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PKC netherlands journal of critical care ETC Mitochondria PKC MAPK A. Contraction mitoK + ATP K + HSP Mitoc hondria Figure 1 Calcium fluxes during excitation-contraction coupling in contraction (A) and relaxation (B). ATP = ATPase, NCX = Na + /Ca 2+ -exchanger, ICa = Ca 2+ influx via voltage dependen L-type Ca 2+ channels, RyR = ryanodin receptor, SR = sarcoplasmic reticulum, SERCA = sarco-endoplasmic reticulum Ca 2+ ATPase, PLB = phospholamban, SL = sarcolemma. Ca 2+ SL Na+ K + ATP Na + •reduced Ca 2+ - overload •reduced oxidative stress Na + •preserved mitochondrial function Ca 2+ RyR Ca 2+ Ca 2+ I SR Ca PLB SERCA ATP NCX Cardioprotection •Less necrosis •Less apoptosis •Improved contractile recovery Mitochondria SL B. Relaxation Na+ Na + ATP K + ATP Na + NCX Ca 2+ RyR NCX SR PLB Ca 2+ Ca 2+ SERCA Mitoc hondria SL SR, and, as cellular Na + -levels remain elevated due to increased Na + - influx via the NHE, cytosolic Ca 2+ will continue to rise via the NCX in the reverse mode. In addition, energy is present for activation of the myofibrillar elements, but in the presence of high Ca 2+ levels, myofibrillar activation leads to sustained force development causing hypercontraction [17]. According to Piper et al. (2004), the development of hypercontraction in combination with ischaemia -induced cytoskeletal and sarcolemmal fragility results in cellular disruption followed by necrotic cell death. In addition, elevation of intracellular Ca 2+ is also associated with activation of a variety of protein kinases, phosphatases and proteases contributing to I/R-injury. Furthermore, mitochondrial function can be negatively affected as mitochondrial Ca 2+ overload induces release of cytochrome C and pro-apoptotic factors into the cytosol [18]. Analogous with myocardial Ca 2+ handling, ROS play an important role as signalling molecules in cell physiology and pathophysiology. However, during I/R-injury, uncontrolled ROS production leads to sarcolemmal damage by lipid peroxidation, modification of protein structure and mitochondrial dysfunction [19]. In particular the application of exogenous ROS to cardiomyocytes induces similar metabolic and physiological alterations including energy depletion, contracture development, reduced contractile function and Ca 2+ overload [20]. Therefore, ROS are strongly implicated in the pathogenesis of I/R-injury. However, in animal studies, ROS-scavenging during I/R-injury has reported negative results and to date the clinical use of antioxidant therapy during I/R-injury has failed to show any beneficial effects. Furthermore, as Ca 2+ overload can increase ROS production [21] and ROS production promotes Ca 2+ overload [20], the exact relationship and contribution of ROS and Ca 2+ overload to I/R-injury remains to be established. Ischaemic preconditioning (classical preconditioning) Many experimental and clinical studies are focused on the development of cardioprotective strategies in order to protect the heart against the adverse sequelae of myocardial ischaemia and subsequent reperfusion. Interestingly, the heart can resist brief ischaemic 556 neth j crit care • volume 10 • no 5 • october 2006
netherlands journal of critical care periods remarkably well and Verdouw et al. (1979) show that repeated brief ischaemic periods favourably alter myocardial energy metabolism [22], whereas Basuk et al. (1986) suggest the possible cardioprotective effect of repeated brief ischaemic periods [23]. The phenomenon of ischaemic preconditioning (IPC) was introduced by Murry et al. (1986) who showed that four five-minute cycles of ischaemia reduced the infarct size after prolonged I/R-injury [24]. The cardioprotective effect of the preconditioning stimulus lasted for about 2 to 4 hours but thereafter protection was reduced [25]. Interestingly, 24 hours after the initial preconditioning stimulus the heart again developed an increased resistance to I/R-injury [26]. The delayed preconditioning response lasts for about 72 hours and this phenomenon is referred to as the ‘second window of protection’. These observations clearly suggest that the myocardium possesses endogenous protective mechanisms, which have been demonstrated in a variety of experimental studies. Due to the potential benefit of an effective clinical cardioprotective strategy, the underlying cellular mechanisms of cardioprotection have been extensively studied and the subject of many reviews [27,28]. Inhibitory G-protein coupled receptor agonists, like adenosine, bradykinin, norepinephrin, opioids, angiotensin and endothelin, can trigger preconditioning of the myocardium. In addition, ROS, NO and Ca 2+ are also able to trigger cardioprotection. Several protein kinases are recognised as important mediators of the protective response: these include protein kinase C (PKC), tyrosine kinases (TK), mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3-kinase). The contribution of the mitoK + ATP channels to preconditioning is complex, as opening of the mitoK + ATP channels is involved as a trigger and mediator in the cardioprotective signalling cascade. In addition, of the possible endeffectors, it has been suggested that the mitoK + ATP channels might be involved in the preservation of mitochondrial function [29]. However, the interaction of the