The effect of EMHP on post-cardiac arrest survival of rats.
1-Ethyl-2-methyl-3-hydroxy-pyrid-4-one (EMHP), a low molecular weight iron chelator that is soluble in hydrocarbon solvents and presumably in lipids, was studied for in vitro inhibition of radical-mediated peroxidation of DNA. We also investigated the acute toxicity of EMHP by administering 40, 100, and 300 mg/kg intravenously to Wistar rats, and we then examined the in vivo effect of the 40 mg/kg dose following a 10-min cardiac arrest and resuscitation in rats. EMHP prevented iron-dependent radical-mediated DNA breaks of the supercoiled plasmid Bluescribe by the Fenton reagent (400 microM iron, 30 microM H2O2) when present at EMHP/Fe ratios of 16:1 and 32:1. The 300-mg/kg dose was lethal in 3 of 5 normal rats, and the 100-mg/kg dose was associated with excessive mortality post-resuscitation. The 40-mg/kg dose was well tolerated post-resuscitation, but it did not improve either 3-day survival or neurologic outcome.
Skjaerlund
J M
JM
Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI.
Krause
G S
GS
Feldman
D M
DM
O'Neil
B J
BJ
White
B C
BC
D000818:Animals; D001921:Brain / Q000098:blood supply; D004247:DNA / Q000187:drug effects; D005609:Free Radicals; D006323:Heart Arrest / Q000188:drug therapy* / Q000628:therapy; D007502:Iron Chelating Agents / Q000627:therapeutic use* / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D015427:Reperfusion Injury / Q000517:prevention & control; D012151:Resuscitation
D005609:Free Radicals; D007502:Iron Chelating Agents; D004247:DNA