CNS sites involved in the cardiovascular and renal effects of nociceptin in rats with heart failure

中枢神经系统部位参与痛敏素对心力衰竭大鼠心血管和肾脏的影响

• 批准号: 10797797
• 负责人: HELMUT B GOTTLIEB
• 金额: $ 10万
• 依托单位: UNIVERSITY OF THE INCARNATE WORD
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797797
• 关键词: Adrenergic beta-Antagonists; Affect; Affinity; Agonist; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradycardia; Cardiovascular Physiology; Cardiovascular system; Categories; Central Nervous System; Chronic; Conscious; Development; Disease; Diuresis; Diuretics; Dynorphins; Enkephalins; Excretory function; Experimental Designs; Extracellular Fluid; Family; Heart failure; Hypotension; Individual; Investigation; Kidney; Knowledge; Ligands; Modeling; Nerve; ORL1 receptor; Opioid; Opioid Peptide; Opioid Receptor; Pathway interactions; Peptides; Pharmaceutical Preparations; Plasma; Potassium; Process; Rattus; Regulation; Renal function; Role; Site; Sodium; System; Urine; Water; beta-Endorphin; disease diagnostic; endogenous opioids; in vivo; kappa opioid receptors; nociceptin; novel; novel therapeutic intervention; novel therapeutics; pharmacologic; receptor; response

In vivo studies in conscious animals indicate that ORL1, for opioid receptor-like one, receptor agonists produce profound changes in the cardiovascular function and renal excretion of water and sodium via an action within the central nervous system (CNS). These observations provide evidence to suggest that central endogenous ORL1 receptors participate in the regulation of cardiovascular and renal function under normal and certain pathophysiological conditions. In regard to endogenous systems, opioid peptides have been categorized into three major families, β-endorphins, enkephalins and dynorphins, and are suggested to be the endogenous ligands for the mu-, delta- and kappa-opioid receptors, respectively. In addition to these subtypes, a fourth opioid receptor termed ORL1 has been identified. The endogenous ligand for the ORL1 receptor has been isolated and is a novel endogenous peptide referred to as nociceptin (N/OFQ). Despite their structural resemblance to endogenous opioid peptides and receptors, the role of nociceptin and the ORL1 receptor in pathophysiological (e.g., heart failure) regulatory processes including the regulation of cardiovascular and renal function, is not known. Activation of ORL1 receptors in conscious healthy rats produce bradycardia, hypotension, and a free water diuresis (increase in excretory urine flow rate without concurrent increase in sodium excretion). In addition, this diuretic effect occurs without the loss of potassium. As such, nociceptin produces pharmacological effects that are similar to the combined effect of several drugs currently used to treat heart failure (e.g., ACE inhibitors, beta blockers, and diuretics). Thus, nociceptin is a potential candidate for the treatment of this disease. However, the sites, mechanism and pathways involved in these responses are unknown. Furthermore, the effects of nociceptin in a heart failure model are still to be established. Proposed experiments are designed to examine the changes produced by selective activation of ORL1 receptors in a heart failure model. The results of these studies will provide fundamental knowledge of how an individual component of the opioid system affects cardiovascular and renal function. This is of importance because the development of novel therapeutics with affinity for a specific opioid receptor subtype will require further investigation under different experimental and pathophysiological conditions.

在清醒动物体内的研究表明，对于阿片受体样受体ORL1， 受体激动剂对心血管功能和肾脏排泄产生深刻的影响 通过中枢神经系统(CNS)内的一种作用来吸收水和钠。这些观察结果 提供证据表明中央内源性ORL1受体参与调节 在正常和某些病理生理条件下的心血管和肾脏功能。在……里面 在内源性系统方面，阿片肽分为三大类， β-内啡肽、脑啡肽和强啡肽被认为是内源性的配体 分别是Mu阿片受体、Delta阿片受体和kappa阿片受体。除了这些亚型外，还有第四种亚型 命名为ORL1的阿片受体已被鉴定。ORL1受体的内源性配体 已经被分离出来，是一种新的内源性多肽，称为伤害素(Niciceptin，N/OFQ)。尽管 它们与内源性阿片肽和受体的结构相似，以及伤害素的作用 和ORL1受体在病理生理(如心力衰竭)调节过程中的作用，包括 对心血管和肾脏功能的调节，目前尚不清楚。 清醒的健康大鼠激活ORL1受体会导致心动过缓、低血压、 和游离水利尿(增加排泄物尿流率，而不同时增加 钠排泄)。此外，这种利尿作用不会丢失钾。因此， 伤害素产生的药理作用类似于几种 目前用于治疗心力衰竭的药物(例如，ACE抑制剂、β受体阻滞剂和利尿剂)。因此， Neciceptin是治疗这种疾病的潜在候选药物。然而，这些网站， 参与这些反应的机制和途径尚不清楚。此外，这一影响， 伤害素在心力衰竭模型中的作用仍有待建立。 拟议的实验旨在检查选择性地 心力衰竭模型中ORL1受体的激活。这些研究的结果将提供 关于阿片系统的单个成分如何影响的基本知识 心血管和肾脏功能。这一点很重要，因为小说的发展 对特定阿片受体亚型有亲和力的治疗方法需要进一步研究 在不同的实验和病理生理条件下。