刺激减少了心肌β受体的数量和 腺苷环化酶活性(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 与阿片受体首次给药相关的效应 在慢性阿片受体抑制期间，阻滞剂可能随着时间的推移而丢失， 随之而来的是心肌功能恶化。我们将管理 纳曲酮，一种口服活性的长效阿片受体阻滞剂，或 安慰剂，在心力衰竭期间或在发生心力衰竭期间服用6周 在稳定的心力衰竭发展后，以确定慢性 阿片受体抑制可增强β-氨基丁酸的发生或程度 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。我们将测量 静息和运动血流动力学、血浆β-内啡肽、ACTH和 儿茶酚胺、压力感受性反射敏感性和左心室肌力 治疗开始和结束时对肾上腺素能药物的反应。我们会的 测定心肌去甲肾上腺素、β-肾上腺素能受体密度、腺苷 环化酶活性，鸟嘌呤核苷酸结合蛋白水平，以及右 离体骨小梁肌肉的心室收缩功能 准备工作。这项研究的结果将加深我们对 内源性阿片类药物在心力衰竭循环中的作用 可能会带来治疗心力衰竭的新方法。

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.