A new pathway of arachidonic acid metabolism has recently been discovered. Although the metabolites from that pathway could be present in almost all cells, the biological actions are largely unknown. Our studies with several structurally dissimilar inhibitors have implicated a role for these substances, the epoxyeicosatrienoic acids (EETs), in the peripheral circulation in physiologic and pathological conditions. To test for a potential role for the EETs in the regulation of tissue blood flow, we propose to characterize the effects of purified synthetic EETs on microvascular hemodynamics, granulocyte/endothelial interactions, and microvascular permeability. These effects will be directly observed with in vivo microscopy and also quantitated with histologic evaluation of fixed, stained tissue specimens. The mechanisms of these effects will be explored by pharmacologically altering the activity of adenylate or gyanylate cyclase in vivo. This information would be integrated with our continued investigation of the effects of various inhibitors on the burn-induced acute inflammatory response in the hamster cheek pouch and on the fat-induced absorptive hyperemia response in the rat intestine. Because EET formation seems to be favored in these conditions, we propose to compare EET concentrations in biological fluids with changes in the microcirculatory variables. Overall, the proposed research could lead to the development of innovative new therapies for the treatment of acute inflammation. Furthermore, these results could reveal the existence of fundamentally new mechanisms of tissue blood flow control.
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