DMD Large equally mixed donor pool

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


     

0090-9556/03/3107-932-937$20.00
DMD 31:932-937, 2003

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
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 Demady, D. R.
Right arrow Articles by Osawa, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Demady, D. R.
Right arrow Articles by Osawa, Y.

METABOLISM-BASED INACTIVATION OF NEURONAL NITRIC-OXIDE SYNTHASE BY COMPONENTS OF CIGARETTE AND CIGARETTE SMOKE

Damon R. Demady1, Ezra R. Lowe1,2, Andrew C. Everett, Scott S. Billecke, Yasuhiko Kamada, Anwar Y. Dunbar, and Yoichi Osawa

From the Department of Pharmacology, the University of Michigan Medical School, Ann Arbor, Michigan

It has been shown that administration of cigarette smoke to rats leads to loss of neuronal nitric-oxide synthase (nNOS) activity and nNOS protein in penile tissue. The exact mechanism for this loss of activity and protein is not known. In the current study, we investigated whether extracts prepared from cigarette smoke or from the cigarette itself could directly inhibit nNOS activity. We discovered that the cigarette smoke extract and the cigarette extract cause a time-, concentration-, and calmodulin-dependent inactivation of nNOS in an in vitro system containing the purified enzyme. L-Arginine, but not D-arginine, protects nNOS from this time-dependent inactivation, suggesting an active site directed event. The kinetics of inactivation are consistent with the metabolism-based or suicide inactivation of nNOS. Based on studies with other metabolism-based inactivators, this cigarette-mediated inactivation may render nNOS more susceptible to proteasomal degradation and thereby may explain the loss of nNOS protein in vivo. The component(s) responsible for nNOS inactivation is not volatile, is not retained by a 3,000 molecular weight cut-off membrane, binds to activated charcoal, and is highly water-soluble under both acidic and basic conditions. The discovery of a direct inactivation of nNOS by an organic, cationic compound(s) present in tobacco and tobacco smoke provides a basis for further study of not only the mechanisms responsible for the biological effects of tobacco but also a search for a potentially novel inactivator of nNOS.

Address correspondence to: Yoichi Osawa, Department of Pharmacology, The University of Michigan Medical School, 1301 Medical Science Research Building III, Ann Arbor, MI 48109-0632. Email: osawa{at}umich.edu




This article has been cited by other articles:


Home page
 HypertensionHome page
W.-Z. Zhang, K. Venardos, J. Chin-Dusting, and D. M. Kaye
Adverse Effects of Cigarette Smoke on NO Bioavailability: Role of Arginine Metabolism and Oxidative Stress
Hypertension, August 1, 2006; 48(2): 278 - 285.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
E. R. Lowe, A. C. Everett, A. J. Lee, M. Lau, A. Y. Dunbar, V. Berka, A.-l. Tsai, and Y. Osawa
TIME-DEPENDENT INHIBITION AND TETRAHYDROBIOPTERIN DEPLETION OF ENDOTHELIAL NITRIC-OXIDE SYNTHASE CAUSED BY CIGARETTES
Drug Metab. Dispos., January 1, 2005; 33(1): 131 - 138.
[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 © 2003 by the American Society for Pharmacology and Experimental Therapeutics.