DTPA Fe(III) decreases cytokines and hypotension but worsens survival with Escherichia coli sepsis in rats.
OBJECTIVE
Nonselective inhibition of nitric oxide (NO) with NO synthase antagonists decreases hypotension but worsens outcome clinically. We investigated whether iron (III) complex of diethylenetriaminepentaacetic acid [DTPA Fe(III)], a scavenger of NO as well as other oxidant mediators, has similar divergent effects in E. coli challenged rats.


METHODS
Animals with venous and arterial catheters and challenged with intrabronchial or intravenous E. coli were randomized to treatment with DTPA Fe(III) in doses from 3 to 800 mg/kg or placebo. Mean blood pressure (MBP) was measured in all animals and plasma NO, cytokines, and blood and lung leukocyte and bacteria counts in animals administered intrabronchial E. coli and DTPA Fe(III) 50 mg/kg or placebo. Animals received antibiotics and were observed 168 h.


RESULTS
Independent of drug regimen or infection site, compared to placebo, DTPA Fe(III) increased MBP although this was greater with high vs. lower doses. Despite increased MBP, DTPA Fe(III) worsened the hazards ratio of survival . At 6 and 24 h DTPA Fe(III) decreased NO but not significantly and decreased four cytokines (tumor necrosis factor-alpha, interleukins 1 and 10, and macrophage inflammatory protein 3alpha) and lung lavage neutrophils. From 6 to 24 h DTPA Fe(III) increased blood bacteria.


CONCLUSIONS
DTPA Fe(III) while increasing blood pressure has the potential to worsen outcome in sepsis. Further preclinical testing is required before this agent is applied clinically.
Li
Yan
Y
Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Li
Xuemei
X
Haley
Michael
M
Fitz
Yvonne
Y
Gerstenberger
Eric
E
Banks
Steven M
SM
Eichacker
Peter Q
PQ
Cui
Xizhong
X
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis* / Q000187:drug effects*; D004927:Escherichia coli Infections / Q000401:mortality*; D005290:Ferric Compounds / Q000009:adverse effects / Q000494:pharmacology*; D007022:Hypotension / Q000517:prevention & control*; D008297:Male; D004369:Pentetic Acid / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000401:mortality*; D015996:Survival Rate
D016207:Cytokines; D005290:Ferric Compounds; D004369:Pentetic Acid