A role for the RISK pathway and KATP channels in pre- and post-conditioning induced by levosimendan in the isolated guinea pig heart

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Title A role for the RISK pathway and KATP channels in pre- and post-conditioning induced by levosimendan in the isolated guinea pig heart
Author Du Toit, Eugene; Genis, A; Opie, L H; Pollesello, P; Lochner, A
Journal Name British Journal of Pharmacology
Year Published 2008
Place of publication United Kingdom
Publisher John Wiley & Sons Ltd.
Abstract Background and purpose: Myocardial reperfusion injury prevents optimal salvage of the ischaemic myocardium, and adjunct therapy that would significantly reduce reperfusion injury is still lacking. We investigated whether (1) the heart could be pre- and/or post-conditioned using levosimendan (levosimendan pre-conditioning (LPC) and levosimendan post-conditioning (LPostC)) and (2) the prosurvival kinases and/or the sarcolemmal or mitochondrial KATP channels are involved. Experimental approach: Isolated guinea pig hearts were treated with two 5 min cycles of levosimendan (0.1 μM) interspersed with vehicle perfusion, or two 5 min cycles of ischaemia/reperfusion, before coronary artery ligation (CAL) for 40 min at 36.5 °C. Hearts were treated with mitochondrial or sarcolemmal KATP channel blockers before LPC or LPostC. For post-conditioning, hearts received three 30 s cycles of ischaemia/reperfusion or levosimendan/vehicle. Hearts were pretreated with levosimendan immediately before CAL (without washout). Cardiac function, infarct size and reperfusion injury salvage kinase activity was assessed. Key results: LPC and LPostC halved the infarct size compared with controls (P<0.05). Treatment with KATP channel blockers before LPC or LPostC reversed this decrease. Pretreating hearts with levosimendan increased activity of extracellular signal-regulated kinase (ERK) 42/44 on reperfusion and had the most marked infarct-lowering effect (P<0.05). Conclusions and implications: (1) Hearts could be pharmacologically pre- and post-conditioned with levosimendan; (2) levosimendan pretreatment is the most effective way to reduce infarct size, possibly by increasing ERK 42/44 activity; (3) benefits of LPC and LPostC were abolished by both KATP channel blockers and (4) LPC may be useful before elective cardiac surgery, whereas LPostC may be used after acute coronary artery events.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1038/bjp.2008.52
Copyright Statement Copyright 2008 The British Pharmacological Society. Published by Blackwell Publishing Ltd. This is the author-manuscript version of the paper. Reproduced in accordance with the copyright policy of the publisher. The definitive version is available at www.blackwell-synergy.com
Volume 154
Issue Number 1
Page from 41
Page to 50
ISSN 0007-1188
Date Accessioned 2009-09-09
Language en_AU
Research Centre Menzies Health Institute Qld
Faculty Griffith Health Faculty
Subject Cardiology (incl Cardiovascular Diseases)
URI http://hdl.handle.net/10072/25669
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1x

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