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netherlands journal of critical care Volatile anesthetics PLC PKC K + sarcK + ATP Ca 2+ NCX AdR Gprotein Na + IP3 Ca 2+ DAG ? ROS PKC PKC ETC Mitochondria PKC MAPK mitoK + ATP K + HSP SL •reduced Ca 2+ - overload •reduced oxidative stress •preserved mitochondrial function Cardioprotection •Less necrosis •Less apoptosis •Improved contractile recovery Figure 2 Cardioprotective signalling pathways involved in volatile anaesthetic-induced preconditioning. Central to the volatile anaesthetic-induced cardioprotective signalling cascade is activation of PKC. PKC activation relies on the production of ROS most likely due to direct inhibitory effects of volatile anaesthetics on the mitochondrial respiratory chain. Other activation pathways are also considered to be involved including activation of G-protein coupled receptors, phospholipase C and diacylglycerol. Interestingly, we recently demonstrated that the reverse mode of the Na + /Ca 2+ -exchanger precedes PKC activation, presumably via facilitation of Ca 2+ influx. [8] The exact sequence of events with respect to the NCX and ROS production remains to be elucidated. Among other isoforms, PKC-δ B. Relaxation treatment during surgery, these patients are subjected to myocardial the procedure, since sevoflurane pretreatment or its institution during reperfusion only, did not + provide similar protection [64]. How- ischaemia induced by aortic cross-clamping. Ramsay Na+ K et al. (1994) + Na reported that a volatile anaesthetic-based anaesthesia during cardiopulmonary bypass graft surgery (CABG) reduced the incidence and showed that sevoflurane pretreatment improved LV function, as ATP ever, Julier et al. ATP(2003) NCXincluded 72 patients in a multi-centre study Na + of peri-operative infarction [57]. The first clinical studies evaluating a classical preconditioning stimulus using volatile anaesthetics [65]. In addition, it was elegantly shown in atrial appendages that suggested by reduced Ca 2+ brain natriuretic peptide (BNP) plasma levels showed a slight reduction in the plasma markers of necrosis (troponin I and creatinine kinase MB), but failed to reach significance PKC-ε to the intercalated disks. However, the patients given sevoflu- after preconditioning, PKC-δ translocated to the sarcolemma and [58,59,60]. However, in the study of Penta de Peppo et al. (1999) the rane were PLB also given significantly more phenylephrine to maintain Ca group of patients anesthetised with enflurane showed evidence 2+ of blood pressure. As α-adrenergic stimulation is cardioprotective due SR SERCA improved contractility of the left ventricle as demonstrated by pressure-area relations [60]. De Hert et al. (2002) were the first to demon- Therefore, the recent study of Fraβdorf et al. (2005) is the first study to the activation of PKC, these observations might be biased [66]. strate that patients receiving sevoflurane during coronary artery surgery had a better post-surgical cardiac function and reduced plasma plasma levels significantly, indicating a reduction of myocardial ne- to show that sevoflurane Ca 2+ pretreatment can reduce postoperative TnI levels of TnI compared to patients subjected to an intravenous anaesthetic regimen [61]. In subsequent studies, they showed that these The phenomenon of cardioprotection by volatile anaesthetics crosis [67]. beneficial effects could also be detected in high risk patients with may be relevant to clinical practice, as at present patients are anaesthetised with this group of anaesthetics as part of daily practice. In- reduced cardiac function [62] and they found that anaesthesia SL with sevoflurane reduced the length of stay in the ICU and in hospital on terestingly, other commonly used anaesthetic agents such as propofol and opioids have also been reported to exert cytoprotective effects comparison with propofol anaesthesia [63]. It was advocated that the volatile anaesthetic should be given throughout the entire duration of [68], but the clinical cardioprotective effect of propofol - when com- NCX and PKC-ε have been considered most important. However, in isolated trabeculae PKC-α activation also seemed to be involved in the preconditioning cascade (unpublished observations). After activation PKC translocate towards several subcellular structures, like the mitochondra, sarcolemma, intercalated disks and the cytoskeleton and modifying protein function due to phosphorylation. Although down-stream signalling targets remain to be elucidated, ATP-sensitive mitochondrial K + (mitoK + ATP ) channels, ATP-sensitive sarcolemmal K + (sarcK + ATP ) channels, sarcoplasmic reticulum and heat shock proteins are considered to be potential candidates. The opening of mitoK + ATP channels is considered a possible end-effector via preservation of mitochondrial