title: Endogenous nitric oxide synthase inhibitors in the biology of disease: markers, mediators, and regulators?
abstract: The asymmetric methylarginines inhibit nitric oxide synthesis in vivo by competing with L-arginine at the active site of nitric oxide synthase. High circulating levels of asymmetric dimethylarginine predict adverse outcomes, specifically vascular events but there is now increasing experimental and epidemiological evidence that these molecules, and the enzymes that regulate this pathway, play a mechanistic role in cardiovascular diseases. Recent data have provided insight into the impact of altered levels of these amino acids in both humans and rodents, however these reports also suggest a simplistic approach based on measuring, and modulating circulating asymmetric dimethylarginine alone is inadequate. This review outlines the basic biochemistry and physiology of endogenous methylarginines, examines both the experimental and observational evidence for a role in disease pathogenesis, and examines the potential for therapeutic regulation of these molecules.
authors.affiliation: Centre for Nephrology, UCL Medical School, Royal Free Campus 2nd Floor, Rowland Hill St, London NW3 2PF. b.caplin@ucl.ac.uk
authors.forename: Ben
authors.initials: B
authors.lastname: Caplin
authors.forename: James
authors.initials: J
authors.lastname: Leiper
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D015415:Biomarkers / Q000097:blood; D002317:Cardiovascular Agents / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000097:blood / Q000201:enzymology* / Q000628:therapy; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019323:omega-N-Methylarginine / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; C059999:dimethylargininase