Recent developments in the field of eicosanoid metabolism point to new directions for research in the treatment of atherosclerotic heart disease and stroke. Cyclooxygenase inhibitors, given early after myocardial infarction, may reduce mortality by up to 50%. Aspirin was protective at low doses but ineffective at high doses and in threatened stroke, reduced mortality by 48% in males only. In animals, anti-inflammatory cyclooxygenase inhibitors suppressed atherosclerosis induced by vascular injury or hypercholesterolemic diets. The calcium channel blockers Nifedipine and Verapamil also protected. In this project the inflammatory prostaglandin and leukotriene products formed by atherosclerotic segments of rabbit arteries will be characterized and their sensitivity to a series of selected anti-inflammatory cyclooxygenase and lipoxygenase inhibitors will be examined. The pattern of products formed will be correlated with the tissue morphology. Particular attention will be paid to products formed in the presence of lymphocytic infltrates. Inhibition of the 5-, 12- and 15-lipoxygenases will be characterized using human and rabbit PMN's, platelets and peripheral blood neutrophils respectively. Eicosanoid products will be identified and assayed using TLC, HPLC, radioimmunoassay and GC/MS by procedures currently in use in this laboratory. The importance of inflammatory eicosanoid synthesis to the process of atherogenesis will be evaluated in an animal model. The influences of prostaglandin and leukotriene inhibitors, given both singly and in combination, will be tested on atherosclerotic plaque formation in the cholesterol fed rabbit. Nifedipine and Verapamil block the chemotactic and vasoconstrictive responses of cells to inflammatory eicosanoids. Synergism with the eicosanoid inhibitors will be investigated. These experiments will provide some of the basic information needed to relate the role of inflammatory eicosanoids in atherogenesis and may assist in the rational design of further clinical trials of anti-atherogenic drugs.
