OBJECTIVE: This study aimed to evaluate the protective effects of bosentan, a dual endothelin receptor antagonist, against skeletal muscle ischemia-reperfusion injury (IRI) in rats. METHODS: A total of 24 male Wistar Albino rats were divided into four groups: control (C, n=6), bosentan-treated (B, n=6), ischemia-reperfusion (IR, n=6), and bosentan plus ischemia-reperfusion (B+IR, n=6). Bosentan (10 mg/kg) was administered 30 minutes prior to reperfusion. In the IR and B+IR groups, ischemia was induced using vascular bulldog clamps for 45 minutes, followed by 120 minutes of reperfusion. RESULTS: Histological and biochemical assessments revealed significant differences among the groups. The disorganization and degeneration scores of the muscle cells in the B+IR group were significantly lower than those in the IR group (P = 0.001). The degree of interstitial edema in the IR group was markedly more severe than in the C and B groups (all P <
0.001), while the interstitial edema score in the B+IR group was significantly lower than that in the IR group (P <
0.001). The total muscle injury scores were markedly reduced in the B+IR group compared to the IR group (P <
0.001). Biochemically, TAS levels were significantly higher in the B+IR group compared to the IR group (1.03 ± 0.18 vs 0.59 ± 0.10 mmol/L, P = 0.016). Conversely, TOS (1.97 ± 0.39 vs 2.86 ± 0.43 IU/mg, P <
0.001) and OSI levels (P <
0.001) were significantly lower in the B+IR group. Additionally, paraoxonase (PON-1) enzyme activity was significantly reduced in the B+IR group compared to the IR group (P <
0.001). These findings suggest that bosentan exerts its protective effects by antagonizing endothelin-1 receptors, thereby mitigating vasoconstriction, oxidative stress, and inflammation. The observed reductions in muscle cell disorganization, interstitial edema, hemorrhage, neutrophil infiltration and oxidative stress markers underscore bosentan's potential as a therapeutic agent for managing ischemia-reperfusion injury. CONCLUSION: Bosentan demonstrates significant protective effects against skeletal muscle IRI by reducing oxidative stress and inflammation through endothelin receptor antagonism. These findings underscore bosentan's potential as a therapeutic agent for mitigating ischemia-reperfusion injury in vascular surgeries and managing critical limb ischemia in clinical settings. Further research is warranted to explore the long-term effects of bosentan on muscle recovery and systemic health following ischemia-reperfusion injury.