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Glucocorticoid receptor antagonism by mifepristone alters phosphocreatine breakdown during sepsis
T Mitsuo1, J Rounds, D Prechek
1Laboratory for Surgical Metabolism and Nutrition, Brigham and Women's Hospital, Boston, Mass., USA.
Objective:
To determine the role of glucocorticoids in the regulation of myocellular energetics induced by sepsis by means of the glucocorticoid receptor antagonist mifepristone (RU 38486).
Design:
Randomized controlled study.
Setting:
University laboratories.
Participants:
Thirty-two adult male Wistar rats.
Methods:
Animals were randomly assigned to 1 of 4 groups. In 2 groups, mifepristone (10 mg/kg) was administered by gavage feeding 2 hours before cecal ligation and single 18-gauge needle puncture or sham operation. The other 2 groups of animals received placebo gavage feedings 2 hours before their surgical procedures. Twenty-four hours after operation, high-energy phosphate ratios, intracellular pH, the forward rate constant for the creatine kinase reaction, and phosphocreatine breakdown rates were measured in the gastrocnemius muscle by in vivo phosphorus 31 magnetic resonance spectroscopy. Tissue and blood samples were collected to measure creatine and adenosine 5'-triphosphate concentrations, Na(+)-K+ adenosine triphosphatase activity, and circulating corticosterone levels.
Results:
Circulating corticosterone levels were twice as high in septic animals as in sham-operation control rats (P < .01). Phosphocreatine breakdown rates and Na(+)-K+ adenosine triphosphatase activity were significantly higher (40% and 75%, respectively; P < .01) in placebo-treated septic rats than in sham-operation control rats. However, phosphocreatine breakdown rates and Na(+)-K+ adenosine triphosphatase activity in mifepristone-treated septic animals were not significantly elevated above control levels.
Conclusion:
Pretreatment with mifepristone reduces the demand for adenosine triphosphate production from phosphocreatine breakdown and downregulates Na(+)-K+ adenosine triphosphatase activity during sepsis.
