1 Institute of Anaesthesiology, University Hospital Zurich, Zurich, Switzerland. 2 Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
Corresponding author: E-mail: michael.zaugg@usz.ch
Abstract
Cardiac preconditioning represents the most potent and consistently reproducible method of rescuing heart tissue from undergoing irreversible ischaemic damage. Major milestones regarding the elucidation of this phenomenon have been passed in the last two decades. The signalling and amplification cascades from the preconditioning stimulus, be it ischaemic or pharmacological, to the putative end-effectors, including the mechanisms involved in cellular protection, are discussed in this review. Volatile anaesthetics and opioids effectively elicit pharmacological preconditioning. Anaesthetic-induced preconditioning and ischaemic preconditioning share many fundamental steps, including activation of G-protein-coupled receptors, multiple protein kinases and ATP-sensitive potassium channels (KATP channels). Volatile anaesthetics prime the activation of the sarcolemmal and mitochondrial KATP channels, the putative end-effectors of preconditioning, by stimulation of adenosine receptors and subsequent activation of protein kinase C (PKC) and by increased formation of nitric oxide and free oxygen radicals. In the case of desflurane, stimulation of - and ß-adrenergic receptors may also be of importance. Similarly, opioids activate
- and
-opioid receptors, and this also leads to PKC activation. Activated PKC acts as an amplifier of the preconditioning stimulus and stabilizes, by phosphorylation, the open state of the mitochondrial KATP channel (the main end-effector in anaesthetic preconditioning) and the sarcolemmal KATP channel. The opening of KATP channels ultimately elicits cytoprotection by decreasing cytosolic and mitochondrial Ca2+ overload.
Br J Anaesth 2003; 91: 55165
Keywords: anaesthesia, perioperative; heart, cardiac preconditioning, cardioprotection
The heart possesses a remarkable ability to adapt to stress by changing its phenotype in a manner that makes it more resistant to further damage. Verdouw and colleagues111 and Reimer and colleagues89 reported favourable ATP handling in response to brief episodes of ischaemia. In 1986, Murry and colleagues69 described, for the first time, the phenomenon of ischaemic preconditioning in canine myocardium. Subjecting hearts to four brief ischaemic episodes (ligation of the circumflex coronary artery) interspersed with 5-min periods of reperfusion before a prolonged 40-min ischaemic insult reduced myocardial infarct size from 30% to only 7% of the area at risk. Since then, this potent endogenous protective mechanism has been confirmed in almost all species, including the mouse, rat, guinea-pig, rabbit, dog, pig and, at least indirectly, the human (reviewed by Przyklenk and Kloner).87 Moreover, ischaemic preconditioning was consistently observed in single cells,60 in superfused myocardial samples,112 in the whole heart and in all types of in vivo experiments. A few years later, in 1993, Marber and colleagues61 and Kuzuya and colleagues49 described another remarkable phenomenon, called late preconditioning, which reflects a second delayed window of protection 1272 h after initiation of preconditioning.
Under most experimental conditions, preconditioning not only reduces infarct size but also alleviates post-ischaemic cardiac dysfunction and arrhythmias. The possibility of an effective clinical use for this innate cardioprotective mechanism has generated enormous interest (more than 3000 articles published). It has elucidated the underlying signalling pathways, with the final aim of mimicking the preconditioned state and its benefits by means of pharmacological agents. Pharmacological preconditioning, in place of ischaemia, may represent a safer way of eliciting protection, particularly in the diseased myocardium. Two anaesthesia research groups (Cason and colleagues9 and Kersten and colleagues42) independently described the preconditioning-mimicking effects of isoflurane for the first time in 1997. However, infarct-limiting properties of halothane and isoflurane were reported as early as 1983 and 1989 respectively by Davis and colleagues.18 19 Subsequent extensive experimental work aimed at elucidating the complex signalling cascade involved in anaesthetic-induced preconditioning. Today, we know that most anaesthetics elicit, enhance or inhibit preconditioning.119 Unlike most other preconditioning-inducing agents, which must be administered directly into the coronary arteries to be effective, anaesthetics can be administered non-selectively with relatively low toxicity. Anaesthetic-mediated or -facilitated cardiac preconditioning around the stressful time of surgery would be particularly beneficial in high-risk cardiac patients.
