bNOS-NO on Neonatal Arterial Presure Regulation in NTS

bNOS-NO 对 NTS 新生儿动脉压调节的影响

• 批准号: 6399882
• 负责人: SHENG-XING MA
• 金额: $ 7.35万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6399882
• 关键词: artery; birth; blood pressure; cesarean section; gamma aminobutyrate; gene expression; hemodynamics; immunocytochemistry; in situ hybridization; medulla oblongata; neuroregulation; neurotransmitter antagonist; neurotransmitter transport; newborn animals; nitric oxide; nitric oxide synthase; norepinephrine; oligonucleotides; pregnancy circulation; protein localization; sheep; solitary tract nucleus; western blottings

DESCRIPTION (provided by applicant): Despite the dramatic rise in circulating norepinephrine (NE) concentrations during transition from fetal to newborn life, arterial blood pressure does not substantively change. However, altered regulation of arterial blood pressure at birth, perhaps due to prematurity or depleted NE following fetal stress, may result in neonatal hypotension or hypertension. The nucleus tractus solitarius (NTS) is the principal sensory nucleus for central control of the circulation. Nitric oxide (NO) in the NTS plays an important role in the central inhibition of sympathetic tone and thus decreases blood pressure. We have recently shown that ovine brain NO synthase (bNOS) expression in the NTS is markedly enhanced in neonates at 4 hours following birth, as compared to the term fetus. Consistent with the postulated role of NO, fetal arterial blood pressure is decreased by fourth ventricle administration of a NO donor and increased by a NO synthesis inhibitor. Furthermore, our preliminary results demonstrate that fourth ventricle administration of a NE uptake inhibitor increases ovine fetal bNOS protein and y-aminobutyric acid (GABA) expression in the NTS and rostral ventral medulla (RVM). We hypothesize that during fetal and neonatal life (1) elevated circulating NE induces up-regulation of bNOS in the NTS during birth transition, and (2) the bNOS-NO-GABA system regulates neonatal arterial blood pressure in the NTS-RVM central sympathetic pathways. In view of the critical importance of fetal/neonatal arterial blood pressure regulation, our major aims are: 1) If exogenous fetal NE mimics up-regulation of bNOS-NO in the NTS and the RVM? 2) If arterial blood pressure increases and NTS bNOS-GABA expression decreases in newborn lambs by fourth ventricle administration of nNOS antisense oligonucleotides before birth? and 3) If the enhanced bNOS and GABA expression in the NTS and RVM regions at birth are promoted by an inhibitor of NE uptake? These studies will examine bNOS expression in the NTS and RVM neurons in the ovine fetus and neonate. Quantification of arterial blood pressure, plasma NE concentrations, bNOS and GABA expressions in brain regions will be incorporated with neuropharmacological manipulations to test our hypotheses. These results will advance our understanding of the sites and mechanisms for bNOS-NO-GABA effects on arterial blood pressure regulation during the transition from fetal to newborn life and will yield new insights regarding noradrenergic mechanisms for bNOS regulation and central neurocardiovascular control at birth.

描述（由申请人提供）：尽管循环急剧增加 从胎儿到新生儿过渡期间的去甲肾上腺素（NE）浓度 生活，动脉血压不会实质性改变。但是，改变了 调节出生时动脉血压的调节，也许是由于早产或 胎儿应激后的NE耗尽，可能导致新生儿低血压或 高血压。核心核Solitarius（NTS）是主要感觉 用于循环中心控制的核。 NTS中的一氧化氮（NO） 在同情语气的中心抑制中起着重要作用，因此 降低血压。我们最近表明，卵脑无合酶 NTS中的（BNO）在4小时时在NTS中的表达显着增强 出生后，与胎儿一词相比。与假定的 NO的作用，胎儿动脉血压通过第四个心室降低 给予无供体，并通过无合成抑制剂增加。 此外，我们的初步结果表明第四脑室 施用NE摄取抑制剂会增加卵巢胎儿BNO蛋白和 Y-氨基丁酸（GABA）在NTS和thostral腹侧髓质中的表达 （RVM）。我们假设在胎儿和新生儿生活中（1）升高 循环NE诱导NTS中BNO的上调 过渡和（2）BNOS-NO-GABA系统调节新生儿动脉血液 NTS-RVM中央交感神经途径中的压力。 鉴于胎儿/新生儿动脉血压的重要性 调节，我们的主要目的是：1）如果外源胎儿NE模拟上调 NTS和RVM中的bnos-no？ 2）如果动脉血压升高，并且 NTS BNOS-GABA表达在新生羔羊中降低了第四脑室 出生前nnos反义寡核苷酸的给药？ 3）如果 NTS和RVM区域中增强的BNO和GABA表达是 由NE摄取的抑制剂促进？这些研究将检查BNO NTS和RVM神经元中的表达在卵巢胎儿和新生儿中。 定量动脉血压，血浆NE浓度，BNO和 大脑区域的GABA表达式将与 神经药物操纵以检验我们的假设。 这些结果将提高我们对地点和机制的理解 BNO-NO-GABA对动脉血压调节的影响 从胎儿过渡到新生生，将产生有关的新见解 BNOS调节和中央神经心血管的去甲肾上腺素能机制 出生时控制。