RT Journal Article SR Electronic T1 l-Arginine Chlorination Results in the Formation of a Nonselective Nitric-Oxide Synthase Inhibitor JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1044 OP 1049 DO 10.1124/jpet.106.104422 VO 318 IS 3 A1 Jian Yang A1 Ruirui Ji A1 Yunhui Cheng A1 Ju-Zhong Sun A1 Lisa K. Jennings A1 Chunxiang Zhang YR 2006 UL http://jpet.aspetjournals.org/content/318/3/1044.abstract AB 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 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) and 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 reactivities, as well as the 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. The American Society for Pharmacology and Experimental Therapeutics