A role for the RISK pathway and KATPchannels in pre‐ and post‐conditioning induced by levosimendan in the isolated guinea pig heart

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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 KATPchannels 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 KATPchannel 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 (PATPchannel 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 (PConclusions 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 KATPchannel blockers and (4) LPC may be useful before elective cardiac surgery, whereas LPostC may be used after acute coronary artery events.

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