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: 10411739
• 负责人: HELMUT B GOTTLIEB
• 金额: $ 11.95万
• 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/10411739
• 关键词: Adrenergic beta-Antagonists; Adult; Affect; Affinity; Agonist; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Area; Blood; Blood Pressure; Bradycardia; Brain; Brain region; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Chronic; Collaborations; Conscious; Coronary artery; Data; Development; Diagnosis; Dimensions; Disease; Diuresis; Diuretics; Dose; Dynorphins; Edema; Electrolytes; Enkephalins; Ensure; Excretory function; Extracellular Fluid; FDA approved; Family; Female; Functional disorder; Generations; Heart; Heart Rate; Heart failure; Homeostasis; Hormonal; Hormone secretion; Human; Hypotension; Immunoassay; Immunohistochemistry; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Institution; Investigation; Kidney; Knowledge; Laboratories; Left ventricular structure; Ligands; Ligation; Liquid substance; Measures; Mediating; Microinjections; Modality; Modeling; Molecular Biology; Morbidity - disease rate; Myocardial Infarction; Nerve; Neural Pathways; Neuraxis; Neuroanatomy; ORL1 receptor; Opioid; Opioid Peptide; Opioid Receptor; Pathway interactions; Patients; Peptide Receptor; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Plasma; Play; Potassium; Process; Productivity; Rattus; Reactive Oxygen Species; Receptor Activation; Regimen; Regulation; Renal function; Renin-Angiotensin-Aldosterone System; Role; Signal Transduction; Site; Sodium; Sympathetic Nervous System; Symptoms; System; Testing; Therapeutic; Third ventricle structure; Urine; Vasopressins; Water; Western Blotting; Workload; beta-Endorphin; cost; cytokine; design; disease diagnostic; endogenous opioids; experimental study; hindbrain; improved; in vivo; innovation; kappa opioid receptors; male; mortality; nociceptin; novel; novel strategies; novel therapeutic intervention; novel therapeutics; paraventricular nucleus; receptor; relating to nervous system; response; side effect; standard of care

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.

在清醒动物中的体内研究表明，ORL 1，阿片样受体样的， 受体激动剂引起心血管功能和肾排泄的深刻变化 水和钠通过中枢神经系统（CNS）内的作用。这些观察结果 提供证据表明，中枢内源性ORL 1受体参与调节 正常和某些病理生理条件下的心血管和肾功能。在 关于内源性系统，阿片肽已被分类为三个主要家族， β-内啡肽，脑啡肽和强啡肽，和被认为是内源性配体， μ-、δ-和κ-阿片受体。除了这些亚型，第四种 被称为ORL 1的阿片受体已经被鉴定。ORL 1受体的内源性配体 已被分离出来，是一种新的内源性肽，称为痛敏肽（N/OFQ）。尽管 它们与内源性阿片肽和受体的结构相似性、痛敏素的作用 以及ORL 1受体在病理生理学上（例如，心力衰竭）调节过程，包括 心血管和肾功能的调节是未知的。 在清醒的健康大鼠中，ORL 1受体的激活产生心动过缓、低血压， 和游离水利尿（排泄尿流速增加，而不同时增加 钠排泄）。此外，这种利尿作用在没有钾流失的情况下发生。因此，在本发明中， 痛敏肽产生的药理学作用类似于几种药物的联合作用 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，在本发明中， 痛敏肽是治疗这种疾病的潜在候选物。然而，这些网站， 参与这些反应的机制和途径尚不清楚。此外， 痛敏肽在心力衰竭模型中的应用仍有待建立。 拟议的实验旨在检查选择性的 心力衰竭模型中ORL 1受体的激活。这些研究的结果将提供 阿片系统的单个成分如何影响 心血管和肾功能。这一点很重要，因为小说的发展 对特定阿片受体亚型具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。