| Summary: | Lower-limb ischemia-reperfusion (IR) is frequent and associated with significant morbidity and mortality. Phosphodiesterase 5 inhibitors demonstrated antioxidant and beneficial effects in several organs submitted to IR, but their effects on muscle mitochondrial functions after lower-limb IR are unknown. Unilateral hindlimb IR (2 h tourniquet followed by 2 h reperfusion) without or with sildenafil (1mg/kg ip 30 minutes before ischemia) was performed in 18 mice. Maximal oxidative capacity (V<sub>Max</sub>), relative contribution of the mitochondrial respiratory chain complexes, calcium retention capacity (CRC)—a marker of apoptosis—and reactive oxygen species (ROS) production were determined using high-resolution respirometry, spectrofluorometry, and electron paramagnetic resonance in gastrocnemius muscles from both hindlimbs. IR significantly reduced mitochondrial V<sub>Max</sub> (from 11.79 ± 1.74 to 4.65 ± 1.11 pmol/s*mg wet weight (ww), <i>p</i> < 0.05, −50.2 ± 16.3%) and CRC (from 2.33 ± 0.41 to 0.84 ± 0.18 µmol/mg dry weight (dw), <i>p</i> < 0.05; −61.1 ± 6.8%). ROS tended to increase in the ischemic limb (+64.3 ± 31.9%, <i>p</i> = 0.08). Although tending to reduce IR-related ROS production (−42.4%), sildenafil failed to reduce muscle mitochondrial dysfunctions (−63.3 ± 9.2%, <i>p</i> < 0.001 and −55.2 ± 7.6% <i>p</i> < 0.01 for V<sub>Max,</sub> and CRC, respectively). In conclusion, lower limb IR impaired skeletal muscle mitochondrial function, but, despite tending to reduce ROS production, pharmacological preconditioning with sildenafil did not show protective effects.
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