bNOS-NO on Neonatal Arterial Presure Regulation in NTS

点击翻译按钮获取中文摘要

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.