bioenergetics. However, RyR additional ROS production in response to channel opening is considered to participate as possible feed forward mechanism in further amplification of the cardioprotective signalling cascade. Other possible end-effects are shortening of the action potential due to sarcK + ATP-opening, heat shock protein-induced stabilisation of the cytoskeleton and preserved sarcoplasmic reticular function. AdR = adenosine receptor, PLC = phospholipase C, DAG = diacylglycerol, IP3 = inositol triphosphate, ROS = reactive oxygen species, ETC = electron transport chain, PKC = protein kinase C, mitoK + ATP = ATP-sensitive mitochondrial K + channels, sarcK + ATP = ATP-sensitive sarcolemmal K + channels, MAPK = mitogen activated protein kinase, HSP = heat shock protein, NCX = Na + /Ca 2+ -exchanger. Mitoc hondria 558 neth j crit care • volume 10 • no 5 • october 2006
netherlands journal of critical care pared to volatile anaesthetics - seems to be limited [61]. Interestingly, in experimental studies morphine was shown to enhance the efficacy of the cardioprotective response induced by volatile anaesthetics thus providing important clinical therapeutic options [43]. These observations may significantly contribute to the development of balanced anaesthesia techniques. Furthermore, it may be interesting to speculate how the anaesthesia technique may even exceed the purpose of cardioprotection and be extended to modulate the general response to surgical stress, thereby protecting several organ systems. It is interesting to realise that the choice of anaesthetic regimen can modify the cytokine production in response to surgery [69], and therefore the protection afforded may extend beyond the operating room. Interestingly, the observation that sevoflurane favourably alters the haemodynamic profile in septic rats (unpublished observations) may suggest that the choice of anaesthetics could influence the management of septic patients not only in the operating room but also in the intensive care unit. However, taking existing controversies upon the clinical induction of protection by anaesthetics into consideration, the need for large well-designed multi-centre trials in order to develop effective clinical cardioprotective strategies has been stressed by various investigators [70,71]. Future directions The clinical relevance of preconditioning may be questioned for several reasons. Preconditioning-induced cardioprotection is elicited by applying a preconditioning stimulus before ischaemia and reperfusion will occur. In clinical practice, the occurrence of ischaemic episodes may often not be predicted. This is the reason that many investigators now focus on postconditioning, thereby applying the protective stimulus during the reperfusion phase. Recently, it was shown that brief ischaemic periods during the initial minutes of reperfusion afford the same amount of protection compared to preconditioning. Zhao et al. (2003) defined this phenomenon as ‘postconditioning’, although the beneficial effects of volatile anaesthetics during reperfusion have already been described in earlier studies [72,73]. Postconditioning seems to depend on similar signalling pathways to preconditioning, and was recently demonstrated to be cardioprotective in a clinical study performed by Staat et al. (2005) [74]. This study may be an important step in the development of clinical cardioprotective strategies that can be applied after the ischaemic phase. Preconditioning has been called a phenomenon of the healthy heart, as several studies have shown that the diseased heart is not effectively protected by preconditioning [75]. This is disappointing as diseased myocardium would benefit most from cardioprotective measures. Several studies aim to address this issue, however, our understanding remains limited. Therefore, studies with specific focus on the mechanism of cardioprotection in the diseased heart would greatly enhance the clinical potential. Finally, to date the use of volatile anaesthetics has mostly been limited to the operating theatre as most ICU ventilators do not meet the technical requirements for the safe application of these agents. Environmental pollution and the risk of occupational exposure have prevented the routine use of volatile anaesthetics in the ICU. Therefore, suitable ventilator systems that limit the risk of occupational exposure have to be developed in order to benefit from the protection of volatile anaesthetics in the ICU. Recent progress on volatile anaesthetic delivery systems for the ICU, such as the volatile anaesthetic reflection filter (AnaConDa ® ), are promising developments [76]. In summary, the past two decades of cardiac research have greatly improved our understanding on the interaction of volatile anaesthetics and the ischaemic heart. This group of anaesthetics has been shown to trigger distinct cardioprotective signalling cascades, which provide the heart with an increased resistance to ischaemic episodes. Despite the increased understanding of the mechanisms responsible, our knowledge has to be extended in order to implement in the clinical situation. However, the results remain promising, and suggest a possible new therapeutic action for volatile anaesthetics. References 1. Weber,NC and Schlack,W. The concept of anaestheticinduced cardioprotection: mechanisms of action. Best Pract Res Clin Anaesthesiol 2005;19:429-443. 