CGMP REGULATION IN THE DEVELOPING PULMONARY VASCULATURE

CGMP 对发育中肺血管的调节

基本信息

项目摘要

The normal transition of gas exchange from the placenta to the lungs at birth depends on a 10-fold increase in pulmonary blood flow, and a sharp decline in pulmonary arterial pressure. This in turn depends upon a dramatic decrease in pulmonary vascular tone. An important stimulus for these events is the increase in alveolar oxygen tension that occurs at birth. Nitric oxide production by the vascular endothelium has been shown to play an integral role in the regulation of vascular tone. Nitric oxide activates the soluble guanylate cyclase enzyme system in vascular smooth muscle to produce cGMP, which mediates relaxation. Cyclic GMP is hydrolyzed and inactivated by phosphodiesterases. Nitric oxide production by the endothelium has been established as having an important role in the transition at birth, and may be developmentally regulated. However, the developmental time sequences for the equally important soluble guanylate cyclase and phosphodiesterase enzyme systems are poorly understood. Understanding the mechanisms producing the transition at birth is important, because in some newborn infants, the normal decrease in pulmonary vascular resistance and increase in pulmonary blood flow does not occur, resulting in persistent pulmonary hypertension of the newborn (PPHN). This syndrome results in substantial morbidity and mortality in otherwise normal term infants. Even though a role for endothelial nitric oxide production has been established in the normal transition at birth, no direct evidence points to decreased nitric oxide synthesis as the cause of persistent pulmonary hypertension. Despite this, inhalation of nitric oxide, a toxic and carcinogenic gas, is being investigated as a treatment for PPHN. We have studied an animal model of persistent pulmonary hypertension produced by ligating the ductus arteriosus of the fetal lamb before birth. We have data that accumulation of cGMP by soluble guanylate cyclase in response to nitric oxide is abnormal in this mode. A decrease in cGMP accumulation in response to endogenous NO may explain why some newborns have persistent pulmonary hypertension. It may further explain why some infants with PPHN do not respond initially, or do not maintain their response to inhaled NO. We therefore propose to study the normal developmental time sequence for the guanylate cyclase enzyme systems producing cGMP, and the phosphodiesterase systems inactivating cGMP in vascular smooth muscle. We will study the effect of oxygen as a direct stimulus for increasing cGMP production, and study whether it potentiates other stimuli which increase cGMP concentrations. Finally, we will study regulation of cGMP production and inactivation in the lamb model of persistent pulmonary hypertension. These data should have direct relevance to a better understanding of the causes of PPHN, and allow the design of safer, more effective treatments.
气体交换从胎盘向肺部正常过渡 出生取决于肺血流的10倍,尖锐 肺动脉压的下降。 这反过来取决于 肺血管张力急剧下降。 一个重要的刺激 这些事件是发生在 出生。 血管内皮产生一氧化氮可以发挥作用 在调节血管张力中的重要作用。 一氧化氮 激活血管光滑中的可溶性鸟苷酸环化酶系统 产生CGMP的肌肉,介导放松。 循环GMP是 被磷酸二酯酶水解并灭活。 一氧化氮的产生 由内皮确定为在 出生时过渡,并且可能受到发展的监管。 但是, 同样重要的可溶性鸟根的发育时间序列 环化酶和磷酸二酯酶系统的理解很少。 了解出生时产生过渡的机制是 重要的是,因为在某些新生婴儿中,正常降低 肺血管耐药性和肺血流增加 没有发生,导致新生儿的持续性肺动脉高压 (PPHN)。 该综合征导致大量的发病率和死亡率 否则正常的婴儿。 即使是内皮氮的角色 在出生时正常过渡中已经建立了氧化物的产生, 没有直接证据指出一氧化氮合成降低为原因 持续性肺动脉高压。 尽管如此,一氮吸入 氧化物是一种有毒和致癌气体,正在研究作为治疗 对于PPHN。 我们研究了持续性肺部的动物模型 通过连接胎儿羔羊管道导管产生的高血压 出生前。 我们的数据可以通过可溶性鸟苷酸来积累CGMP 在这种模式下,对一氧化氮的响应是异常的。 减少 在响应内源性的CGMP积累中,可以解释为什么有些 新生儿具有持续的肺动脉高压。 它可以进一步解释 为什么有些患有PPHN的婴儿最初没有反应或不保留 他们对吸入否的反应。 因此,我们建议研究正常的发育时间序列 产生CGMP的鸟苷酸环化酶系统,并 磷酸二酯酶系统使CGMP在血管平滑肌中失活。 我们 将研究氧作为增加CGMP的直接刺激的影响 生产并研究它是否增强了其他刺激 CGMP浓度。 最后,我们将研究CGMP生产的调节 并在持续性肺动脉高压的羔羊模型中失活。 这些数据应直接相关,以更好地理解 PPHN的原因,并允许设计更安全,更有效的治疗方法。

项目成果

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ROBIN H. STEINHORN的其他基金

CGMP REGULATION IN THE DEVELOPING PULMONARY VASCULATURE
CGMP 对发育中肺血管的调节
  • 批准号:
    6091466
    6091466
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:
cGMP Regulation in the Developing Pulmonary Vasculature
发育中肺血管系统的 cGMP 监管
  • 批准号:
    7415152
    7415152
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:
cGMP Regulation in the Developing Pulmonary Vasculature
发育中肺血管系统的 cGMP 监管
  • 批准号:
    7250205
    7250205
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:
cGMP Regulation in the Developing Pulmonary Vasculature
发育中肺血管系统的 cGMP 监管
  • 批准号:
    7620060
    7620060
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:
REDOX REGULATION IN THE PERINATAL PULMONARY VASCULATURE
围产期肺血管的氧化还原调节
  • 批准号:
    8651640
    8651640
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:
REDOX REGULATION IN THE PERINATAL PULMONARY VASCULATURE
围产期肺血管的氧化还原调节
  • 批准号:
    8511773
    8511773
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:
CGMP REGULATION IN THE DEVELOPING PULMONARY VASCULATURE
CGMP 对发育中肺血管的调节
  • 批准号:
    2460136
    2460136
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:
CGMP Regulation in the Developing Pulmonary Vasculature
CGMP 对发育中肺血管的调节
  • 批准号:
    6610957
    6610957
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:
cGMP Regulation in the Developing Pulmonary Vasculature
发育中肺血管系统的 cGMP 监管
  • 批准号:
    7049926
    7049926
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:
CGMP Regulation in the Developing Pulmonary Vasculature
CGMP 对发育中肺血管的调节
  • 批准号:
    6784582
    6784582
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:

相似海外基金

CGMP REGULATION IN THE DEVELOPING PULMONARY VASCULATURE
CGMP 对发育中肺血管的调节
  • 批准号:
    6091466
    6091466
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:
CGMP REGULATION IN THE DEVELOPING PULMONARY VASCULATURE
CGMP 对发育中肺血管的调节
  • 批准号:
    2460136
    2460136
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:
CGMP Regulation in the Developing Pulmonary Vasculature
CGMP 对发育中肺血管的调节
  • 批准号:
    6526976
    6526976
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:
CGMP Regulation in the Developing Pulmonary Vasculature
CGMP 对发育中肺血管的调节
  • 批准号:
    6610957
    6610957
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别:
CGMP Regulation in the Developing Pulmonary Vasculature
CGMP 对发育中肺血管的调节
  • 批准号:
    6784582
    6784582
  • 财政年份:
    1995
  • 资助金额:
    $ 9.71万
    $ 9.71万
  • 项目类别: