1044 Leukotrienes Stimulate Endothelial Prostacyclin Synthesis

The slow-reacting substances (SRS) consist of leukotrienes C, D, and E (LTC, -D, -E) 1 and are derived from the lipoxygenase pathway of arachidonic acid (20:4) metabolism. In examining possible mechanisms for the vasoactive effects of SRS (1-4), we found that cultures o f human endothelial cells release the vasodilatory agent, prostacyclin, on exposure to 10 -9 to 10 -6 M LTC (5). Previous reports indicated that several structurally unrelated vasoactive substances such as histamine (6) and bradykinin (7) also stimulate prostacyclin synthesis by endothelium. Toge ther these results suggested that the leukotrienes and other vasoactive substances may promote vasodilation through a common mechanism. To fur ther examine the specificity of leukotrienes in initiating 20:4 release and the synthesis of prostacyclin, we exposed human endothelial cells to the cysteine-containing leukotrienes, LTC, LTD, and LTE, and to 5(S), 12(R)dihydroxy-eicosa-6,14 cis-8,10 trans tetraenoic acid or LTB. These studies permit ted the demonstrat ion that L T C and L T D promote the release of prostacyclin, but that L T E and LTB were inactive in stimulating endothelial cell 20:4 metabolism. T h e additional finding that endothelial cells metabolize L T C to L T D and LTE suggested one mechanism whereby the vasoactive effects of these substances are modulated.