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

Department of Biomedical Sciences, Faculty of Health Sciences, University of Stellenbosch, Western Cape, South Africa.
British Journal of Pharmacology (Impact Factor: 4.84). 05/2008; 154(1):41-50. DOI: 10.1038/bjp.2008.52
Source: PubMed


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 K(ATP) channels are involved.
Isolated guinea pig hearts were treated with two 5 min cycles of levosimendan (0.1 microM) interspersed with vehicle perfusion, or two 5 min cycles of ischaemia/reperfusion, before coronary artery ligation (CAL) for 40 min at 36.5 degrees C. Hearts were treated with mitochondrial or sarcolemmal K(ATP) 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.
LPC and LPostC halved the infarct size compared with controls (P<0.05). Treatment with K(ATP) 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).
(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 K(ATP) channel 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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    • "Very early on, however, it appeared that levosimendan also has molecular targets other than cardiac troponin C, and other pharmacological actions other than inotropy [26]. The additional pharmacological effects of levosimendan are: (i) vasodilation, through the opening of potassium channels on the sarcolemma of smooth muscle cells in the vasculature [39] [40] [41] [42]; and (ii) cardioprotection, through the opening of mitochondrial potassium channels in cardiomyocytes [43] [44] [45] [46]. Additionally, it was demonstrated in vitro that levosimendan is a very potent and selective PDEIII inhibitor [47] [48]. "
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    • "Therefore, treatment with the K ATP channel opener levosimendan prior to myocardial ischaemia will mimic ischaemic preconditioning. According to ex-vivo data obtained by Toit and colleagues, levosimendan preconditioning can reduce infarct size by 90% [11]. Also, when compared with milrinone in an animal model setting, there was less mortality with levosimendan: after occlusion and reperfusion of the coronary vessels, 70% of dogs treated with levosimendan before ischaemia–reperfusion survived, as compared to 20% of those treated with milrinone [17]. "
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    • "On the other hand, other pharmacologic effects of levosimendan have been described that might also be beneficial, such as anti-ischemic properties (Du Toit et al., 2008; Grossini et al., 2005; Kersten et al., 2000; Leprán et al., 2006; Levijoki et al., 2001; Papp et al., 2006), improved endothelial function (Parissis et al., 2008), and anti-aggregatory effects on platelets Ambrus et al., 2012; Bent and Plaschke, 2013; Kaptan et al., 2008; Plaschke et al., 2012). "
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