Protective effect of the endothelin antagonist Bosentan against ischemic skeletal muscle necrosis

Abstract

We tested the hypothesis that blocking of the endothelin system by Bosentan, a combined endothelin-A and -B receptor antagonist (Hoffmann La Roche, Basel, Switzerland), improves postischemic skeletal muscle reperfusion and reduces tissue damage. 16 Wistar rats were subjected to 3 h and 15 min hindlimb tourniquet ischemia at 27°C. Perfusion was continuously measured with Laser Doppler Flowmetry (LDF) in the anterior tibial muscle during ischemia and the first 2 h of reperfusion. Perfusion indices were calculated for each 15 min, by dividing each LDF value by the preischemic LDF value of the leg. The areas under the perfusion index curves were compared. 72h after ischemia, histomorphom-etry of necrosis and no-reflow zones, and counting of neutrophils were done in cross-sections of the muscles. The animals were randomized into two groups. The treatment group received an injection of Bosentan 15 mg/kg 10 min before ischemia, and this dose was repeated 5 min before reperfusion of the hind-limbs. The treatment group obtained an improved reperfusion (4.48 vs. 1.72, p = 0.02). The median cross-sectional area of necrosis was smaller in the treatment group, 70% vs. 93% (p = 0.02), while neither the areas of no-reflow nor the neutrophil counts in reperfused necrotic areas were different. This study supports the hypothesis that Bosentan seems to improve reperfusion and reduces postischemic skeletal muscle damage.