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Beneficial effects of dantrolene on sepsis-induced diaphragmatic dysfunction are associated with downregulation of high-mobility group box 1 and calpain-caspase-3 proteolytic pathway
Ist Teil von
The Journal of surgical research, 2016-02, Vol.200 (2), p.637-647
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2016
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
Abstract Background Intracellular calcium overload is a major contributing factor to diaphragmatic dysfunction triggered by sepsis. In this study, the possible role of dantrolene, a ryanodine receptor inhibitor, in preventing the release of calcium from the sarcoplasmic reticulum in diaphragmatic dysfunction and weakness was explored. Methods A middle-grade severity sepsis rat model was established for the effects of treatment with dantrolene, on diaphragm harvested 24 h after cecal ligation and puncture (CLP), and analyzed using functional, histologic, and biomarker assays. Results It was found that in septic rats, treatment with dantrolene significantly improved the contractility, relaxation, and fatigue index of the diaphragm in a dose-dependent manner. The benefits are associated with improvement in ultrastructural changes of Z band integrity and myofilament arrangements along with increases both in the ratio of slow-twitch type composition. Moreover, dantrolene effectively inhibits the overexpression of high-mobility group box 1 and reduces the calpain-1-caspase-3 proteolytic activity. Conclusions Dantrolene can effectively attenuate the dysfunction of diaphragm in septic rats; Furthermore, the beneficial effects were associated with downregulation of high-mobility group box 1 and calpain-1-caspase-3 proteolytic activity.