Mechanisms of cardiac preconditioning
Definition and time course of preconditioned states
The classic or early preconditioned state of cardiac tissue is an immediate consequence of multiple brief episodes of sublethal cardiac ischaemia, and is defined as a state of marked protection against subsequent prolonged ischaemia. While multiple, brief antecedent ischaemic episodes may have additive effects,91 too many repetitive stimuli abolish the protection.37 Of note, preconditioning per se does not prevent myocardial cell death, but significantly delays its occurrence during the first 23 h of sustained ischaemia (temporal limitation of protection). Although the gold standard end-point for assessing the preconditioned state and its protection is the reduction in infarct size, preconditioning also improves post-ischaemic functional recovery and decreases arrhythmogenicity in many experimental approaches. Improved preservation of ATP reserves and attenuated ST-segment alterations in the ECG, though considered to be surrogate markers of effective cardiac protection, are highly species-dependent and therefore may not serve as valid markers for preconditioning.21 46 The protection elicited by preconditioning is typically present immediately after the stimulus, but vanishes after 23 h (classic or early preconditioning).87 Additional, though less pronounced, protection occurs 1224 h after the initial preconditioning stimulus and lasts for up to 72 h (second window of protection or late/delayed preconditioning).6 Consistent with this delayed type of protection, late preconditioning is dependent on de novo synthesis of cardioprotective proteins. In contrast to most classic or early preconditioning models, late preconditioning consistently protects against stunning.100 Lastly, and most importantly, a multitude of additional stressful stimuli (apart from ischaemia), including oxidative (hyperoxia), mechanical (stretch),75 electrical (rapid pacing), thermal and chemical (hormonal, ionic (calcium)66 and pharmacological) stressors, can induce the same archetypal early and late protective response in cardiac tissue.
Signalling cascades and amplification of the preconditioning stimulus
Receptors
The concept that brief renal, mesenteric or skeletal muscle ischaemia of remote origin can effectively precondition the heart is consistent with humoral induction of the preconditioned state (remote preconditioning) (reference 116 and references therein). Also consistent with this notion is the fact that regional cardiac ischaemia can initiate global protection and render remote myocardium resistant to infarction (preconditioning at a distance).86 Ischaemic preconditioning is mediated via several sarcolemmal receptors, which are mostly linked to inhibitory G-protein (Gi),72 namely adenosine (A-1, A-3), purinoceptors (P2Y), endothelin (ET1), acetylcholine (M2), 1- and ß-adrenergic, angiotensin II (AT1), bradykinin (B2) and opioid (
1,
) receptors, which couple to a highly complex network of kinases (for review see reference 3). The involvement of many receptors or triggers in mediating preconditioning reflects the biological redundancy in this life-saving signal transduction pathway. The importance of the individual receptors depends heavily on the species and the preconditioning stimulus itself.103 The main signalling steps and components of early and delayed preconditioning are summarized schematically in Figure 1.
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Specific aspects
Adenosine is considered to be one of the most relevant triggers of early and late preconditioning.87 Adenosine is released from cells in the ischaemic zone by upregulation of ectosolic or membrane-associated 5'-nucleotidase (responsible for adenosine phosphate ester dephosphorylation)44 and activates the respective receptors on cardiomyocytes in an autacoid manner. A3 receptor-initiated protection seems to last longer than A1 receptor-initiated protection, which may be explained by the differential coupling of the A1 receptor to phospholipase C and the A3 receptor to phospholipase D.12 Consistent with the pivotal role of adenosine, Haedrick and colleagues28 reported marked cardioprotection against ischaemia in murine hearts overexpressing A1 receptors. Adenosine may be less important as an effective preconditioning trigger in the rat heart model,54 where -adrenergic receptors (mainly
1B) play a major role.36 In contrast, in rabbit and canine hearts
-adrenergic receptor agonists abolish preconditioning. These observations support the concept that multiple receptor systems of varying importance can contribute to cardioprotection in different animal models (Fig. 1).
