Received for publication March 13, 2006.
Revised May 16, 2006.
Accepted for publication May 18, 2006.

L-arginine chlorination results in the formation of a nonselective nitric oxide synthase inhibitor

Abstract

Reduced nitric oxide (NO) bioavailability and impaired vascular function are the key pathological characteristics of inflammatory diseases such as atherosclerosis. We have recently found that leukocyte-derived hypochlorous acid (HOCl) is able to react with the nitric oxide synthase (NOS) substrate L-arginine to produce chlorinated L-arginine (cl-L-arg). Interestingly, cl-L-arg potently inhibits the formation of NO metabolites in cultured endothelial cells. It is unknown whether cl-L-arg has a direct inhibitory effect on endothelial NOS (eNOS). In addition, the effect of cl-L-arg on the other NOS isoforms, neuronal NOS (nNOS), inducible NOS (iNOS), is also unknown. Therefore, we designed the current study to test the effects of cl-L-arg on eNOS, nNOS, and iNOS. Using recombinant NOS, we found that cl-L-arg had a direct inhibitory effect on the activity of NOS. The effect of cl-L-arg on NOS activity is nonselective, as all three NOS isoforms were inhibited with a similar IC₅₀. We further determined the effect of cl-L-arg on the three NOS isoforms at the tissue level. The results demonstrated that cl-L-arg potently inhibited all three NOS isoform-mediated vessel reactivity, as well as NOS signaling molecule cGMP. cl-L-arg might serve as a novel endogenous NOS inhibitor and an important mediator for vascular dysfunction under inflammatory conditions such as atherosclerosis. Blocking cl-L-arg formation may be a new therapeutic approach to cardiovascular diseases.

Key words: Inflammation, L-arginine, atherosclerosis, endothelial dysfunction, leukocyte, nitric oxide synthase

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