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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    • "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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    ABSTRACT: In cardiac surgery, postoperative low cardiac output has been shown to correlate with increased rates of organ failure and mortality. Catecholamines have been the standard therapy for many years, although they carry substantial risk for adverse cardiac and systemic effects, and have been reported to be associated with increased mortality. On the other hand, the calcium sensitiser and potassium channel opener levosimendan has been shown to improve cardiac function with no imbalance in oxygen consumption, and to have protective effects in other organs. Numerous clinical trials have indicated favourable cardiac and non-cardiac effects of preoperative and perioperative administration of levosimendan. A panel of 27 experts from 18 countries has now reviewed the literature on the use of levosimendan in on-pump and off-pump coronary artery bypass grafting and in heart valve surgery. This panel discussed the published evidence in these various settings, and agreed to vote on a set of questions related to the cardioprotective effects of levosimendan when administered preoperatively, with the purpose of reaching a consensus on which patients could benefit from the preoperative use of levosimendan and in which kind of procedures, and at which doses and timing should levosimendan be administered. Here, we present a systematic review of the literature to report on the completed and ongoing studies on levosimendan, including the newly commenced LEVO-CTS phase III study (NCT02025621), and on the consensus reached on the recommendations proposed for the use of preoperative levosimendan. Copyright © 2015. Published by Elsevier Ireland Ltd.
    International Journal of Cardiology 04/2015; 184(1). DOI:10.1016/j.ijcard.2015.02.022 · 4.04 Impact Factor
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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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    ABSTRACT: The effects of levosimendan on cerebrovascular lesions and mortality were investigated in models of primary and secondary stroke. We aimed to determine whether the effects of levosimendan are comparable to and/or cumulative with those of valsartan, and to investigate whether levosimendan-induced vasodilation has a role in its effects on stroke. In a primary stroke Dahl/Rapp rat model, mortality rates were 70% and 5% for vehicle and levosimendan, respectively. Both stroke incidence (85% vs. 10%, P<0.001) and stroke-associated behavioral deficits (7-point neuroscore: 4.59 vs. 5.96, P<0.001) were worse for vehicle compared to levosimendan. In a secondary stroke model in which levosimendan treatment was started after cerebrovascular incidences were already detected, mean survival times were 15 days with vehicle, 20 days with levosimendan (P=0.025, vs. vehicle), 22 days with valsartan (P=0.001, vs. vehicle), and 31 days with levosimendan plus valsartan (P<0.001, vs. vehicle). The respective survivals were 0%, 16%, 20% and 59%, and the respective incidences of severe lesions were 50%, 67%, 50% and 11%. In this rat model, levosimendan increased blood volume of the cerebral vessels, with significant effects in the microvessels of the cortex (∆R=3.5±0.15 vs. 2.7±0.17 ml for vehicle; P=0.001) and hemisphere (∆R=3.2±0.23 vs. 2.6±0.14 ml for vehicle; P=0.018). Overall, levosimendan significantly reduced stroke-induced mortality and morbidity, both alone and with valsartan, with apparent cumulative effects, an activity in which the vasodilatory effects of levosimendan have a role.
    European Journal of Pharmacology 01/2015; 750. DOI:10.1016/j.ejphar.2015.01.037 · 2.53 Impact Factor
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    • "For instance, autacoids, formed during conditioning manoeuvres , can trigger protection by inducing activation of the mitochondrial K + ATP channel (mitoKATP), which then induces the generation of ROS and RNS, both required for conditioning-induced protection (O'Rourke, 2000; Cohen et al., 2001; Forbes et al., 2001; Oldenburg et al., 2002; 2004; Gucek and Murphy, 2010; Di Lisa et al., 2011; Murphy et al., 2012; 2014; Penna et al., 2013a) (Figure 1). Notably, I-PreC can be mimicked by pharmacological interventions, including the administration of free radical donors/generators, NO donors, and even nitroxyl anion (HNO/NO − ) and ONOO − donors (Wink et al., 1993; Pagliaro, 2003; Pagliaro et al., 2003; du Toit et al., 2008; Tocchetti et al., 2011), whereas pre-and post-conditioning can be blocked by radical scavengers (Penna et al., 2006b; Cohen et al., 2008). Although the cardioprotective effect of conditioning strategies have been proven in several species including humans, it seems that the presence of cardiovascular risk factors, ageing, co-morbidities and other concomitant medications may interfere with cardioprotective signalling pathways (for extensive reviews, see Ferdinandy et al., 2007; Ovize et al., 2013; Hausenloy et al., 2013). "
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    ABSTRACT: The morbidity and mortality from coronary artery disease (CAD) remain significant worldwide. The treatment for acute myocardial infarction has improved over the past decades, including early reperfusion of culprit coronary arteries. Although it is mandatory to reperfond the ischemic territory as soon as possible, paradoxically this leads to additional myocardial injury, namely ischemia/reperfusion injury, in which a pivotal role is played by redox stress and for which no effective therapy is currently available. In this review, we report evidence that redox environment plays pivotal roles not only in ischemia/reperfusion injury, but also in cardioprotection. In fact cardioprotective strategies, such as pre- and post-conditioning, result in a robust reduction of infarct size in animals and redox signaling plays a role of paramount importance in these conditioning strategies. Nitrosative signaling and cysteine redox modifications, such as S-nitrosation/-nitrosylation, are also emerging as very important mechanisms in conditioning cardioprotection. The reasons of the switch from protective oxidative/nitrosative signaling to deleterious oxidative/nitrosative/nitrative stress are not fully understood. The complex regulation of this switch is, at least in part, responsible of the diminished or absent cardioprotection by conditioning protocols observed in aging animals and with comorbidities as well as in humans. Therefore, it is important to understand at a mechanistic level the reasons for these differences before proposing a safe and useful transition of ischemic or pharmacological conditioning. Indeed, more mechanistic novel therapeutic strategies are required to protect the heart from ischemia/reperfusion injury and to improve clinical outcomes in patients with CAD.
    British Journal of Pharmacology 10/2014; 172(8). DOI:10.1111/bph.12975 · 4.84 Impact Factor
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