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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

基本信息

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
项目类别：
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

项目摘要

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。