title: Genetic and pharmacological inhibition of dimethylarginine dimethylaminohydrolase 1 is protective in endotoxic shock.
abstract: OBJECTIVE
  The overproduction of vascular NO contributes toward the circulatory collapse observed in patients with septic shock. Dimethylarginine dimethylaminohydrolase (DDAH), which has 2 isoforms, metabolizes asymmetrically methylated arginines (asymmetric mono- or di-methylarginine), endogenously produced NO synthase inhibitors. We wished to investigate whether reducing DDAH1 activity, using genetic and pharmacological approaches, is protective during lipopolysaccharide-induced endotoxic shock.
  
  
  RESULTS
  Experiments were conducted in DDAH1 heterozygous knockout mice (DDAH1(+/-)) or naive rats treated with a synthetic pharmacological DDAH inhibitor (L-257). We demonstrate for the first time that L-257 is DDAH1 selective using recombinant human DDAH proteins. DDAH1 mRNA was expressed in aortic but not macrophage cDNA, and consistent with this expression profile, L-257 selectively inhibited NO production from lipopolysaccharide-treated aorta but not macrophages, in culture. Conscious and anesthetized cardiovascular hemodynamics were monitored using implanted radiotelemetry devices or invasive catheters, respectively. Lipopolysaccharide was administered intravenously to model endotoxemia, and all animals presented with circulatory shock. DDAH1(+/-) mice or L-257-treated rats displayed attenuation in the rate of developed hypotension compared with wild-type littermates or vehicle control animals, respectively.
  
  
  CONCLUSIONS
  Pharmacological and genetic reduction of DDAH1 activity is protective against the vascular changes observed during endotoxic shock.
authors.affiliation: Pharmacology and Therapeutics Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King's College London, Franklin-Wilkins Bldg, 150 Stamford St, London SE1 9NH, UK. manasi.nandi@kcl.ac.uk
authors.forename: Manasi
authors.initials: M
authors.lastname: Nandi
authors.forename: Peter
authors.initials: P
authors.lastname: Kelly
authors.forename: Belen
authors.initials: B
authors.lastname: Torondel
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Anna
authors.initials: A
authors.lastname: Starr
authors.forename: Yue
authors.initials: Y
authors.lastname: Ma
authors.forename: Philip
authors.initials: P
authors.lastname: Cunningham
authors.forename: Raymond
authors.initials: R
authors.lastname: Stidwill
authors.forename: James
authors.initials: J
authors.lastname: Leiper
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009569:Nitric Oxide / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D009569:Nitric Oxide; D000581:Amidohydrolases; C059999:dimethylargininase