HUMORAL CONTROL OF PULMONARY AND SYSTEMIC CIRCULATION

这项申请的长期目标是改善我们的 目前的理解体液机制，有助于 调节肺血管床的张力。 肺是一个 主要器官的合成和灭活的各种 血管活性激素 前列腺素和血栓素A2（TXA 2）是 在许多肺部疾病中由肺释放， 肺栓塞、革兰氏阴性脓毒症和成人呼吸道感染 痛苦综合症 尽管TXA 2被释放， 对这种物质的反应是众所周知的， 在生理温度和pH值下半衰期短。因为TXA 2 是这样一个不稳定的因素，它还没有被隔离， 以纯净的物质为特点。 因此，药理学方法可以 有助于研究这种不稳定激素的作用， 测试TXA 2具有显著的血管收缩作用的工作假设， 肺血管床的活动。 在这个提议中- 心脏和经中隔导管插入技术和生化 研究将用于研究TXA 2反应的性质。 本提案的第一个目的是表征TXA 2受体 完整胸猫肺血管床的机制 兔子 在这些实验中，TXA 2的反应将是 其特征在于使用化学稳定的前列腺素内过氧化物 其作用类似于TXA 2和3血栓烷的类似物 受体阻断剂。 在确定选择性和 血栓素受体阻断剂的性质， 假设血管收缩剂对外源性 内源性释放的花生四烯酸部分是由于 将测试TXA 2的形成。 下一个具体目标将 涉及旨在分析对白三烯的反应的实验 D4、血小板活化因子和乙酰胆碱，三种介质 它们被证明可以释放TXA 2。 具体假设 肺血管对这些介质的反应包括 将测试TXA 2的释放。 的实验 乙酰胆碱，LTD 4和PAF将检查 对这些代理人的回应。 亚甲基蓝， 抑制可溶性鸟苷酸环化酶的药物，用于血管扩张 对乙酰胆碱和PAF的反应将在 肺血管床 血栓素受体的作用 拮抗剂和合成抑制剂将在 完整胸猫和兔肺血管床。

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.