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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Aug 20;93(17):9138–9141. doi: 10.1073/pnas.93.17.9138

Iron chelates bind nitric oxide and decrease mortality in an experimental model of septic shock.

W M Kazmierski 1, G Wolberg 1, J G Wilson 1, S R Smith 1, D S Williams 1, H H Thorp 1, L Molina 1
PMCID: PMC38608  PMID: 8799167

Abstract

The hydroxamic acid siderophore ferrioxamine B [FeIII(HDFB)+] and the iron complex of diethylenetri-aminepentaacetic acid [FeIII(DTPA)2-] protected mice against death by septic shock induced by Corynebacterium parvum + lipopolysaccharide. Although FeIII(DTPA)2- was somewhat more effective than FeIII(HDFB)+, the iron-free ligand H4DFB+ was significantly more effective than DTPA. The hydroxamic acid chelator has a much higher iron affinity than the amine carboxylate, allowing for more efficient formation of the FeIII(HDFB)+ complex upon administration of the iron-free ligand. Electrochemical studies show that FeIII(DTPA)2- binds NO stoichiometrically upon reduction to iron(II) at biologically relevant potentials to form a stable NO adduct. In contrast, FeIII(HDFB)+ is a stable and efficient electrocatalyst for the reduction of NO to N2O at biologically relevant potentials. These results suggest that the mechanism of protection against death by septic shock involves NO scavenging and that particularly effective drugs that operate a low dosages may be designed based on the principle of redox catalysis. These complexes constitute a new family of drugs that rely on the special ability of transition metals to activate small molecules. In addition, the wealth of information available on siderophore chemistry and biology provides an intellectual platform for further development.