2. de Ruijter,W, Musters,RJP, Boer,C, Stienen,GJM, Simonides,WS, de Lange,JJ. The Cardioprotective Effect of Sevoflurane Depends on Protein Kinase C Activation, Opening of Mitochondrial K+ATP Channels, and the Production of Reactive Oxygen Species. Anesth Analg 2003;97:1370-1376. 3. Bouwman,RA, Musters,RJ, Beek-Harmsen,BJ, De Lange,JJ, Boer,C. Reactive oxygen species precede protein kinase C-delta activation independent of adenosine triphosphate-sensitive mitochondrial channel opening in sevoflurane-induced cardioprotection. Anesthesiology 2004;100:506-514. 4. Gordon,AM, Regnier,M, Homsher,E. Skeletal and cardiac muscle contractile activation: tropomyosin “rocks and rolls”. News Physiol Sci 2001;16:49-55. 5. Hanley,PJ, ter Keurs,HE, Cannell,MB. Excitationcontraction coupling in the heart and the negative inotropic action of volatile anesthetics. Anesthesiology 2004;101:999-1014. 6. Hannon,JD and Cody,MJ. Effects of volatile anaesthetics on sarcolemmal calcium transport and sarcoplasmic reticulum calcium content in isolated myocytes . Anesthesiology 2002;96:1457-1464. 7. Haworth,RA and Goknur,AB. Inhibition of sodium/calcium exchange and calcium channels of heart cells by volatile anesthestics. Anesthesiology 1995;82:1255-1265. 8. Bouwman,RA, Salic,K, Padding,G, Eringa,EC, van Beek- Harmsen,BJ, Matsuda,T, et al. Cardioprotection via activation of protein kinase C-δ depends on modulation of the reverse mode of the Na+/Ca2+-exchanger. Circulation (Surgical Supplement) 2006; accepted for publication. 9. Hanley,PJ and Loiselle,DS. Mechanisms of force inhibition by halothane and isoflurane in intact rat cardiac muscle. J Physiol 1998;506 ( Pt 1):231-244. 10. Davies,LA, Gibson,CN, Boyett,MR, Hopkins,PM, Harrison,SM. Effects of isoflurane, sevoflurane, and halothane on myofilament Ca2+ sensitivity and sarcoplasmic reticulum Ca2+ release in rat ventricular myocytes. Anesthesiology 2000;93:1034-1044. 11. Graham,MD, Bru-Mercier,G, Hopkins,PM, Harrison,SM . Transient and sustained changes in myofilament sensitivity to Ca2+ contribute to the inotropic effects of sevoflurane in rat ventricle. Br J Anaesth 2005;94:279- 286. 12. Kloner,RA and Jennings,RB. Consequences of brief ischaemia : stunning, preconditioning, and their clinical implications: part 1. Circulation 2001;104:2981-2989. 13. Jennings,RB, Murry,CE, Steenbergen,C, Jr., Reimer,KA. Development of cell injury in sustained acute ischaemia . Circulation 1990;82:II2-12. 14. Schafer,C, Ladilov,Y, Inserte,J, Schafer,M, Haffner,S, Garcia-Dorado,D, et al. Role of the reverse mode of the Na+/Ca2+ exchanger in reoxygenation-induced cardiomyocyte injury. Cardiovasc Res 2001;51:241-250. 15. Vanden Hoek,TL, Li,C, Shao,Z, Schumacker,PT, Becker,LB. Significant levels of oxidants are generated by isolated cardiomyocytes during ischaemia prior to reperfusion . J Mol Cell Cardiol 1997;29:2571-2583. 16. Kevin,LG, Novalija,E, Riess,ML, Camara,AKS, Rhodes,SS, Stowe,DF. Sevoflurane Exposure Generates Superoxide but Leads to Decreased Superoxide During Ischaemia and Reperfusion in Isolated Hearts. Anesth Analg 2003;96:949-955. 17. Piper,HM, Garcia-Dorado,D, Ovize,M. A fresh look at reperfusion injury. Cardiovasc Res 1998;38:291-300. 18. Logue,SE, Gustafsson,AB, Samali,A, Gottlieb,RA. Ischaemia /reperfusion injury at the intersection with cell death. J Mol Cell Cardiol 2005;38:21-33. 19. Kim,MS and Akera,T. O2 free radicals: cause of ischaemia -reperfusion injury to cardiac Na+-K+-ATPase. Am J Physiol 1987;252:H252-H257. 20. Goldhaber,JI and Qayyum,MS. Oxygen free radicals and excitation-contraction coupling. Antioxid Redox Signal 2000;2:55-64. 21. Lazou,A, Seraskeris,S, Tsiona,V, Drossos,G. Oxidative status and anti-oxidant enzyme activity during calcium paradox in the rat isolated heart. Clin Exp Pharmacol Physiol 2000;27:160-166. 22. Verdouw,PD, Remme,WJ, de Jong,JW, Breeman,WA. Myocardial substrate utilization and hemodynamics following repeated coronary flow reduction in pigs. Basic Res Cardiol 1979;74:477-493. 23. Basuk,WL, Reimer,KA, Jennings,RB. Effect of repetitive brief episodes of ischaemia on cell volume, electrolytes and ultrastructure. J Am Coll Cardiol 1986;8:33A-41A. neth j crit care • volume 10 • no 5 • october 2006 559
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