title: Pharmacological inhibition of DDAH1 improves survival, haemodynamics and organ function in experimental septic shock.
abstract: The aim of the present study was to investigate the therapeutic effects of pharmacological inhibition of DDAH1 (dimethylarginine dimethylaminohydrolase 1), an enzyme that metabolizes endogenously produced nitric oxide synthase inhibitors, principally ADMA (asymmetric dimethylarginine). The present study employs a series of rodent models to evaluate the effectiveness a DDAH1-selective inhibitor (L-257). Short-term models involved the development of endotoxaemia using lipopolysaccharide and long-term models involved the intraperitoneal administration of faecal slurry. In order to generate the most relevant model possible, following induction of severe sepsis, animals received appropriate fluid resuscitation and in some models vasopressor therapy. The effects of L-257 on survival, haemodynamics and organ function were subsequently assessed. Survival was significantly longer in all L-257 treatment groups (P<0.01) and no adverse effects on haemodynamics and organ function were observed following L-257 administration to either animals with sepsis or naïve animals. Haemodynamic performance was preserved and the noradrenaline dose required to maintain target blood pressure was reduced in the treated animals (P<0.01). Animals receiving L-257 had significantly increased plasma ADMA concentrations. Plasma nitrite/nitrate was reduced as was severity of sepsis-associated renal dysfunction. The degree of tachycardia was improved as were indices of tissue and microvascular perfusion. The results of the present study show that the selective DDAH-1 inhibitor L-257 improved haemodynamics, provided catecholamine sparing and prolonged survival in experimental sepsis. Further studies will determine its potential utility in human septic shock.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: *Nitric Oxide Signalling Group, MRC Clinical Science Centre, Imperial College London, London, U.K.
authors.forename: Simon
authors.initials: S
authors.lastname: Lambden
authors.affiliation: †Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, U.K.
authors.forename: Valerie
authors.initials: V
authors.lastname: Taylor
authors.affiliation: *Nitric Oxide Signalling Group, MRC Clinical Science Centre, Imperial College London, London, U.K.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sujkovic
authors.affiliation: ‡Institute of Pharmaceutical Science, King's College London, London, U.K.
authors.forename: Manasi
authors.initials: M
authors.lastname: Nandi
authors.affiliation: *Nitric Oxide Signalling Group, MRC Clinical Science Centre, Imperial College London, London, U.K.
authors.forename: James
authors.initials: J
authors.lastname: Tomlinson
authors.affiliation: †Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, U.K.
authors.forename: Alex
authors.initials: A
authors.lastname: Dyson
authors.affiliation: §School of Crystallography, Birkbeck College, University of London, London, U.K.
authors.forename: Neil
authors.initials: N
authors.lastname: McDonald
authors.affiliation: ∥Department of Chemistry, University College London, London, U.K.
authors.forename: Stephen
authors.initials: S
authors.lastname: Caddick
authors.affiliation: †Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, U.K.
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
authors.affiliation: *Nitric Oxide Signalling Group, MRC Clinical Science Centre, Imperial College London, London, U.K.
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* / Q000378:metabolism / Q000627:therapeutic use; D019446:Endotoxemia / Q000188:drug therapy* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005440:Fluid Therapy; D006439:Hemodynamics / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology; D008297:Male; D009638:Norepinephrine / Q000627:therapeutic use; D010538:Peritonitis / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy*
chemical_list: D004791:Enzyme Inhibitors; C000589294:N(omega)-(2-methoxyethyl)arginine; C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase; D009638:Norepinephrine