Glucocorticoid receptor antagonism by mifepristone alters phosphocreatine breakdown during sepsis
T. Mitsuo, J. Rounds, D. Prechek, D. W. Wilmore and D. O. Jacobs
Laboratory 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.