various intracellular signalling pathways during cardioprotection is complex and the exact mechanism and definition of end-effector proteins remain to be elucidated Anaesthetic-induced preconditioning As long ago as 1976, Bland and Lowenstein described the beneficial effects of halothane on the severity of the ischaemic injury [30]. Subsequently, Davis et al. (1983) reported that halothane pretreatment reduced infarct size after I/R-injury [31]. Following the introduction of the concept of ischaemic preconditioning by Murry et al. in1986, [24], further extensive research on the mechanism of anaesthetic-induced protective signalling was carried out and has been summarised in several recent reviews [1,32,33]. In a number of experimental studies halothane, enflurane, isoflurane and sevoflurane were shown to reduce infarct size after I/R [34,35,36]. In addition to a reduction of cardiomyocyte cell death, several studies show that volatile anaesthetics also improve postischaemic contractile function [2,37]. Like ischaemic preconditioning, volatile anaesthetics also induce a second window of cardioprotection [38]. Finally, in several experimental studies, the application of volatile anaesthetics solely during reperfusion was also shown to reduce infarct size [39]. Only two minutes of sevoflurane exposure during reperfusion maximally protected the myocardium [40], and therefore mimics the recently reported phenomenon of postconditioning by brief ischaemic periods during reperfusion [41]. The exact mechanism of cardioprotection afforded by volatile anaesthetics remains unresolved, however the protective effect seems to rely on the same intracellular signalling pathways involved in ischaemic preconditioning, including protein kinase C (PKC), ROS and mitoK + ATP channels. Figure 2 shows the cardioprotective signalling pathways involved in anaesthetic-induced cardioprotection. In addition to ROS, PKC and mitoK + ATP channels, volatile anaesthetic-induced cardioprotective signalling seems to rely on a variety of other signalling molecules. These include G-protein-coupled receptors (adenosine receptor [42], opioids receptor [43] and α- and β-adrenoreceptors [44]), G-proteins [45] in addition to other kinasedependent pathways like the phosphatidylinositol-3-kinase (PI3kinase)/protein kinase B (PKB) signalling pathway [46], nitric oxide (NO) synthase/NO/cyclic guanine monophosphate (cGMP)/protein kinase G (PKG)-pathway [45] and protein tyrosine kinase signalling pathway [47]. Currently, the exact interaction between the different protective signalling pathways remains unclear. Mechanisms of protection: end-effector proteins The end-effector mechanisms that indeed result in cardioprotective activity induced by volatile anaesthetics remain unknown and the subject of speculation. However, reduction of cellular Ca 2+ overload, ROS production and preservation of mitochondrial function have been associated with improved contractility, improved metabolic function and a reduction of infarct size, and may form the main endeffector targets for cardioprotective signalling pathways. Reduced cellular Ca 2+ loading due to volatile anaesthetics has been attributed to the depressant effects on the various elements of the myocardial Ca 2+ homeostasis (see: “effect of anaesthetics on excitation-contraction coupling”). In contrast to elevation of ROS during anaesthetic preconditioning, ROS production during and after I/R has been demonstrated to be reduced in preconditioned hearts and may contribute to anaesthetic-induced cardioprotection [48]. During ischaemia and reperfusion the mitochondria were demonstrated to be the major source of ROS [49], and therefore preservation of mitochondrial bioenergetics is the suggested underlying mechanism for reduced production of ROS in preconditioned hearts. Finally, several other mechanisms which may provide cardioprotection have been proposed. These include reduced membrane damage, reduced cytoskeletal fragility, reduced Ca 2+ sensitivity (thereby preventing hypercontracture), preservation of cardiac (SR) Ca 2+ handling and a reduced activation of pro-apoptotic signalling pathways [27,50,51,52]. Clinical implications Despite the interesting progress on the mechanism of cardioprotective signalling in experimental animal studies, the most important question is whether the phenomenon of preconditioning can be used in the development of clinical cardioprotective strategies. The phenomenon of ischaemic preconditioning in patients was reported soon after its introduction in animal studies, however, the choice of anaesthetic agent during surgery was generally believed not to influence the occurrence of ischaemic episodes [53]. Nevertheless, in vitro experiments in isolated human atrial trabeculae showed enhanced contractile recovery due to pretreatment with volatile anaesthetics [54]. Interestingly, the cardioprotective signalling cascade seems to rely on similar signal transduction elements as does ischaemic preconditioning such as PKC, ROS as well as mitoK + ATP channels [55,56]. Several clinical studies that focus on the cardioprotective effect of volatile anaesthetics were performed on patients scheduled for coronary artery surgery. As part of their neth j crit care • volume 10 • no 5 • october 2006 557
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