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Originally published In Press as doi:10.1074/jbc.M100191200 on May 24, 2001

J. Biol. Chem., Vol. 276, Issue 29, 27159-27165, July 20, 2001
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L-Arginine Chlorination Products Inhibit Endothelial Nitric Oxide Production*

Chunxiang ZhangDagger , Chris Reiter§, Jason P. Eiserich§, Brenda Boersma, Dale A. Parks§||, Joseph S. Beckman§||, Stephen Barnes**, Marion Kirk**, Stephan Baldus§, Victor M. Darley-Usmar||Dagger Dagger , and C. Roger WhiteDagger ||§§

From the Dagger  Departments of Medicine, Vascular Biology and Hypertension Program, § Anesthesiology,  Pharmacology and Toxicology, and Dagger Dagger  Pathology, ** Comprehensive Cancer Center Mass Spectrometry Shared Facility, and the || Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294

The myeloperoxidase-derived oxidant hypochlorous acid (HOCl) is thought to contribute to endothelial dysfunction, but the mechanisms underlying this inhibitory effect are unknown. The present study tested the hypothesis that HOCl and L-arginine (L-Arg) react to form novel compounds that adversely affect endothelial function by inhibiting nitric oxide (NO) formation. Using spectrophotometric techniques, we found that HOCl and L-Arg react rapidly (k = 7.1 × 105 M-1 s-1) to form two major products that were identified by mass spectrometry as monochlorinated and dichlorinated adducts of L-Arg. Pretreatment of bovine aortic endothelial cells with the chlorinated L-Arg metabolites (Cl-L-Arg) inhibited the A23187-induced formation of the NO metabolites nitrate (NO<UP><SUB>3</SUB><SUP>−</SUP></UP>) and nitrite (NO<UP><SUB>2</SUB><SUP>−</SUP></UP>) in a concentration-dependent manner. Preincubation of rat aortic ring segments with Cl-L-Arg resulted in concentration-dependent inhibition of acetylcholine-induced relaxation. In contrast, blood vessels relaxed normally to the endothelium-independent vasodilator sodium nitroprusside. In vivo administration of Cl-L-Arg to anesthetized rats increased carotid artery vascular resistance. A greater than 10-fold excess of L-Arg was required to reverse the inhibitory effects of Cl-L-Arg in vivo and in vitro. Reaction of HOCl with D-arginine (D-Arg) did not result in the formation of inhibitory products. These results suggest that HOCl reacts with L-Arg to form chlorinated products that act as nitric-oxide synthase inhibitors.

* This work was supported in part by Grants HL-54815 and HL-03812 from the National Institutes of Health. The mass spectrometer was purchased by funds from National Institutes of Health Instrumentation Grant S10RR06487 and from this institution. Operation of the University of Alabama at Birmingham Comprehensive Cancer Center Mass Spectrometry Shared Facility was supported in part by NCI Core Research Support Grant P30 CA13148 to the UAB Comprehensive Cancer.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§§ To whom correspondence should be addressed: University of Alabama at Birmingham, Zeigler Research Bldg., Rm. 1046, Birmingham, AL 35294, Tel.: 205-934-1296, Fax: 205-934-0424, E-mail: crwhite@uab.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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