Document Detail

Nitric oxide/cGMP signalling mediates the cardioprotective action of adrenomedullin in reperfused myocardium.
MedLine Citation:
PMID:  19714395     Owner:  NLM     Status:  MEDLINE    
We demonstrated previously that adrenomedullin (AM), when given during early reperfusion, limited infarct size in rat heart. The present study was undertaken to provide direct evidence of the NO-dependency of AM's cardioprotective action by assessing NO biosynthesis and involvement of the soluble guanylyl cyclase (sGC) pathway. Perfused hearts from male CD-1 mice were subjected to 30-min left coronary occlusion and 60-min reperfusion. Infarct size was determined by tetrazolium staining. AM 10 nM was administered from 20 min after coronary occlusion until 10 min after reperfusion. Coronary effluent was analysed for NO2- and NO3-, and myocardial samples were analysed for NO2-, NO3-, nitroso-adducts and cGMP concentration. To examine the role of NO/sGC signalling in the infarct-limiting action of AM, further hearts received the sGC inhibitor ODQ 2 microM. AM treatment stimulated NO synthesis, indicated by increased NO2- efflux in coronary effluent throughout reperfusion (summarised as area under curve, AM 29.2 +/- 3.9 vs. control 14.4 +/- 2.8 micromol min2 mL(-1), P < 0.05). AM limited infarct size (35.4 +/- 2.7 vs. 12.2 +/- 2.3%, P < 0.01), associated with a 2.45-fold increase (P < 0.05) in myocardial cGMP concentration at 10 min after reperfusion. ODQ abolished the infarct size-limiting effect of AM (28.9 +/- 4.3%). These data provide the first evidence that AM increases NO bioavailability in intact murine myocardium and confirm that the NO/sGC/cGMP pathway is central to the cytoprotective action of AM against ischaemia-reperfusion injury.
Shabaz A Hamid; Matthias Totzeck; Christina Drexhage; Iain Thompson; Robert C Fowkes; Tienush Rassaf; Gary F Baxter
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-08-28
Journal Detail:
Title:  Basic research in cardiology     Volume:  105     ISSN:  1435-1803     ISO Abbreviation:  Basic Res. Cardiol.     Publication Date:  2010 Mar 
Date Detail:
Created Date:  2010-01-21     Completed Date:  2010-03-31     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0360342     Medline TA:  Basic Res Cardiol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  257-66     Citation Subset:  IM    
Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
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MeSH Terms
Adrenomedullin / administration & dosage,  metabolism*
Cyclic GMP / metabolism*
Guanylate Cyclase / metabolism*
Myocardial Infarction / etiology,  metabolism*,  pathology,  prevention & control
Myocardial Reperfusion Injury / complications,  metabolism*,  pathology,  prevention & control
Myocardium / pathology
Nitric Oxide / biosynthesis*
Signal Transduction
Grant Support
PG/03/030//British Heart Foundation
Reg. No./Substance:
10102-43-9/Nitric Oxide; 148498-78-6/Adrenomedullin; 7665-99-8/Cyclic GMP; EC Cyclase

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