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.
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