Role of natriuretic peptides in the ductus arteriosus

利尿钠肽在动脉导管中的作用

• 批准号: 8442344
• 负责人: John Jeffrey Reese
• 金额: $ 36.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442344
• 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; 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; public health relevance; receptor; receptor coupling; repaired; research study; response; saluretic; second messenger; therapeutic target; treatment strategy

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.

描述（由申请人提供）：利钠肽（NP）通过其利尿、利尿钠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。患有动脉导管未闭 (PDA) 的婴儿由于心脏负荷过重，ANP 和 BNP 水平升高。 PDA 治疗后 NP 水平很快恢复正常。这些发现表明，NP 主要反映心脏状态，但我们推测，在 PDA 存在的情况下，NP 持续升高可能会增强 DA 松弛，并创建前馈机制以进一步抑制 DA 关闭。我们观察到 NP 诱导 DA 扩张，这进一步推测 NP 给药可能是维持产后 DA 通畅的新方法。关于 NP 在 DA 发育中的作用或作为 DA 音调介质的信息很少。我们的初步数据表明，Npr1、Npr2 和 Npr3 受体在胎儿和新生小鼠 DA 中存在差异表达。在胎儿和新生儿氧气条件下，将分离的胎儿小鼠 DA 暴露于不同的 NP 中，会产生 CNP>ANP>BNP 的剂量依赖性扩张。此外，患有 PDA 的小鼠循环 NP 水平升高。我们假设：1) NP 介导 DA 松弛，并可能延长出生后 DA 的通畅时间，2) 由于 PDA 和继发性充血性心力衰竭导致出生后 NP 水平升高，有助于将 DA 维持在非收缩状态。该假设将在三个具体目标中进行检验。目标 1 将确定胎儿和新生儿 DA、PDA 小鼠模型以及培养的 DA 细胞中 NP 及其受体的表达模式。目标 2 将在体外确定 NP 诱导的 DA 音调变化：野生型（早产儿与足月）小鼠、用 NP 拮抗剂、Npr1 (-/-) 和 Npr2 (-/-) 处理的野生型小鼠小鼠、具有 PDA 表型的小鼠（COX-1(-/-) /COX-2(-/-) 和 COX 抑制小鼠）以及出生后 P1 和 P2 的闭合 DA老鼠。 cGMP 产量和受体亲和力将被确定。目标 3 将确定体内：足月新生儿暴露于 NP 的反应（以防止产后闭合）；胎儿暴露于 NP 受体拮抗剂的反应（诱导胎儿 DA 收缩）；以及 NP 拮抗剂对 PDA 小鼠模型的影响（诱导新生儿 PDA 收缩）。这些研究将提供关于 NP 作为 DA 介体的新作用的新信息，并确定调节 DA 音调的新的潜在治疗靶点。

项目成果

Spontaneous Rhythmic Contractions (Vasomotion) of the Isolated, Pressurized Ductus Arteriosus of Preterm, but Not Term, Fetal Mice.

早产但非足月胎儿小鼠离体加压动脉导管的自发节律性收缩（血管运动）。

• 发表时间: 2012-01
• 作者: Vucovich, Megan;Ehinger, Noah;Poole, Stanley D;Lamb, Fred S;Reese, Jeff
• 通讯作者: Reese, Jeff

Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies.

扑热息痛对动脉导管未闭闭合的功效可能是剂量依赖性的：来自人类和小鼠研究的证据。

• 发表时间: 2014-09
• 影响因子: 3.6
• 作者: El;Jain, Amish;Corcoran, David;Shah, Prakesh S;Hooper, Christopher W;Brown, Naoko;Poole, Stanley D;Shelton, Elaine L;Milne, Ginger L;Reese, Jeff;McNamara, Patrick J
• 通讯作者: McNamara, Patrick J

Inadvertent relaxation of the ductus arteriosus by pharmacologic agents that are commonly used in the neonatal period.

新生儿期常用药物导致动脉导管意外松弛。

• 发表时间: 2010-06
• 影响因子: 3.4
• 作者: Reese, Jeff;Veldman, Ale;Shah, Lisa;Vucovich, Megan;Cotton, Robert B
• 通讯作者: Cotton, Robert B

Reflections on the early years of neonatology. Paul R. Swyer: the beginnings of Canadian neonatology at The Hospital for Sick Children in Toronto and insights into his early career.

对新生儿学早期的反思。

• 发表时间: 2018-04
• 作者: Reese, Corey Nason;Reese, Jeff
• 通讯作者: Reese, Jeff

Transcriptional profiling reveals ductus arteriosus-specific genes that regulate vascular tone.

转录谱揭示了调节血管张力的动脉导管特异性基因。

• DOI: 10.1152/physiolgenomics.00171.2013
• 发表时间: 2014-07-01
• 期刊: Physiological genomics
• 影响因子: 4.6
• 作者: Elaine L. Shelton;G. Ector;C. Galindo;Christopher W. Hooper;N. Brown;Irene Wilkerson;Elise R. Pfaltzgraff
• 通讯作者: Elise R. Pfaltzgraff