Role of natriuretic peptides in the ductus arteriosus

利尿钠肽在动脉导管中的作用

基本信息

批准号：
8235789
负责人：
John Jeffrey Reese
金额：
$ 38.61万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8235789
关键词：
Address Adult Affinity Area Atrial Natriuretic Factor Binding Biological Assay Biological Markers Birth Blood Blood Circulation Blood Pressure Blood Vessels Brain Brain natriuretic peptide Bypass C-Type Natriuretic Peptide Cardiac Cells Child Clinical Clinical Trials Clinical Trials Design Combined Modality Therapy Complement Complex Conflict (Psychology)Congestive Heart Failure Cyclic AMP Cyclic GMP Data Development Dinoprostone Diuretics Dose Ductal Ductus Arteriosus Evaluation Exposure to Failure Family member Fetal Lung Fetus Fluid Balance Fluid overload Gene Expression Gene Proteins Generations Goals Guanylate Cyclase Health Heart Atrium Heart failure Hormones Immunohistochemistry In Situ Hybridization In Vitro Infant Ion Channel Knockout Mice Knowledge Life Ligand Binding Ligands Link Mediating Mediator of activation protein Medical Methodology Modeling Monitor Mus Myocardial Myography Natriuretic Peptides Newborn Infant Nitric Oxide Operative Surgical Procedures Organ Oxygen Oxygen measurement, partial pressure, arterial PTGS2 gene Particulate Patent Ductus Arteriosus Pathway interactions Pattern Peptide Receptor Perinatal Exposure Phenotype Physiological Placenta Play Pregnancy Process Property Prostaglandins Protein Isoforms Rattus Regulation Relaxation Role Second Messenger Systems Sheep Shunt Device Signal Transduction Signaling Molecule Smooth Muscle Myocytes Soluble Guanylate Cyclase Stretching System Testing Therapeutic Tissues Up-Regulation Uterus Vascular Endothelium Vasodilator Agents Vasomotor Western Blotting Wild Type Mouse atrial natriuretic factor receptor B autocrine base blood pressure regulation body system cGMP production congenital heart disorder constriction cyclic GMP-binding protein cyclooxygenase 1 enterotoxin receptor feeding fetal fetal blood in utero in vivo inhibitor/antagonist insight mouse model neonate novel novel strategies paracrine peptide B polypeptide C postnatal premature prevent receptor receptor coupling repaired research study response saluretic second messenger therapeutic target treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Natriuretic peptides (NPs) regulate blood pressure and fluid balance via their diuretic, natriuretic, and vasoactive properties, and are biomarkers of heart failure in adults and children. Infants with patent ductus arteriosus (PDA) have increased ANP and BNP levels due to cardiac overload. NP levels normalize soon after PDA treatment. These findings suggest that NPs primarily reflect cardiac status, but we speculate that ongoing elevation of NPs in the presence of PDA could augment DA relaxation and create a feed-forward mechanism to further inhibit DA closure. Our observation that NPs induce DA dilation prompts further speculation that NP administration may be a novel approach to maintain patency of the postnatal DA. Little information exists on the role of NPs in DA development or as mediators of DA tone. Our preliminary data show that the Npr1, Npr2, and Npr3 receptors are differentially expressed in the fetal and newborn mouse DA. Exposure of the isolated fetal mouse DA to different NPs produced dose-dependent dilation to CNP>ANP>BNP under fetal and newborn oxygen conditions. Moreover, mice with PDA have elevated circulating NP levels. We hypothesize that: 1) NPs mediate relaxation of the DA and may prolong patency of the postnatal DA, and 2) elevated postnatal NP levels due to PDA and secondary congestive heart failure help to maintain the DA in a non-contractile state. This hypothesis will be examined in three specific aims. Aim 1 will determine the expression pattern of NPs and their receptors in the fetal and newborn DA, in mouse models of PDA, and cultured DA cells. Aim 2 will determine, in vitro, NP-induced changes in the tone of DAs from: wild type (preterm vs. term) mice, wild type mice treated with NP antagonists, Npr1 (-/-) and Npr2 (-/-) mice, mice with a PDA phenotype (COX-1(-/-) /COX-2(-/-) and COX-inhibited mice), and the closed DA of postnatal P1 and P2 mice. cGMP production and receptor affinity will be determined. Aim 3 will determine, in vivo: the response of term newborns exposed to NPs (to prevent postnatal closure); the response to fetal exposure to NP receptor antagonists (to induce fetal DA constriction); and the effect of NP antagonists on mouse models of PDA (to induce PDA constriction in neonates). These studies will provide new information on novel roles for NPs as DA mediators and identify new potential therapeutic targets for modulation of DA tone. PUBLIC HEALTH RELEVANCE: The ductus arteriosus is a fetal blood vessel whose patency is critical for survival in the womb due to its role in transmitting oxygenated blood from the placenta to fetal organs and tissues. Abnormal constriction of this vessel in the fetus or failure to properly close in the newborn is harmful, particularly in premature newborns, but the mechanisms that regulate this vessel are poorly understood. This proposal will test the hypothesis that natriuretic peptides, signaling molecules that are important for fluid balance and blood pressure control, play a significant role in regulation of the normal ductus arteriosus, and contribute to pathological states where the ductus arteriosus fails to constrict after birth.

