OPIATE RECEPTOR INHIBITION IN CONGESTIVE HEART FAILURE

我们最近发现血浆β-内啡肽和促肾上腺皮质激素 实验性右心衰竭中促肾上腺皮质激素 (ACTH) 增加，并且 急性给予阿片受体拮抗剂会增加心脏 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。 我们进一步证明了 急性有益血流动力学效应是通过 δ 受体介导的 介导的交感神经刺激。 这些结果表明内源性 阿片肽可能在调节中发挥重要作用 慢性心力衰竭中的循环，其作用取决于 β-肾上腺素受体偶联腺苷酸环化酶的功能完整性 活动。 我们建议研究慢性阿片受体的影响 抑制心力衰竭。 我们推测，由于过度同情 心力衰竭时的刺激会减少心肌β受体的数量 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 与阿片受体初始给药相关的影响 在慢性阿片受体抑制过程中，阻滞剂可能会随着时间的推移而消失， 心肌功能随之恶化。 我们将管理 纳曲酮，一种口服活性长效阿片受体阻断剂，或 安慰剂，在心力衰竭发生期间或持续 6 周 出现稳定心力衰竭后，确定是否为慢性心力衰竭 阿片受体抑制会增强β-受体的发作或程度 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、压力反射敏感性和左心室正性肌力 治疗开始和结束时对肾上腺素能药物的反应。 我们会 测量心肌去甲肾上腺素、β-肾上腺素受体密度、腺苷酸 环化酶活性、鸟嘌呤核苷酸结合蛋白水平以及右 使用孤立的小梁肌测量心室收缩功能 准备。 研究结果将进一步加深我们对 内源性阿片类药物在心力衰竭循环中的作用，可能 可能会导致心力衰竭的新治疗方法。

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.