REGULATION OF PULMONARY CIRCULATION IN FETUS AND NEWBORN

描述：(根据申请者的抽象和具体目标改编。) 胎儿的肺在出生时经历了一系列复杂的变化 包括肺血管阻力降低和九倍 肺血流量增加。这些变化主要发生在 胎儿出生时动脉血氧分压升高的反应。这种对氧气的反应 随着胎儿接近足月妊娠而增加。这是失败的 适应常常导致持续性的肺动脉高压 新生儿，这是一种与高死亡率和发病率相关的疾病。 然而，氧气引起肺血管扩张的机制是 不知道。拟议的研究将调查以下假设：1) 出生时发生的肺血管扩张是由 人胎肺合成和释放嘌呤核苷酸的研究 对胎儿动脉血氧分压升高的反应；2)嘌呤核苷酸然后引起 刺激内皮释放对肺血管的扩张作用 一氧化氮(EDNO)；3)肺组织反应性增加。 血管向氧的成熟是由于释放增多所致 核苷酸对氧气的响应和/或增加的敏感性 受体对血管扩张的核苷酸作用，与妊娠有关。这个 具体的目标是调查1)独立的影响 单纯换气和充氧换气对血浆核苷酸的影响 近足月胎羊肺动脉和肺静脉的水平； 2)8-苯茶碱(一种P1受体拮抗剂)和 雪巴克隆蓝(P2受体拮抗剂)对胎儿免疫反应的影响 肺循环至通气量为3%O2、5%CO2和92%N2，以及 室内空气通风；3)抑制剂吲哚美辛的作用 前列环素合成的抑制因子--硝基L精氨酸， 亚甲蓝，鸟苷环化酶抑制剂和格列本脲，以及 三磷酸腺苷敏感钾通道抑制剂，对肺血管的作用 腺苷和三磷酸腺苷的作用；4)腺苷、三磷酸腺苷、 乙酰胆碱、缓激肽和硝普钠对肺血管的影响 妊娠110、120和132天胎羊的抵抗力； 血浆腺苷和三磷酸腺苷在大鼠肺动脉和肺组织中的浓度 妊娠110天、120天和132天的肺静脉。这些研究可能 提供有关氧致肺损伤机制的新信息 出生时的血管扩张。

DESCRIPTION: (Adapted from the applicant's abstract and Specific Aims.) The fetal lung undergoes a complex series of changes at birth which include a decrease in pulmonary vascular resistance and ninefold increase in pulmonary blood flow. These changes occur primarily in response to an increase in fetal PaO2 at birth. This response to oxygen increases as fetus approaches term gestation. Failure of this adaptation often results in persistent pulmonary hypertension of the newborn, a condition associated with high mortality and morbidity. However, the mechanism by which oxygen causes pulmonary vasodilation is not known. The proposed studies will investigate the hypotheses that 1) pulmonary vasodilation occurring at birth is caused by increased production and release of purine nucleotides by the fetal lung in response to increase in fetal PaO2; 2) purine nucleotides then cause pulmonary vasodilation by stimulation of release of endothelium derived nitric oxide (EDNO); and 3) the increase in response of pulmonary vessels to oxygen with maturation is caused by augmentation of release of nucleotides in response to oxygen and/or increased sensitivity of receptors to vasodilator effects of nucleotides, with gestation. The Specific Aims are to investigate 1) the independent effects of ventilation alone and ventilation with oxygenation on plasma nucleotide levels in pulmonary artery and pulmonary vein in near term fetal lambs; 2) the effects of 8-phenyltheophylline (a P1 receptor antagonist) and cibacron blue (a P2 receptor antagonist) on the response of fetal pulmonary circulation to ventilation with 3% O2, 5% CO2 and 92% N2, and ventilation with room air; 3) the effects of indomethacin, an inhibitor of PGI2 production, nitro-L-arginine, an inhibitor of EDRF synthesis, methylene blue, an inhibitor of guanylate cyclase and glybenclamide, an inhibitor of ATP-sensitive potassium channels, on pulmonary vascular effects of adenosine and ATP; 4) the effects of adenosine, ATP, acetylcholine, bradykinin and nitroprusside on the pulmonary vascular resistance in fetal lambs at 110, 120 and 132 days of gestation; and 5) plasma concentrations of adenosine and ATP in pulmonary artery and pulmonary vein at 110, 120 and 132 days of gestation. These studies may provide new information about the mechanisms of oxygen induced pulmonary vasodilation at birth.