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

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

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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.

在有意识的动物中的体内研究表明，对于阿片受体样的ORL1，受体激动剂在心血管功能和肾脏排泄中产生深刻的变化通过中枢神经系统（CNS）中的作用的水和钠的作用。这些观察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功能。关于内源系统，阿片类药物已分为三个主要家庭， β-内啡肽，eNkephalins和dynorphins，并被认为是内源配体 Mu-，delta-和kappa-阿片受体。除了这些亚型，第四个已鉴定出称为ORL1的阿片受体。 ORL1受体的内源配体已被分离出来，是一种新型的内源性肽，称为NociTptin（N/OFQ）。尽管它们与内源性阿片类肽和受体的结构相似，nocceptin的作用以及病理生理（例如心力衰竭）调节过程中的ORL1受体包括心血管和肾功能的调节尚不清楚。有意识健康大鼠中ORL1受体的激活产生心动过缓，低血压，和自由的水利尿剂（极端尿流量增加而不会同时增加钠极端）。此外，这种利尿作用发生而不会丧失钾。像这样， NociTptin产生的药物作用与几种综合作用相似目前用来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）。那， Nocceptin是治疗该疾病的潜在候选者。但是，这些站点，这些反应中涉及的机制和途径尚不清楚。此外，心力衰竭模型中的NociTptin仍将建立。拟议的实验旨在检查选择性产生的变化心力衰竭模型中ORL1受体的激活。这些研究的结果将提供关于阿片类药物系统中各个组成部分如何影响的基本知识心血管和肾功能。这很重要，因为新颖的发展对特定阿片类药物接收器亚型的亲和力的治疗将需要进一步研究在不同的实验和病理生理条件下。