L-Arginine Chlorination Products Inhibit Endothelial Nitric Oxide Production

Chunxiang Zhang, Chris Reiter, Jason P. Eiserich, Brenda Boersma, Dale A. Parks, Joseph S. Beckman, Stephen Barnes, Marion Kirk, Stephan Baldus, Victor M. Darley-Usmar, C. Roger White

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67 Scopus citations


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 (NO3 -) and nitrite (NO2 -) 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.

Original languageEnglish (US)
Pages (from-to)27159-27165
Number of pages7
JournalJournal of Biological Chemistry
Issue number29
StatePublished - Jul 20 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry


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