MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on July 16, 2004; DOI: 10.1124/mol.104.001354

0026-895X/04/6604-1043-1053$20.00
Mol Pharmacol 66:1043-1053, 2004

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.104.001354v1
66/4/1043    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Meij, J. T. A.
Right arrow Articles by Yu, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Meij, J. T. A.
Right arrow Articles by Yu, L.

Differential Mechanisms of Nitric Oxide- and Peroxynitrite-Induced Cell Death

Johanna T. A. Meij, Carole L. Haselton, Kristin L. Hillman, Dhanasekaran Muralikrishnan1, Manuchair Ebadi, and Lei Yu

University of Cincinnati College of Medicine, Cincinnati, Ohio (J.T.A.M., L.Y.); and University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota (C.L.H., K.L.H., D.M., M.E.)

Nitric oxide (NO) contributes to cellular degeneration in various disorders, particularly in the nervous system. NO targets cell proteins such as soluble guanylyl cyclase, but its detrimental effects are generally attributed to its reaction product with superoxide, peroxynitrite. To understand the mechanisms of NO-induced cell stress, we studied the effects of the NO donors diethylenetriamine and spermine NONOate and the peroxynitrite donor 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride (SIN-1) in SH-SY5Y and NG108-15 neuroblastoma cells. All three compounds induced a dose- and time-dependent decrease in viable cells, which was not blocked by the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. The two NONOates were ~15-fold more potent in SH-SY5Y than in NG108-15 cells, whereas the EC50 values of SIN-1 in SH-SY5Y and NG108-15 cells were in the same order. This led us to conclude that the mechanisms of NO and peroxynitrite did not converge. This was supported by our other findings. NONOates induced DNA fragmentation and an increase in cellular caspase-3 activity that preceded the gradual decline in cell viability. In contrast, SIN-1 induced a transient decline in ATP levels and a delayed loss of cell viability with no significant increase in caspase-3 activity or DNA laddering. Moreover, post-treatment with insulin inhibited caspase-3 activation and loss of cell viability in NONOate- but not in SIN-1–exposed cells. These findings suggest that NO is a potent toxin independent of peroxynitrite formation.

Received April 12, 2004; accepted July 15, 2004

Address correspondence to: Dr. Johanna T.A. Meij, Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, OH 45267-0521. E-mail: meijjt{at}ucmail.uc.edu




This article has been cited by other articles:


Home page
 Toxicol SciHome page
M. M. Tiwari, K. J. Messer, and P. R. Mayeux
Inducible Nitric Oxide Synthase and Apoptosis in Murine Proximal Tubule Epithelial Cells
Toxicol. Sci., June 1, 2006; 91(2): 493 - 500.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2004 by the American Society for Pharmacology and Experimental Therapeutics