描述（由申请人提供）：亚钠肽（NPS）通过其利尿剂，纳特里尔特和血管活性特性调节血压和液体平衡，并且是成人和儿童心力衰竭的生物标志物。具有专利导管（PDA）的婴儿因心脏超负荷而增加的ANP和BNP水平升高。 PDA治疗后不久，NP水平正常化。这些发现表明NP主要反映心脏状况，但我们推测在存在PDA的情况下NP的持续升高可以增强DA松弛，并创建一种进率的机制，以进一步抑制DA的闭合。我们对NP诱导DA扩张的观察结果促使人们进一步猜测NP给药可能是维持产后DA的通畅性的新方法。关于NP在DA开发中的作用或作为DA音调的介体的作用的信息很少。我们的初步数据表明，NPR1，NPR2和NPR3受体在胎儿和新生小鼠DA中差异表达。在胎儿和新生儿氧条件下，分离的胎儿小鼠DA暴露于不同NP的NPS导致剂量依赖性扩张> ANP> BNP。此外，具有PDA的小鼠的NP水平升高。我们假设：1）NP介导DA的松弛并可能延长产后DA的标准，以及2）由于PDA和继发性心脏心力衰竭而导致的产后NP水平升高，有助于将DA保持在非合同状态。该假设将以三个特定目的进行研究。 AIM 1将在PDA的小鼠模型和培养的DA细胞中确定NP及其受体的表达模式。 Aim 2 will determine, in vitro, NP-induced changes in the tone of DAs from: wild type (preterm vs. term) mice, wild type mice treated with NP antagonists, Npr1 (-/-) and Npr2 (-/-) mice, mice with a PDA phenotype (COX-1(-/-) /COX-2(-/-) and COX-inhibited mice), and the closed DA of postnatal P1 and P2小鼠。将确定CGMP的产生和受体亲和力。 AIM 3将确定体内：暴露于NPS的新生儿一词的反应（以防止产后关闭）；对胎儿暴露于NP受体拮抗剂的反应（诱导胎儿DA收缩）； NP拮抗剂对PDA小鼠模型的影响（诱导新生儿的PDA收缩）。这些研究将提供有关NP作为DA介质的新作用的新信息，并确定调节DA音调的新潜在治疗靶标。公共卫生相关性：动脉导管是一种胎儿血管，由于其在从胎盘从胎盘传输到胎儿器官和组织中的作用，其对子宫生存至关重要。该血管在胎儿中的异常收缩或在新生儿中未正确关闭的情况是有害的，尤其是在新生儿中，但对调节该血管的机制知之甚少。该提案将检验以下假设：亚催化肽，对液体平衡和血压控制很重要的信号分子，在调节正常性动脉导管中起重要作用，并有助于病理状态，而病原体动脉导管在诞生后无法收缩。