bNOS-NO on Neonatal Arterial Presure Regulation in NTS

描述(由申请人提供)：尽管发行量大幅上升 胎儿向新生儿过渡过程中去甲肾上腺素(NE)的浓度 生活中，动脉血压没有实质性变化。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耗竭，可能导致新生儿低血压或 高血压。孤束核(NTS)是主要感觉 中央控制血液循环的核。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，绵羊脑中没有合酶 (Bnos)在新生儿NTS中的表达在4小时后显著增强。 出生后的，与胎儿相比的。与假设的一致 一氧化氮在第四脑室降低胎儿动脉血压中的作用 给予NO供体，并由NO合成抑制剂增加。 此外，我们的初步结果表明，第四脑室 给予去甲肾上腺素摄取抑制剂可增加绵羊胎儿bNOS蛋白和 γ-氨基丁酸(GABA)在NTS和头端延髓腹侧的表达 (RVM)。我们假设在胎儿和新生儿的生命中(1)升高 出生时循环去甲肾上腺素诱导NTS中BNOS的上调 (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/新生儿动脉血压的重要性 调控，我们的主要目标是：1)如果外源性胎儿NE模仿上调 2)如果动脉血压升高， 新生羔羊第四脑室NTS bnos-GABA表达降低 产前使用nNOS反义寡核苷酸？以及3)如果 出生时NTS和RVM区bNOS和GABA表达增强为 被去甲肾上腺素摄取抑制剂促进？这些研究将考察英国的国家和地区。 绵羊胎儿和新生儿NTS和RVM神经元的表达。 动脉血压、血浆去甲肾上腺素浓度、bNOS和 大脑区域的GABA表达将与 神经药理学操作来检验我们的假说。 这些结果将促进我们对以下方面的理解 BNOS-NO-GABA在动脉血压调节中的作用 从胎儿到新生儿的过渡，将产生关于 去甲肾上腺素调节bnos的机制与中枢神经心血管 出生时的控制力。

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.