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）：尽管流通量急剧上升 从胎儿到新生儿过渡期间去甲肾上腺素 (NE) 浓度 一生中，动脉血压不会发生实质性变化。然而，改变了 出生时动脉血压的调节，可能是由于早产或 胎儿应激后 NE 耗尽，可能导致新生儿低血压或 高血压。孤束核（NTS）是主要的感觉器官 中央控制循环的核心。 NTS 中的一氧化氮 (NO) 在交感神经张力的中枢抑制中起重要作用，因此 降低血压。我们最近发现羊脑 NO 合酶 新生儿 NTS 中的 (bNOS) 表达在 4 小时内显着增强 出生后，与胎儿相比。与假设一致 NO的作用，胎儿动脉血压经第四脑室降低 给予NO供体并通过NO合成抑制剂增加。 此外，我们的初步结果表明，第四脑室 给予 NE 摄取抑制剂可增加绵羊胎儿 bNOS 蛋白， NTS 和延髓头腹侧的 γ-氨基丁酸 (GABA) 表达 （RVM）。我们假设在胎儿和新生儿生命期间 (1) 出生时循环 NE 诱导 NTS 中 bNOS 上调 (2) bNOS-NO-GABA 系统调节新生儿动脉血 NTS-RVM 中枢交感神经通路的压力。 鉴于胎儿/新生儿动脉血压的至关重要 调节，我们的主要目标是：1）如果外源性胎儿 NE 模拟上调 NTS 和 RVM 中的 bNOS-NO？ 2) 如果动脉血压升高并且 新生羔羊第四脑室 NTS bNOS-GABA 表达降低 出生前给予 nNOS 反义寡核苷酸？ 3) 如果 出生时 NTS 和 RVM 区域的 bNOS 和 GABA 表达增强 NE摄取抑制剂促进？这些研究将检查 bNOS 在绵羊胎儿和新生儿的 NTS 和 RVM 神经元中表达。 动脉血压、血浆 NE 浓度、bNOS 和 大脑区域中的 GABA 表达将被纳入 神经药理学操作来检验我们的假设。 这些结果将增进我们对网站和机制的理解 bNOS-NO-GABA 对动脉血压调节的影响 从胎儿到新生儿生命的过渡，并将产生关于 bNOS 调节和中枢神经心血管的去甲肾上腺素能机制 出生时控制。