Effect of the Phosphodiesterase 5 Inhibitor Sildenafil on Ischemia-Reperfusion-Induced Muscle Mitochondrial Dysfunction and Oxidative Stress
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 unkn...
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MDPI AG
2019-04-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/8/4/93 |
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doaj-38c276bc612f43d5b48c25b2636a79932020-11-25T00:45:51ZengMDPI AGAntioxidants2076-39212019-04-01849310.3390/antiox8040093antiox8040093Effect of the Phosphodiesterase 5 Inhibitor Sildenafil on Ischemia-Reperfusion-Induced Muscle Mitochondrial Dysfunction and Oxidative StressLiliane Tetsi0Anne-Laure Charles1Isabelle Georg2Fabienne Goupilleau3Anne Lejay4Samy Talha5Myriam Maumy-Bertrand6Claire Lugnier7Bernard Geny8Unistra, Fédération de Médecine Translationnelle, Equipe d’Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, FranceUnistra, Fédération de Médecine Translationnelle, Equipe d’Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, FranceUnistra, Fédération de Médecine Translationnelle, Equipe d’Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, FranceUnistra, Fédération de Médecine Translationnelle, Equipe d’Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, FranceUnistra, Fédération de Médecine Translationnelle, Equipe d’Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, FranceUnistra, Fédération de Médecine Translationnelle, Equipe d’Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, FranceIRMA, équipe MoCo et LabEx IRMIA, 7 rue René Descartes, 67084 Strasbourg CEDEX, FranceUnistra, Fédération de Médecine Translationnelle, Equipe d’Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, FranceUnistra, Fédération de Médecine Translationnelle, Equipe d’Accueil 3072, « Mitochondrie, Stress oxydant et Protection Musculaire », Institut de Physiologie, 67000 CEDEX, FranceLower-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.https://www.mdpi.com/2076-3921/8/4/93cyclic nucleotide phosphodiesterasesildenafilmuscleischemiareperfusionperipheral arterial diseasemitochondriareactive oxygen speciesoxidative stresscalcic retention capacity |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Liliane Tetsi Anne-Laure Charles Isabelle Georg Fabienne Goupilleau Anne Lejay Samy Talha Myriam Maumy-Bertrand Claire Lugnier Bernard Geny |
| spellingShingle |
Liliane Tetsi Anne-Laure Charles Isabelle Georg Fabienne Goupilleau Anne Lejay Samy Talha Myriam Maumy-Bertrand Claire Lugnier Bernard Geny Effect of the Phosphodiesterase 5 Inhibitor Sildenafil on Ischemia-Reperfusion-Induced Muscle Mitochondrial Dysfunction and Oxidative Stress Antioxidants cyclic nucleotide phosphodiesterase sildenafil muscle ischemia reperfusion peripheral arterial disease mitochondria reactive oxygen species oxidative stress calcic retention capacity |
| author_facet |
Liliane Tetsi Anne-Laure Charles Isabelle Georg Fabienne Goupilleau Anne Lejay Samy Talha Myriam Maumy-Bertrand Claire Lugnier Bernard Geny |
| author_sort |
Liliane Tetsi |
| title |
Effect of the Phosphodiesterase 5 Inhibitor Sildenafil on Ischemia-Reperfusion-Induced Muscle Mitochondrial Dysfunction and Oxidative Stress |
| title_short |
Effect of the Phosphodiesterase 5 Inhibitor Sildenafil on Ischemia-Reperfusion-Induced Muscle Mitochondrial Dysfunction and Oxidative Stress |
| title_full |
Effect of the Phosphodiesterase 5 Inhibitor Sildenafil on Ischemia-Reperfusion-Induced Muscle Mitochondrial Dysfunction and Oxidative Stress |
| title_fullStr |
Effect of the Phosphodiesterase 5 Inhibitor Sildenafil on Ischemia-Reperfusion-Induced Muscle Mitochondrial Dysfunction and Oxidative Stress |
| title_full_unstemmed |
Effect of the Phosphodiesterase 5 Inhibitor Sildenafil on Ischemia-Reperfusion-Induced Muscle Mitochondrial Dysfunction and Oxidative Stress |
| title_sort |
effect of the phosphodiesterase 5 inhibitor sildenafil on ischemia-reperfusion-induced muscle mitochondrial dysfunction and oxidative stress |
| publisher |
MDPI AG |
| series |
Antioxidants |
| issn |
2076-3921 |
| publishDate |
2019-04-01 |
| description |
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. |
| topic |
cyclic nucleotide phosphodiesterase sildenafil muscle ischemia reperfusion peripheral arterial disease mitochondria reactive oxygen species oxidative stress calcic retention capacity |
| url |
https://www.mdpi.com/2076-3921/8/4/93 |
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