T. Mitsuo et al., GLUCOCORTICOID RECEPTOR ANTAGONISM BY MIFEPRISTONE ALTERS PHOSPHOCREATINE BREAKDOWN DURING SEPSIS, Archives of surgery, 131(11), 1996, pp. 1179-1185
Objective: To determine the role of glucocorticoids in the regulation
of myocellular energetics induced by sepsis by means of the glucocorti
coid receptor antagonist mifepristone (RU 38486). Design: Randomized c
ontrolled study. Setting: University laboratories. Participants: Thirt
y-two adult male Wistar rats. Methods: Animals were randomly assigned
to 1 of 4 groups. In 2 groups, mifepristone (10 mg/kg) was administere
d by gavage feeding 2 hours before cecal ligation and single 18-gauge
needle puncture or sham operation. The other 2 groups of animals recei
ved placebo gavage feedings 2 hours before their surgical procedures.
Twenty-four hours after operation, high-energy phosphate ratios, intra
cellular pH, the forward rate constant for the creatine kinase reactio
n, and phosphocreatine breakdown rates were measured in the gastrocnem
ius muscle by in vivo phosphorus 31 magnetic resonance spectroscopy. T
issue and blood samples were collected to measure creatine and adenosi
ne 5'-triphosphate concentrations, Na+-K+ adenosine triphosphatase act
ivity, and circulating corticosterone levels. Results: Circulating cor
ticosterone levels were twice as high in septic animals as in sham-ope
ration 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 septi
c animals were not significantly elevated above control levels. Conclu
sion: Pretreatment with mifepristone reduces the demand for adenosine
triphosphate production from phosphocreatine breakdown and downregulat
es Na+-K+ adenosine triphosphatase activity during sepsis.