ROS are important intracellular signalling molecules and are increased during sublethal oxidative stress (preconditioning stimulus). They play a pivotal role in triggering early and delayed cardioprotection and are probably derived from mitochondria.13 ROS activate phospholipase C and PKC, which, in turn, amplify the preconditioning stimulus. Murry and colleagues70 first demonstrated that administration of radical scavengers blocks the beneficial effects of early ischaemic preconditioning. Evidence for an essential role of ROS in the establishment of late preconditioning was reported by Sun and colleagues.100 Thus, generation of ROS during the initiation of preconditioning represents an essential trigger for early and delayed cardioprotection.
NO is able to induce a cardioprotective effect against myocardial stunning and infarction. Recent studies provided direct evidence of enhanced biosynthesis of NO in the myocardium subjected to brief episodes of ischaemia and reperfusion, probably via increased (endogenous constitutive) NOS activity.7 Although most studies indicate that endogenous NO is not necessary for ischaemia-induced early preconditioning, exogenous or pharmacologically increased endogenous NO production elicits an early preconditioning effect (i.e. NO is sufficient but not necessary for early preconditioning).7 Conversely, NO has an obligatory role in late preconditioning.27
Late or delayed preconditioning (delayed acquisition of tolerance to ischaemia)
In contrast to early preconditioning, late preconditioning requires NO formation and increased synthesis of protective proteins (for detailed review see reference 7). Again, PKC and multiple kinases are involved in the signalling cascade, leading to activation of several transcription factors, such as nuclear factor-B (NF-
B), which leads to the sustained expression of a number of proteins thought to be responsible for the delayed protection phase (right part of Fig. 1). Disruption of the inducible NOS (iNOS) gene completely abrogates the delayed infarct-sparing effect, which points to the obligatory role of inducible NOS in the cardioprotection afforded by delayed preconditioning.27 Because of the dominant role of NO, late preconditioning is viewed as a state of enhanced NO synthesis, NO acting as a trigger (produced by constitutive NOS) initially and subsequently as an effector (produced by inducible NOS). The most likely cardioprotective effects of NO in late preconditioning are: (i) inhibition of Ca2+ influx; (ii) antagonism of ß-adrenergic stimulation; (iii) reduced contractility and myocardial oxygen consumption; (iv) opening of KATP channels; (v) antioxidant actions; and (vi) activation of COX-2 with the synthesis of prostanoids. Other enzymes associated with delayed protection are aldose reductase, which catalyses sorbitol to glucose and detoxifies ROS-derived lipid aldehydes, manganese superoxide dismutase (MnSOD), and the anti-apoptotic protein Bcl-2. Biosynthesis of heat shock proteins (Hsp27, Hsp70) is not increased, but this family of protective proteins is subject to post-translational modification.17 Recent findings also indicate that activation of mitochondrial KATP channels plays a role in delayed protection, as 5-hydroxydecanoate (a specific mitochondrial KATP channel blocker), administered immediately before sustained ischaemia, can inhibit protection elicited 24 h after the initial preconditioning stimulus.5
Pharmacology of sarcolemmal and mitochondrial KATP channels, the putative end-effectors of preconditioning
Cardiomyocytes have two distinct types of KATP channels, one located in the surface membrane and another in the inner mitochondrial membrane (Figs 1 and 2) (for review see reference 26). Preconditioning can be pharmacologically mimicked by KATP channel openers and abolished by KATP channel inhibitors (Table 1). Sarcolemmal KATP channels are colocalized (i.e. physically bound)15 with the creatine phosphatecreatine kinase system and provide a direct link between the metabolic state and cellular excitability. Mitochondrial KATP channels regulate mitochondrial volume state, mitochondrial membrane potential, formation of ROS and energy production. The molecular structure of mitochondrial KATP channels is largely unknown. In contrast, sarcolemmal KATP channels are composed of hetero-octamers of four pore-forming subunits (four Kir6.1 or Kir6.2 subunits form an inward-rectifying K+ channel with a conductance of 80 pS) and four sulfonylurea receptors (SUR1, SUR2A or SUR2B). The most common expression pattern of sarcolemmal KATP channels is Kir6.2/SUR1 in the pancreas, Kir6.1/SUR2B and Kir6.2/SUR2B in vascular smooth muscle, and Kir6.2/SUR2A in the heart. Kir6.2/SUR2A is responsible for the early depolarization in ischaemic heart tissue, which represents the basis for the clinically observed injury current of ischaemia (molecular basis of ischaemic ECG ST-segment changes).53
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How might the KATP channels modulate infarct size?
