The major objective of this research project is to evaluate synthetic analogs of thromboxanes in terms of their cardiovascular and biochemical properties relevant to their potential usefulness in life-threatening ischemic situations such as myocardial ischemia, hemorrhagic and traumatic shock. First, each analog, after its structure is confirmed, will be classified as an agonist, antagonist, activator, or inhibitor of classical prostaglandins, prostacyclin (PGI2) or thromboxane (TxA2). Secondly, each compound will be assigned a biological profile based on key biological actions (i.e., inhibition of platelet aggregation, lysosomal membrane stabilization, coronary vasoactivity and cardiac inotropicity). Thirdly, each promising compound will be studied in several well-defined pathophysiologic models including acute myocardial ischemia in cats, traumatic shock in rats, and arachidonic acid-induced thrombosis in rabbits, for prolongation of survival, reduction in ischemic tissue damage, prevention of proteolysis and toxic products of proteolysis, and formation of thromboxane A2 and prostacyclin. In this manner, we should be able to find useful new therapeutic agents (e.g., prostacyclin analogs, thromboxane inhibitors) as well as useful biological tools for prostaglandin research (e.g., thromboxane agonists, prostacyclin synthetase inhibitors).
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