© 2002 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Nitric oxide as a mediator of delayed pharmacological (A1 receptor triggered) preconditioning; is eNOS masquerading as iNOS?
The Hatter Institute and Centre for Cardiology (Division of Medicine), University College London Medical School, Department of Cardiology, University College London Hospitals, Grafton Way, London WC1E 6DB, UK
* Corresponding author, The Hatter Institute for Cardiovascular Studies, Department of Academic Cardiology, University College Hospital, Gower Street, London WC1E 6AU, UK. Tel.: +44-20-7380-9888; fax: +44-20-7388-5095 hatter-institute{at}ucl.ac.uk
Background: Nitric oxide (NO), synthesised from the inducible isoform of nitric oxide synthase (iNOS), is implicated in mediating second window of protection (SWOP)/delayed ischemic preconditioning. However the role of NO and iNOS in delayed pharmacological protection remains unclear and is the subject of this investigation. Methods: To test the hypothesis that iNOS is necessary for delayed pharmacological preconditioning, the adenosine A1 receptor agonist, 2-chloro N6 cyclopentyl adenosine (CCPA) (25 µg/kg i.v.) or saline was administered to wild type (WT) or iNOS gene knockout mice (KO). Twenty-four hours later, the hearts were isolated, Langendorff perfused and subjected to 35 min ischemia/30 min reperfusion prior to infarct size determination. Results: WT and KO control hearts had identical infarct sizes of 37±3% and 37±2%, respectively. CCPA significantly reduced infarct size in WT hearts to 22±2% and also, unexpectedly, in KO hearts (27±2%). This protection was abrogated with the non-specific NOS inhibitor, N
nitro L-arginine methyl ester (L-NAME, 100 µM), and could be mimicked in naïve hearts with the NO donor, donor S-nitroso N-acetyl DL penicillamine (SNAP, 1 µM). Delayed protection appeared to be mediated by NO synthesis in both WT and KO hearts. Additional studies using Western blot analysis demonstrated endothelial NOS (eNOS) upregulation and increased NOx release in both WT and KO hearts. Conclusions: This is the first study to demonstrate a role for eNOS in delayed A1 receptor triggered (pharmacological) preconditioning, potentially representing a new pharmacological target for protecting the ischemic heart.
KEYWORDS Adenosine; Nitric oxide; Infarction; Preconditioning
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