L-Arginine Chlorination Products Inhibit Endothelial Nitric Oxide Production

Academic Article

Abstract

  • 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.
  • Digital Object Identifier (doi)

    Author List

  • Zhang C; Reiter C; Eiserich JP; Boersma B; Parks DA; Beckman JS; Barnes S; Kirk M; Baldus S; Darley-Usmar VM
  • Start Page

  • 27159
  • End Page

  • 27165
  • Volume

  • 276
  • Issue

  • 29