THE INFLUENCE OF ARACHIDONIC-ACID METABOLITES ON LEUKOCYTE ACTIVATION AND SKELETAL-MUSCLE INJURY AFTER ISCHEMIA AND REPERFUSION

Derivatives of arachidonic acid have been found to play a role in the reperfusion injury of various tissues. These compounds have a broad spectrum of activity, including modulation of white blood cell response to injured tissue. This study was designed to determine the effect of thromboxane and lipoxygenase derivatives on the local and systemic response to ischemia and reperfusion of skeletal muscle. Fifteen dogs were separated into three groups and subjected to gracilis muscle ischemia followed by 2 hours of reperfusion. One group served as controls, one group was treated with OKY-046 (a thromboxane synthetase inhibitor), and one group was treated with diethylcarbamazine (a lipoxygenase inhibitor). White blood cell activation as measured by superoxide anion production, and eicosanoid levels were measured both in the gracilis venous effluent and central venous circulation. These results were compared to infarct size in the gracilis muscle. OKY-046 significantly reduced thromboxane production in both the central venous (102 +/- 30 to 31 +/- 9 pg/ml, p < 0.05) and gracilis samples (107 +/- 22 to 25 +/- 6 pg/ml, p < 0.005). This was accompanied by a reduced white cell activation in the central venous blood (15 +/- 1 to 10 +/- 1 nmol O2-, p < 0.05), but did not affect infarct size or white cell activation in the gracilis. Conversely, diethylcarbamazine significantly reduced both white cell activation (16 +/- 1 to 10 +/- 1 nmol O2-, p < 0.005) and infarct size in the gracilis muscles (61.6% +/- 4.5% to 28.5% +/- 8.6%, p < 0.01), as well as reduced systemic white blood cell activation. We conclude that arachidonic acid metabolites are important mediators in both the local and systemic response to skeletal muscle ischemia. Lipoxygenase derivatives act both locally and systemically to activate white blood cells, whereas thromboxane blockade blunts the systemic response without altering the local tissue injury.