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Selected References

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  1. Billiar T. R., Curran R. D., Stuehr D. J., Stadler J., Simmons R. L., Murray S. A. Inducible cytosolic enzyme activity for the production of nitrogen oxides from L-arginine in hepatocytes. Biochem Biophys Res Commun. 1990 May 16;168(3):1034–1040. doi: 10.1016/0006-291x(90)91133-d. [DOI] [PubMed] [Google Scholar]
  2. Cooper S. R., McArdle J. V., Raymond K. N. Siderophore electrochemistry: relation to intracellular iron release mechanism. Proc Natl Acad Sci U S A. 1978 Aug;75(8):3551–3554. doi: 10.1073/pnas.75.8.3551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Furchgott R. F., Zawadzki J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373–376. doi: 10.1038/288373a0. [DOI] [PubMed] [Google Scholar]
  4. Gearing A. J., Beckett P., Christodoulou M., Churchill M., Clements J., Davidson A. H., Drummond A. H., Galloway W. A., Gilbert R., Gordon J. L. Processing of tumour necrosis factor-alpha precursor by metalloproteinases. Nature. 1994 Aug 18;370(6490):555–557. doi: 10.1038/370555a0. [DOI] [PubMed] [Google Scholar]
  5. Harbrecht B. G., Billiar T. R., Stadler J., Demetris A. J., Ochoa J., Curran R. D., Simmons R. L. Inhibition of nitric oxide synthesis during endotoxemia promotes intrahepatic thrombosis and an oxygen radical-mediated hepatic injury. J Leukoc Biol. 1992 Oct;52(4):390–394. doi: 10.1002/jlb.52.4.390. [DOI] [PubMed] [Google Scholar]
  6. Hoe S., Rowley D. A., Halliwell B. Reactions of ferrioxamine and desferrioxamine with the hydroxyl radical. Chem Biol Interact. 1982 Jul 15;41(1):75–81. doi: 10.1016/0009-2797(82)90018-7. [DOI] [PubMed] [Google Scholar]
  7. Kilbourn R. G., Gross S. S., Jubran A., Adams J., Griffith O. W., Levi R., Lodato R. F. NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci U S A. 1990 May;87(9):3629–3632. doi: 10.1073/pnas.87.9.3629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kilbourn R. G., Joly G., Cashon B., DeAngelo J., Bonaventura J. Cell-free hemoglobin reverses the endotoxin-mediated hyporesponsivity of rat aortic rings to alpha-adrenergic agents. Biochem Biophys Res Commun. 1994 Feb 28;199(1):155–162. doi: 10.1006/bbrc.1994.1208. [DOI] [PubMed] [Google Scholar]
  9. Kim B. K., Huebers H., Pippard M. J., Finch C. A. Storage iron exchange in the rat as affected by deferoxamine. J Lab Clin Med. 1985 Apr;105(4):440–448. [PubMed] [Google Scholar]
  10. Klabunde R. E., Ritger R. C. NG-monomethyl-l-arginine (NMA) restores arterial blood pressure but reduces cardiac output in a canine model of endotoxic shock. Biochem Biophys Res Commun. 1991 Aug 15;178(3):1135–1140. doi: 10.1016/0006-291x(91)91010-a. [DOI] [PubMed] [Google Scholar]
  11. Komarov A., Mattson D., Jones M. M., Singh P. K., Lai C. S. In vivo spin trapping of nitric oxide in mice. Biochem Biophys Res Commun. 1993 Sep 30;195(3):1191–1198. doi: 10.1006/bbrc.1993.2170. [DOI] [PubMed] [Google Scholar]
  12. Kubrina L. N., Caldwell W. S., Mordvintcev P. I., Malenkova I. V., Vanin A. F. EPR evidence for nitric oxide production from guanidino nitrogens of L-arginine in animal tissues in vivo. Biochim Biophys Acta. 1992 Mar 13;1099(3):233–237. doi: 10.1016/0005-2728(92)90032-w. [DOI] [PubMed] [Google Scholar]
  13. Lai C. S., Komarov A. M. Spin trapping of nitric oxide produced in vivo in septic-shock mice. FEBS Lett. 1994 May 30;345(2-3):120–124. doi: 10.1016/0014-5793(94)00422-6. [DOI] [PubMed] [Google Scholar]
  14. Maeda H., Akaike T., Yoshida M., Suga M. Multiple functions of nitric oxide in pathophysiology and microbiology: analysis by a new nitric oxide scavenger. J Leukoc Biol. 1994 Nov;56(5):588–592. doi: 10.1002/jlb.56.5.588. [DOI] [PubMed] [Google Scholar]
  15. McGeehan G. M., Becherer J. D., Bast R. C., Jr, Boyer C. M., Champion B., Connolly K. M., Conway J. G., Furdon P., Karp S., Kidao S. Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor. Nature. 1994 Aug 18;370(6490):558–561. doi: 10.1038/370558a0. [DOI] [PubMed] [Google Scholar]
  16. Mizoguchi Y., Tsutsui H., Miyajima K., Sakagami Y., Seki S., Kobayashi K., Yamamoto S., Morisawa S. The protective effects of prostaglandin E1 in an experimental massive hepatic cell necrosis model. Hepatology. 1987 Nov-Dec;7(6):1184–1188. doi: 10.1002/hep.1840070603. [DOI] [PubMed] [Google Scholar]
  17. Mohler K. M., Sleath P. R., Fitzner J. N., Cerretti D. P., Alderson M., Kerwar S. S., Torrance D. S., Otten-Evans C., Greenstreet T., Weerawarna K. Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing. Nature. 1994 Jul 21;370(6486):218–220. doi: 10.1038/370218a0. [DOI] [PubMed] [Google Scholar]
  18. Molina y Vedia L., McDonald B., Reep B., Brüne B., Di Silvio M., Billiar T. R., Lapetina E. G. Nitric oxide-induced S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase inhibits enzymatic activity and increases endogenous ADP-ribosylation. J Biol Chem. 1992 Dec 15;267(35):24929–24932. [PubMed] [Google Scholar]
  19. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  20. Nussler A. K., Billiar T. R. Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol. 1993 Aug;54(2):171–178. [PubMed] [Google Scholar]
  21. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  22. Peters G., Keberle H., Schmid K., Brunner H. Distribution and renal excretion of desferrioxamine and ferrioxamine in the dog and in the rat. Biochem Pharmacol. 1966 Jan;15(1):93–109. doi: 10.1016/0006-2952(66)90114-6. [DOI] [PubMed] [Google Scholar]
  23. Petros A., Bennett D., Vallance P. Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock. Lancet. 1991 Dec 21;338(8782-8783):1557–1558. doi: 10.1016/0140-6736(91)92376-d. [DOI] [PubMed] [Google Scholar]
  24. Rahhal S., Richter H. W. Reaction of hydroxyl radicals with the ferrous and ferric iron chelates of diethylenetriamine-N,N,N',N",N"- pentaacetate. Free Radic Res Commun. 1989;6(6):369–377. doi: 10.3109/10715768909087920. [DOI] [PubMed] [Google Scholar]
  25. Schaich K. M., Borg D. C. Fenton reactions in lipid phases. Lipids. 1988 Jun;23(6):570–579. doi: 10.1007/BF02535600. [DOI] [PubMed] [Google Scholar]
  26. Thiemermann C., Szabó C., Mitchell J. A., Vane J. R. Vascular hyporeactivity to vasoconstrictor agents and hemodynamic decompensation in hemorrhagic shock is mediated by nitric oxide. Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):267–271. doi: 10.1073/pnas.90.1.267. [DOI] [PMC free article] [PubMed] [Google Scholar]

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