Dantrolene reduces serum TNFalpha and corticosterone levels and muscle calcium, calpain gene expression, and protein breakdown in septic rats.
The effects of dantrolene on serum TNFalpha and corticosterone levels and on muscle calcium, calpain gene expression, and protein breakdown were studied in rats with abdominal sepsis induced by cecal ligation and puncture. Treatment of rats with 10 mg/kg of dantrolene 2 h before and 8 h after induction of sepsis reduced serum TNFalpha and corticosterone, muscle calcium levels, mRNA levels for m- and mu-calpain, and the muscle specific calpain p94, as well as total and myofibrillar protein breakdown rates, determined as release of tyrosine and 3-methylhistidine, respectively, from incubated extensor digitorum longus muscles. The results support the concept that increased calcium concentrations may be an important mechanism of sepsis-induced muscle protein breakdown. The data also indicate that other mechanisms, in addition to reduced muscle calcium concentrations such as decreased levels of TNFalpha and glucocorticoids, may contribute to the anti-catabolic effects of dantrolene during sepsis. The observations are important from a clinical standpoint because they suggest that the catabolic response in skeletal muscle during sepsis may be prevented by treatment with a calcium antagonist.
Fischer
D R
DR
Department of Surgery, University of Cincinnati, Ohio, USA.
Sun
X
X
Williams
A B
AB
Gang
G
G
Pritts
T A
TA
James
J H
JH
Molloy
M
M
Fischer
J E
JE
Paul
R J
RJ
Hasselgren
P O
PO
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D003620:Dantrolene / Q000494:pharmacology*; D008297:Male; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D009124:Muscle Proteins; D009125:Muscle Relaxants, Central; D014409:Tumor Necrosis Factor-alpha; D002154:Calpain; D003620:Dantrolene; D002118:Calcium; D003345:Corticosterone