Pathophysiologic modulation of arachidonate metabolism.

Low concentrations of lipid hydroperoxides are necessary to activate the biosynthesis of prostaglandins and other autacoids from arachidonate. When the concentration is too low (less than 10(-9) M) that biosynthesis is suppressed. However, lipid peroxides at concentrations higher than micromolar can inactivate prostacyclin synthase and, at higher levels, even prostaglandin H synthase. Thus, lipid hydroperoxides may be important regulators of biological processes, and their reliable quantitation is important in interpreting the physiologic status of a tissue. The plasma levels of lipid hydroperoxide that are indicated by the thiobarbituric acid (TBA) assay of normal human plasma (26-63 microM) would be high enough to totally inactivate prostacyclin synthase and thus they seem incompatible with a healthy vascular system. To resolve this paradox, we have developed a new assay which directly measures the level of lipid hydroperoxide. Controlled studies showed that the TBA-positive response of normal human plasma gave values for hydroperoxide that had no clear relationship to the actual level of hydroperoxide that was present and were 50-100 times greater than the directly observed values. The new direct assay indicates that the normal level of plasma lipid hydroperoxide may be approximately 0.5 microM. Such a level may provide chronic stress on the ability of vascular endothelial cells to provide sufficient amounts of the antithrombotic autacoid, prostacyclin. Our results indicate that relatively slight elevations from the normal circulating hydroperoxide levels might be expected to have undesirable effects, and that a reliable monitoring of plasma hydroperoxide levels may be useful.