The cellular consequences of the opening of the KATP channels are depicted in Figure 2AC.
Sarcolemmal KATP channels
Although the intracellular Ca2+ transients for contraction and relaxation are governed mainly by the Ca2+ pump (SERCA2) and the ryanodine Ca2+-release channel (RYR) in the sarcoplasmic reticulum, a significant amount of the cytosolic Ca2+ is recruited from the extracellular space, mainly via the Na+/Ca2+ exchanger and the voltage-gated L-type Ca2+ channels (Fig. 1). Membrane hyperpolarization, by the opening of sarcolemmal KATP channels, as in cardioplegia, may shorten action potential duration (Fig. 2C). As a consequence, less Ca2+ enters the myocytes from outside and attenuates Ca2+ overload.
Mitochondrial KATP channels
Three main concepts, which do not exclude, but rather complement, each other, are currently under investigation (Fig. 2). According to Marbán and his group, opening of the mitochondrial KATP channel leads to depolarization of the inner mitochondrial membrane.68 Uncoupling of mitochondria and increased formation of ROS have been reported previously.22 Although this change is modest, it has a significant effect on mitochondrial Ca2+ load because of the non-linear dependence of Ca2+ flux on the membrane potential. It is hypothesized that depolarization of the inner mitochondrial membrane (by 12% at a diazoxide concentration of 10 µmol litre1, corresponding to a change from 200 to 176 mV) attenuates mitochondrial Ca2+ accumulation by lowering the driving force for Ca2+ uptake. The decreased mitochondrial Ca2+ overload during ischaemia114 may prevent opening of the mitochondrial permeability transition pores and guarantee optimal conditions for ATP production.35 Conversely, mitochondrial matrix contraction (30%) and intermembrane space expansion is a direct consequence of anoxic blockade of electron transport during ischaemia (Fig. 2B). While mitochondrial K+ influx ceases (a compensatory consequence of the H+ pumping from the matrix into the intermembrane space), mitochondrial K+ efflux (K+/H+ antiporter) continues until a new equilibrium at a lower matrix volume is reached. This leads to dissociation of the mitochondrial creatine kinase octameric complex from the outer and inner membranes.51 Garlid and colleagues now propose that opening of the mitochondrial KATP channel decreases the ischaemia-induced swelling of the mitochondrial interspace, which would preserve functional coupling between adenosine nucleotide translocase and mitochondrial creatine kinase (preservation of structure/function).47 51 This, in turn, secures the transport of newly synthesized ATP from the site of production by ATP synthase on the inner mitochondrial membrane to the cytosol. Thus, both mechanisms contribute to an uninterrupted supply of high-energy phosphate substrates from the mitochondria to the sites of energy consumption. A third possibility for the means by which mitochondrial KATP channels may elicit protection is based on the observation of the increased formation of ROS (generation of a pro-oxidant environment probably derived from the cytochrome b-c1 segment of complex III of the respiratory chain).22 Pain and colleagues78 demonstrated that diazoxide is protective even if it is only present before (rather than during) the sustained ischaemia, which implies that mitochondrial KATP channel opening would serve as a trigger of preconditioning, but would not mediate cardioprotection per se (effector). According to this concept, ROS (or the intracellular redox state) would stimulate the activation of multiple transcriptional factors (NF-
B, activator protein-1, hypoxia- inducible factor, protein kinases, protein phosphatases and various ion channels (Ca2+/K+/Na+ channels, Na+/Ca2+ or Na+/H+ exchanger)), ultimately leading to cardioprotection.
