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dc.contributor.authorHole, Lisa Drangeen_US
dc.contributor.authorLarsen, Terje H.en_US
dc.contributor.authorFossan, Kjell Oveen_US
dc.contributor.authorLimé, Fredriken_US
dc.contributor.authorSchjøtt, Janen_US
dc.date.accessioned2014-06-20T09:41:14Z
dc.date.available2014-06-20T09:41:14Z
dc.date.issued2014-05-27eng
dc.identifier.issn2050-6511
dc.identifier.urihttps://hdl.handle.net/1956/8006
dc.description.abstractAim: Chemotherapy with doxorubicin is limited by cardiotoxicity. Free radical generation and mitochondrial dysfunction are thought to contribute to doxorubicin-induced cardiac failure. In this study we wanted to investigate if opening of mitochondrial KATP-channels by diazoxide is protective against doxorubicin cardiotoxicity, and if 5-hydroxydecanoate (5-HD), a selective mitochondrial KATP-channel antagonist, abolished any protection by this intervention. Methods: Wistar rats were divided into 7 groups (n = 6) and followed for 10 days with 5 intervention groups including the following treatments: (1) Diazoxide and doxorubicin, (2) diazoxide and 5-hydroxydecanoate (5-HD), (3) 5-HD and doxorubicin, (4) diazoxide and saline and (5) 5-HD and saline. On day 1, 3, 5 and 7 the animals received intraperitoneal (i.p.) injections with 10 mg/kg diazoxide and/or 40 mg/kg 5-HD, 30 minutes before i.p. injections with 3.0 mg/kg doxorubicin. One control group received only saline injections and the other control group received saline 30 minutes prior to 3.0 mg/kg doxorubicin. On day 10 the hearts were excised and Langendorff-perfused. Cardiac function was assessed by an intraventricular balloon and bioch emical effects by release of hydrogen peroxide (H2O2) and troponin-T (TnT) in effluate from the isolated hearts, and by myocardial content of doxorubicin. Results: Doxorubicin treatment produced a significant loss in left ventricular developed pressure (LVDP) (p < 0.05) and an increase in both H2O2 and TnT release in effluate (p < 0.05). Diazoxide significantly attenuated the decrease in LVDP (p < 0.05) and abolished the increased release of H2O2 and TnT (p < 0.05). 5-HD abolished the effects of pretreatment with diazoxide, and these effects were not associated with reduced myocardial accumulation of doxorubicin. Conclusions: Pretreatment with diazoxide attenuates doxorubicin-induced cardiac dysfunction in the rat, measured by physiological indices and TnT and H2O2 in effluate from isolated hearts. The effect could be mediated by opening of mitochondrial KATP-channels, reduced doxorubicin-associated free radical generation and decreased cardiomyocyte damage. Diazoxide represents a promising protective intervention against doxorubicin-induced acute cardiotoxicity.en_US
dc.language.isoengeng
dc.publisherBioMed Centraleng
dc.relation.ispartof<a href="http://hdl.handle.net/1956/9591" target="blank">Cardiotoxicity of Doxorubicin. A Study of Methods and Protective Interventions in Rat Models</a>eng
dc.rightsAttribution CC BYeng
dc.rights.urihttps://creativecommons.org/licenses/by/2.0/eng
dc.subjectDoxorubicineng
dc.subjectTroponin Teng
dc.subjectHydrogenperoxideeng
dc.subjectDoxorubicinoleng
dc.subjectHearteng
dc.subjectRateng
dc.subject5-hydroxydecanoateeng
dc.subjectCardiotoxicityeng
dc.subjectEx vivoeng
dc.subjectDiazoxideeng
dc.titleDiazoxide protects against doxorubicin-induced cardiotoxicity in the raten_US
dc.typePeer reviewed
dc.typeJournal article
dc.date.updated2014-06-03T19:10:07Z
dc.description.versionpublishedVersionen_US
dc.rights.holderCopyright 2014 Hole et al.
dc.source.articlenumber28
dc.identifier.doihttps://doi.org/10.1186/2050-6511-15-28
dc.identifier.cristin1136159
dc.source.journalBMC Pharmacology and Toxicology
dc.source.volume15


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