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    Pharmacological inhibition of DDAH1 improves survival, haemodynamics and organ function in experimental septic shock

    Wang, Z. and Lambden, S. and Taylor, V. and Sujkovic, E. and Nandi, M. and Tomlinson, J. and Dyson, A. and McDonald, Neil Q. and Caddick, S. and Singer, M. and Leiper, J. (2014) Pharmacological inhibition of DDAH1 improves survival, haemodynamics and organ function in experimental septic shock. Biochemical Journal 460 (2), pp. 309-316. ISSN 0264-6021.

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    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.

    Metadata

    Item Type: Article
    Keyword(s) / Subject(s): drug research, infection, nitric oxide, nitric oxide synthase, shock.
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 08 Jul 2014 13:34
    Last Modified: 06 Dec 2016 10:43
    URI: http://eprints.bbk.ac.uk/id/eprint/10068

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