title: Pretreatment with brain natriuretic peptide reduces skeletal muscle mitochondrial dysfunction and oxidative stress after ischemia-reperfusion.
abstract: Brain natriuretic peptide (BNP) reduces the extent of myocardial infarction. We aimed to determine whether BNP may reduce skeletal muscle mitochondrial dysfunctions and oxidative stress through mitochondrial K(ATP) (mK(ATP)) channel opening after ischemia-reperfusion (IR). Wistar rats were assigned to four groups: sham, 3-h leg ischemia followed by 2-h reperfusion (IR), pretreatment with BNP, and pretreatment with 5-hydroxydecanoic acid, an mK(ATP) channel blocker, before BNP. Mitochondrial respiratory chain complex activities of gastrocnemius muscles were determined using glutamate-malate (V(max)), succinate (V(succ)), and N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride ascorbate (V(TMPD/asc)). Apoptosis (Bax-to-Bcl2 mRNA ratio and caspase-3 activity) and oxidative stress (dihydroethidium staining) were also assessed. Compared with the sham group, IR significantly decreased V(max), reflecting complex I, II, and IV activities (-36%, 3.7 ± 0.3 vs. 5.8 ± 0.2 μmol O(2)·min(-1)·g dry wt(-1), P < 0.01), and V(TMPD/asc), reflecting complex IV activity (-37%, 8.6 ± 0.8 vs. 13.7 ± 0.9 μmol O(2)·min(-1)·g dry wt(-1), P < 0.01). IR increased Bax-to-Bcl2 ratio (+57%, 1.1 ± 0.1 vs. 0.7 ± 0.1, P < 0.05) and oxidative stress (+45%, 9,067 ± 935 vs. 6,249 ± 723 pixels, P > 0.05). BNP pretreatment reduced the above alterations, increasing V(max) (+38%, P < 0.05) and reducing Bax-to-Bcl2 ratio (-55%, P < 0.01) and oxidative stress (-58%, P < 0.01). BNP protection against deleterious IR effects on skeletal muscles was abolished by 5-hydroxydecanoic acid. Caspase-3 activities did not change significantly. Conversely, BNP injected during ischemia failed to protect against muscle injury. In addition to maintaining the activity of mitochondrial respiratory chain complexes and possibly decreasing apoptosis, pretreatment with BNP protects skeletal muscle against IR-induced lesions, most likely by decreasing excessive production of radical oxygen species and opening mK(ATP) channels.
authors.affiliation: Service de Physiologie et d'Explorations Fonctionnelles, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. samy.talha@chru-strasbourg.fr
authors.forename: Samy
authors.initials: S
authors.lastname: Talha
authors.forename: Jamal
authors.initials: J
authors.lastname: Bouitbir
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Charles
authors.forename: Joffrey
authors.initials: J
authors.lastname: Zoll
authors.forename: Paola
authors.initials: P
authors.lastname: Goette-Di Marco
authors.forename: Ferhat
authors.initials: F
authors.lastname: Meziani
authors.forename: François
authors.initials: F
authors.lastname: Piquard
authors.forename: Bernard
authors.initials: B
authors.lastname: Geny
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D003652:Decanoic Acids / Q000494:pharmacology; D004579:Electron Transport / Q000187:drug effects / Q000502:physiology; D006880:Hydroxy Acids / Q000494:pharmacology; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000502:physiology*; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D003652:Decanoic Acids; D006880:Hydroxy Acids; D054086:KATP Channels; D026902:Potassium Channel Blockers; D017382:Reactive Oxygen Species; D020097:Natriuretic Peptide, Brain; C052853:5-hydroxydecanoic acid; D053148:Caspase 3