Other mechanisms involved in cardiac preconditioning
In whole-organ preparations and in vivo experiments, preconditioning protection is also attributable to the protective effects on the endothelium of the coronary vasculature,52 the inhibition of platelet aggregation34 and leucocyte adhesion.43 Thus, the benefits of preconditioning clearly extend beyond the cardiomyocyte.
Anaesthetic-induced preconditioning
Preconditioning can be pharmacologically elicited by anaesthetics. Volatile anaesthetics, opioids and a small group of anaesthetics primarily used in animal experiments were found to induce or enhance preconditioning in cardiac tissue. Table 2 summarizes the effects of these anaesthetics on mitochondrial and sarcolemmal KATP channels. Current knowledge about anaesthetic-induced preconditioning from in vitro systems and animal experiments will now be discussed. Evidence for anaesthetic-induced preconditioning in humans will be presented in Part II of this review.118
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Key signalling components involved in preconditioning elicited by volatile anaesthetics were unravelled recently by means of specific blockers for signalling steps (Fig. 3). Using an in vivo rabbit model with regional ischaemia combined with a Langendorff model, Cope and colleagues14 showed that 8-sulfophenyl theophylline, a non-specific adenosine receptor blocker, inhibited the preconditioning effect of halothane. The effect was also inhibited by chelerythrine, a highly specific PKC blocker. Similarly, high doses of bisindolylmaleimide, a PKC inhibitor, blocked isoflurane-enhanced recovery of canine stunned myocardium.107 Isoflurane and halothane are known to affect PKC activity. PKC-induced coronary vasoconstriction is inhibited by halothane, but enhanced by isoflurane.79 Another study indicated that neither isoflurane nor halothane inhibited PKC-induced alterations in coronary vascular tone.76 As in Copes study,14 Cason and colleagues9 demonstrated in an in vivo rabbit model with regional ischaemia that 8-sulfophenyl theophylline could inhibit isoflurane-mediated preconditioning. In a dog model of regional ischaemia, Kersten and colleagues41 reported that the effects of isoflurane on post-ischaemic recovery were partially inhibited by 8-cyclophenyl-1,3-dipropylxanthine, an adenosine 1-specific receptor blocker. In this study, isoflurane-induced protection was associated with decreases in endogenous adenosine release, which is the opposite of what is observed in ischaemic preconditioning. A1 receptors were also found to mediate protection in isoflurane- but not halothane-treated human atrial trabecular strips31 and myocytes.90 Toller and colleagues105 reported the important role of Gi-proteins in establishing the isoflurane-induced preconditioned state by showing complete blockade of preconditioning in response to pertussis toxin before treatment in an in vivo dog model of regional ischaemia. The significance of all these signalling components could be confirmed at the cellular level using adult rat ventricular myocytes.120
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Results from patch-clamp experiments demonstrated either an increased open probability of the sarcolemmal KATP channel for a given ATP concentration in response to isoflurane but inhibitory effects on overall channel activity (excised patch configuration),30 or no effect on sarcolemmal KATP channel activity at all (whole-cell and excised patch configuration).24 90 In contrast to isoflurane, halothane inhibits the sarcolemmal KATP channel in human90 and guinea-pig myocytes.50 Isoflurane facilitates cardiac sarcolemmal KATP channels preactivated by the non-specific KATP channel opener pinacidil,50 the PKC activator phorbol 12,13-dibutyrate and the metabolic inhibitor 2,4-dinitrophenol,24 indicating a priming effect of these agents on this channel. Two recent studies addressed the effect of volatile anaesthetics on mitochondrial KATP channels. In both studies, myocyte-inherent flavoprotein-induced fluorescence (autofluorescence) was used to measure mitochondrial KATP channel activity. Marbán and his group93 showed that the