Calcium antagonists decrease plasma and tissue concentrations of tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-1 alpha in a mouse model of endotoxin.
Calcium plays an important role in the toxic effects of endotoxin, and calcium antagonists also have been shown to improve survival in animals challenged with endotoxin. Calcium may be involved in regulating cytokine production. Therefore, the protective effect of calcium-antagonists in endotoxin may be due to decreased cytokine formation and/or systemic release. In a mouse model of endotoxin, dantrolene (10 mg/kg) and azumolene (20 mg/kg), drugs that decrease calcium release from intracellular stores, or diltiazem (20 mg/kg), a calcium channel blocker, decreased plasma tumor necrosis factor-alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha), and IL-1 beta (47.2, 63.2, and 62.4%, respectively, p < .05) when the animals were injected intraperitoneally with endotoxin. Dantrolene and azumolene decreased IL-1 alpha by 56.6 and 65.4%, respectively, (p < .05) and IL-1 beta by 51.7 and 69.7%, respectively (p < .05). Diltiazem had no effect on IL-1 alpha or IL-1 beta. Dantrolene decreased TNF-alpha in lung (26.1%), liver (29.4%), and spleen (35.4%) (p < .05) and IL-1 alpha in lung (30.0%) and liver (25.4%) (p < .05). The present findings indicate that calcium-antagonists may be efficacious in treating cytokine mediated inflammatory disorders.
Hotchkiss
R S
RS
Department of Anesthesiology, Washington University, St Louis, Missouri 63110, USA.
Osborne
D F
DF
Lappas
G D
GD
Karl
I E
IE
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000502:physiology; D002451:Cell Compartmentation / Q000187:drug effects; D003620:Dantrolene / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology*; D004731:Endotoxins / Q000633:toxicity*; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014781:Viscera / Q000378:metabolism
D004731:Endotoxins; D007093:Imidazoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D010080:Oxazoles; D014409:Tumor Necrosis Factor-alpha; C061387:azumolene; C044101:endotoxin, Escherichia coli; D004110:Diltiazem; D003620:Dantrolene; D002118:Calcium