The Role of Leukotrienes in Controlling Postischemic Skeletal Muscle Function

Abstract

This study investigates the role of leukotrienes in controlling postischemic alterations in skeletal muscle edema and viability. In a rodent model of six-hour unilateral hindlimb ischemia and four-hour reperfusion, gastrocnemius muscle edema (GME, wet:dry weight ratio) and viability (GMV, nitroblue tetrazolium) were assessed and indices calculated to compare results from the reperfused limb with those from the contralateral normal limb. The influence of leukotrienes B ₄ (LTB4) and C₄D₄E₄ (peptidoleukotrienes, PLT) on these changes was assessed by employing specific receptor antagonists (RA) to these mediators, infused intravenously from thirty minutes prior to and throughout reperfusion. Normal (N; ten-hour general anesthesia, no ischemia) and ischemic animals (I; six-hour ischemia only) did not develop either muscle edema or necrosis (GME-N: 1.00 [0.98-1.01], I: 1.01 [0.99-1.03]; GMV-N: 1.00 [1.00-1.00], I: 1.00 [1.00-1.00]) while control animals (C; ischemia and reperfusion alone) demonstrated both (GME: 1.23 [1.09-1.37]; GMV: 0.53 [0.33-0.61]; P<0.01 vs N,I). In rats receiving the LTB4 RA (SC 41930, 1 mg/kg) muscle viability was preserved, GMV: 1.00 (1.00-1.00), P<0.01 vs C and muscle edema reduced (GME: 1.08 [1.05-1.10], P<0.01 vs C). In contrast the PLT RA (ICI 198615, 550 μg/kg) promoted a further deterioration in viability (GMV: 0.29 [0.17-0.33], P<0.05 vs C; P<0.01 vs N,I) with no amelioration of edema (GME: 1.26 [1.20-1.31], ns vs C). These results demonstrate that postischemic skeletal muscle injury is controlled by leukotrienes, with PLT having a beneficial role and LTB4 appearing to enhance reperfusion injury.