Role of natriuretic peptides in the ductus arteriosus

描述（由申请人提供）：利钠肽（NPs）通过其利尿剂、利钠剂和血管活性特性调节血压和体液平衡，是成人和儿童心力衰竭的生物标志物。婴儿动脉导管未闭（PDA）增加ANP和BNP水平由于心脏负荷过重。在PDA治疗后，NP水平很快恢复正常。这些发现表明，NPs主要反映心脏状态，但我们推测，在PDA存在的情况下，NPs的持续升高可能会增强DA舒张，并产生一种前馈机制，进一步抑制DA关闭。我们观察到NP诱导DA扩张，进一步推测NP给药可能是一种维持出生后DA通畅的新方法。关于NPs在DA发育中的作用或作为DA音调的介质的信息很少。我们的初步数据显示，Npr1、Npr2和Npr3受体在胎儿和新生小鼠DA中存在差异表达。在胎儿和新生儿缺氧条件下，分离的胎鼠DA暴露于不同的NPs会产生CNP>ANP>BNP的剂量依赖性扩张。此外，PDA小鼠的循环NP水平升高。我们假设：1)NPs介导DA的松弛并可能延长出生后DA的通畅；2)由于PDA和继发性充血性心力衰竭导致的出生后NP水平升高有助于维持DA处于非收缩状态。这一假设将在三个具体目标中进行检验。目的1将确定NPs及其受体在胎儿和新生儿DA、PDA小鼠模型和培养DA细胞中的表达模式。Aim 2将在体外确定：野生型（早产与长期）小鼠、NP拮抗剂处理的野生型小鼠、Npr1（-/-）和Npr2（-/-）小鼠、PDA表型小鼠(COX-1（-/-) /COX-2（-/-）和cox -抑制小鼠）以及出生后P1和P2小鼠的封闭DA的NP诱导的DAs音调变化。cGMP的产生和受体亲和力将被确定。目标3将在体内确定：足月新生儿暴露于NPs的反应（防止产后闭合）；胎儿暴露于NP受体拮抗剂（诱导胎儿DA缩窄）后的反应；以及NP拮抗剂对小鼠PDA模型的影响（诱导新生儿PDA收缩）。这些研究将为NPs作为DA介质的新作用提供新的信息，并确定DA音调调节的新的潜在治疗靶点。

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.