Abstract
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 (VMax), 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 VMax (from 11.79 ± 1.74 to 4.65 ± 1.11 pmol/s*mg wet weight (ww), p < 0.05, −50.2 ± 16.3%) and CRC (from 2.33 ± 0.41 to 0.84 ± 0.18 µmol/mg dry weight (dw), p < 0.05; −61.1 ± 6.8%). ROS tended to increase in the ischemic limb (+64.3 ± 31.9%, p = 0.08). Although tending to reduce IR-related ROS production (−42.4%), sildenafil failed to reduce muscle mitochondrial dysfunctions (−63.3 ± 9.2%, p < 0.001 and −55.2 ± 7.6% p < 0.01 for VMax, 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.
Highlights
Peripheral arterial disease (PAD) is frequent and associated with significant morbidity and mortality [1,2]
Antioxidants 2019, 8, 93 of PAD are multiple, related to general or local arterial injuries and result in vessel obstruction leading to limb ischemia [5]
Mitochondria play a central role in cell homeostasis, since they are the primary sites of energy production through ATP synthesis
Summary
Peripheral arterial disease (PAD) is frequent and associated with significant morbidity and mortality [1,2]. PAD overall prevalence ranges from 3% to 10%, increasing to 15–20% in persons older than 70 years of age [3]. Antioxidants 2019, 8, 93 of PAD are multiple, related to general (wound, contusion, compression) or local arterial injuries (atherosclerosis, embolic events, thrombosis, dissections of the arterial wall) and result in vessel obstruction leading to limb ischemia [5]. Lower limb ischemia requires surgical revascularization, possibly associated with thrombolysis, but revascularization might be impossible in some cases, highlighting the need for new therapeutic approaches [2,6]. Recent improvement in the knowledge of PAD pathophysiology might be useful to open new therapeutic approaches. Skeletal muscle mitochondrial dysfunctions, together with increased reactive oxygen species (ROS) production are key factors. Mitochondria play a central role in cell homeostasis, since they are the primary sites of energy production through ATP synthesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
