HUMORAL CONTROL OF PULMONARY AND SYSTEMIC CIRCULATION

此应用程序的长期目标是改进我们的 目前对体液机制的理解有助于 肺血管床张力的调节。肺是一种 合成和失活多种酶的主要器官 血管活性荷尔蒙。前列腺素和血栓素A2 在一些肺部疾病中由肺部释放，包括 肺栓塞、革兰氏阴性败血症与成人呼吸道 窘迫综合症。尽管TXA2发布了，但几乎没有 对这种物质的反应是已知的，因为它非常 生理温度和pH下的半衰期较短。因为TXA2 是这样一个不稳定的因素，它还没有被分离出来， 以纯物质为特征的。因此，药理学方法可以 有助于研究这种不稳定荷尔蒙的作用 检验TXA2具有显著血管收缩作用的工作假设 肺血管床的活动。在这项建议中，正确的- 心脏和经间隔插管技术与生化 研究将被用来研究TXA2反应的性质。 这项建议的第一个目标是表征TXA2受体 猫全胸肺血管床形成机制的研究 还有兔子。在这些实验中，TXA2的反应将是 以化学稳定的前列腺素内过氧化为特征的 其作用类似于TXA2和3-血栓烷的类似物 受体阻滞剂。在确定了选择性和 血栓素受体阻滞剂的性质、 假设血管收缩反应对外源性和 内源性释放的花生四烯酸部分是由于 将测试TXA2的形成。下一个具体目标将是 涉及旨在分析白三烯反应的实验 D4，血小板激活因子和乙酰胆碱，三种介质 已被证明可以释放TXA2。具体的假设 肺血管对这些介质的反应包括 将测试TXA2的释放情况。实验中使用 乙酰胆碱、LTD4和PAF将检查声调依赖 对这些代理的回复。亚甲基蓝的影响 抑制可溶性鸟苷环化酶对血管扩张剂的作用 对乙酰胆碱和PAF的反应将在 肺血管床。血栓素A受体的作用 拮抗剂和合成抑制剂将在 完好的猫和兔的肺血管床。

The long-term objective of this application is to improve our current understanding of humoral mechanisms which contribute to the regulation of tone in the pulmonary vascular bed. The lung is a major organ for the synthesis and inactivation of a variety of vasoactive hormones. Prostaglandins and thromboxane A2 (TXA2) are released by the lung in a number of pulmonary disorders including pulmonary embolism, gram negative sepsis, and the adult respiratory distress syndrome. Although TXA2 is released, little if anything is known about responses to this substance because of its extremely short half-life at physiologic temperature and pH. Because TXA2 is such an unstable factor, it has not yet been isolated and characterized as a pure substance. Thus, pharmacologic methods may be useful in studying the actions of this unstable hormone and for testing the working hypothesis that TXA2 has marked vasoconstrictor activity in the pulmonary vascular bed. In this proposal right- heart and transseptal catheterization techniques and biochemical studies will be utilized to study the nature of TXA2 responses. The first aim of this proposal is to characterize TXA2 receptor mechanisms in the pulmonary vascular bed of the intact-chest cat and rabbit. In these experiments, TXA2 responses will be characterized using chemically stable prostaglandin endoperoxide analogs whose actions mimic those of TXA2 and 3 thromboxane receptor blocking agents. After determining the selectivity and properties of the thromboxane receptor blocking agents, the hypothesis that vasoconstrictor responses to exogenous and endogenously released arachidonic acid are due in part to the formation of TXA2 will be tested. The next specific aim will involve experiments designed to analyze responses to leukotriene D4, platelet activating factor, and acetylcholine, three mediators which have been shown to release TXA2. The specific hypothesis that pulmonary vascular responses to these mediators involve release of TXA2 will be tested. The experiments with acetylcholine, LTD4, and PAF will examine the tone-dependence of responses to these agents. The influence of methylene blue, an agent which inhibits soluble guanylate cyclase, on vasodilator responses to acetylcholine, and PAF will be investigated in the pulmonary vascular bed. The effects of the thromboxane receptor antagonists and synthesis inhibitors will be compared in the pulmonary vascular bed in the intact-chest cat and rabbit.