N0 has been identified as a secretory product mediating diverse functions in mammalian systems including as a regulator of blood flow, as a mediator for the neurotransmitter glutamate, and as a cytotoxic mediator of macrophages. N0 is synthesized by the enzyme nitric oxide synthase (N0S) which exists in three isoforms, commonly referred to as cN0S, eN0S, and iN0S. A key to the successful prevention of toxic N0 formation is the development of inhibitors of N0S that are isoform selective, cell permeable, and non-toxic in vivo. This laboratory has pioneered the development and characterization of a novel class of N0S inhibitors, the imidazoleindazole class, which include the agents 7- nitroindazole and 1-phenylimidazole. Further, the investigator has recently identified that aminoguanidine is an isoform selective, non- toxic mechanism based inactivator of iN0S. The current grant proposes to examine the relationship of structure with the mechanism of inhibition and the isoform selectivity of aminoarginine analogs. Further, using C14-aminoguanidine, it is planned to determine the chemical mechanism of N0S inhibition both in vitro and in vivo in cells known to contain the cN0S and iN0S isoforms. Studies will be extended to compare the inhibition of isolated affinity purified N0S isoforms with that in intact cellular systems. These studies will clarify the factors operating in living cells that govern the sensitivity of the iN0S to inhibition by these agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES006897-03
Application #
6203495
Study Section
Project Start
1999-09-01
Project End
2000-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Jan, Yi-Hua; Richardson, Jason R; Baker, Angela A et al. (2016) Novel approaches to mitigating parathion toxicity: targeting cytochrome P450-mediated metabolism with menadione. Ann N Y Acad Sci 1378:80-86
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Heck, Diane E; Kagan, Valerian E; Shvedova, Anna A et al. (2005) An epigrammatic (abridged) recounting of the myriad tales of astonishing deeds and dire consequences pertaining to nitric oxide and reactive oxygen species in mitochondria with an ancillary missive concerning the origins of apoptosis. Toxicology 208:259-71
Fakhrzadeh, Ladan; Laskin, Jeffrey D; Gardner, Carol R et al. (2004) Superoxide dismutase-overexpressing mice are resistant to ozone-induced tissue injury and increases in nitric oxide and tumor necrosis factor-alpha. Am J Respir Cell Mol Biol 30:280-7
Heck, Diane E; Gerecke, Donald R; Vetrano, Anna M et al. (2004) Solar ultraviolet radiation as a trigger of cell signal transduction. Toxicol Appl Pharmacol 195:288-97

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