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.
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.
Department of Anesthesiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, P.R. China.
Yu-wei
YW
Qiu
Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, P.R. China.
Dan
D
Chen
Department of Anesthesiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, P.R. China.
Mei-ying
MY
Xu
Department of Anesthesiology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, P.R. China. Electronic address: lishitong59@hotmail.com.
Shi-tong
ST
Li
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003620:Dantrolene / Q000494:pharmacology* / Q000627:therapeutic use; D003964:Diaphragm / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D024243:HMGB1 Protein / Q000378:metabolism*; D008297:Male; D009125:Muscle Relaxants, Central / Q000494:pharmacology* / Q000627:therapeutic use; D059748:Proteolysis / Q000187:drug effects*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology
D015415:Biomarkers; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D009125:Muscle Relaxants, Central; D002154:Calpain; C000606071:Capn1 protein, rat; D053148:Caspase 3; D003620:Dantrolene
Cecal ligation and puncture; Diaphragm; High-mobility group box 1; Proteolysis; Sepsis