The major long-term objective of this proposed research project is to synthesize and evaluate a variety of potential lipid mediators of circulatory disease, including (a) thromboxane A2 (TxA2) and thromboxane analogs, (b) platelet activating factor (PAF) and PAF analogs, and (c) lipoxins (Lx) (e.g., LxA4, LxB4, LxA5, LxB5). These lipid compounds will be studied as mediators or inhibitors of ischemic (e.g., myocardial ischemia) and shock (e.g., hemorrhagic, endotoxic) disorders. The primary purpose will be to define the potential role of these purported mediators in these disease states and to develop analogs or other agents as pharmacologic antagonists against these mediators. In order to achieve these objectives, studies are planned in which TxA2 and a key TxA2 analog, number of PAF analogs, and a series of lipoxins will be synthesized. These compounds will then be studied in terms of their biochemical interaction with other classes of lipid mediators (e.g., PAF analogs will be studied for their ability to release leukotrienes and thromboxanes; TxA2 analogs will be studied for PAF and leukotriene release). In a comprehensive manner, these analogs will then be studied in selected models of circulatory disease in which the parent mediator has been shown to be involved. These models constitute both in vitro preparations (e.g., isolated perfused cat coronary arteries, isolated guinea pig pulmonary parenchymal strips, isolated perfused rat hearts) and in vivo models (e.g., cat myocardial ischemia, rabbit endotoxic shock, guinea pig anaphylactic shock, and rat hemorrhagic shock). We hope to obtain potentially useful compounds in this manner. Successful investigations should lead to (a) useful tools in studying the role of these lipid mediators in pathphysiologic processes,and (b) potentially valuable therapeutic agents in the treatment of ischemia and shock-like disorders.
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