REGULATION OF PULMONARY CIRCULATION IN FETUS AND NEWBORN

描述：（改编自申请人的摘要和具体目标。） 胎儿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， 肺血流量增加。 这些变化主要发生在 对出生时胎儿PaO 2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。 失败的原因 适应常常导致持续的肺动脉高压， 新生儿，一种与高死亡率和发病率相关的疾病。 然而，氧气引起肺血管舒张的机制是 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增加的 胎儿肺嘌呤核苷酸的产生和释放 对胎儿PaO 2增加的反应; 2）嘌呤核苷酸然后引起 通过刺激内皮细胞衍生的释放的肺血管舒张 一氧化氮（EDNO）;和3）肺反应的增加 血管向氧的成熟是由释放的增强引起的 和/或增加的敏感性， 受体的核苷酸的血管舒张作用，与妊娠。 的 具体目的是研究1）以下因素的独立影响： 单纯通气和通气加氧合对血浆核苷酸的影响 近足月胎羊肺动脉和肺静脉中的水平; 2)8-苯基茶碱（P1受体拮抗剂）和 Cibacron blue（一种P2受体拮抗剂）对胎儿的反应 肺循环至通气（3% O2、5% CO2和92% N2），以及 用室内空气通风; 3）吲哚美辛，一种抑制剂的作用 PGI 2生产，硝基-L-精氨酸，EDRF合成的抑制剂， 亚甲蓝，鸟苷酸环化酶和格列本脲的抑制剂， ATP敏感性钾通道抑制剂，对肺血管 腺苷和ATP的作用; 4）腺苷，ATP， 乙酰胆碱、缓激肽和硝普钠对肺血管的影响 妊娠110、120和132天时胎羊的抵抗力;和5） 肺动脉腺苷和ATP浓度， 在妊娠第110、120和132天的肺静脉。 这些研究可能 为氧致肺损伤的机制提供新的信息 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.