redox state of these endogenous fluorophores directly reflected mitochondrial KATP channel activity, and that the opening of this channel was closely associated with significant protection against ischaemia. Kohro and colleagues45 demonstrated in guinea-pig myocytes that mitochondrial KATP channel activity was increased by 10% when exposed to isoflurane 0.7 mM or sevoflurane 1 mM. Administration of propofol or pentobarbital abrogated this effect. However, the concentrations used in these experiments were high (23 vol/vol % for isoflurane and 45 vol/vol % for sevoflurane, corresponding to more than 2 MAC isoflurane or sevoflurane at 37°C), and the effect on the mitochondrial KATP channel was small compared with other preconditioning drugs. These observations may reflect toxic effects of volatile anaesthetics on oxidative phosphorylation rather than pharmacologically relevant effects on mitochondrial KATP channels. In the study by Zaugg and colleagues,120 isoflurane and sevoflurane did not elicit increased channel activity per se at lower concentrations, but enhanced diazoxide-induced flavoprotein oxidation. These results support the concept of channel priming by volatile anaesthetics, which was described recently by Sato and colleagues.93 They proposed a resting, primed and open state of the mitochondrial KATP channel on the basis of the observation that adenosine did not affect basal mitochondrial KATP channels but significantly enhanced opening by diazoxide, a highly selective opener of mitochondrial KATP channels. This concept of channel priming (including the sarcolemmal and the mitochondrial KATP channel) also appears to extend to isoflurane- and sevoflurane-induced preconditioning. The primed channel state allows easy and rapid opening at the initiation of ischaemia. In their studies, Zaugg and colleagues120 also presented evidence that volatile anaesthetics mediate their protection by selectively enhancing mitochondrial KATP channels through the triggering of multiple PKC-coupled signalling pathways, namely NO and adenosine/Gi signalling pathways. An overwhelming body of evidence now demonstrates that biosynthesis of NO plays a pivotal role in decreasing ischaemic damage in heart tissue.7 It is not surprising, therefore, that NO and cGMP may be major players in volatile anaesthetic-induced protection. NO/cGMP signalling and basal NOS activity were reported to play a fundamental role in pacing associated-preconditioning in the isolated heart.102 It may well be that volatile anaesthetics differentially modulate the activity of the various isoenzymes of NOS (nNOS, eNOS, iNOS), which are ubiquitous but heterogeneously distributed in myocytes. The observation that isoflurane-induced preconditioning (2% vol/vol) in -chloralose-anaesthetized rabbits is inhibited by free radical scavengers supports the concept that generation of radicals, either by means of altered NO synthesis or by enhanced formation of ROS/NO (possibly by opening mitochondrial KATP channels), is important.67 Recently, desflurane-induced preconditioning was shown to be inhibited by phentolamine (
-adrenergic blockade) and propranolol (ß-adrenergic blockade), which is in accordance with the notion that desflurane releases a significant amount of catecholamines in cardiac tissue.32 It may be that low and high concentrations of volatile anaesthetics activate distinct signalling pathways, resulting in sequential activation of the two KATP channel subtypes. Taken together, these results show that the preconditioning effects of volatile anaesthetics are triggered by multiple signalling cascades and mediated mainly by mitochondrial KATP channels, but sarcolemmal KATP channels may also contribute to the protection elicited by volatile anaesthetics.
The cardioprotective effects of volatile anaesthetics can be enhanced by cariporide, a Na+H+ exchange inhibitor.62 One additional interesting mechanism by which volatile anaesthetics could elicit their protection was described by Piriou and colleagues.84 In this study, the use of gadolinium to block mechano-gated channels, which are activated by isoflurane,80 abolished isoflurane-induced preconditioning. Pre-ischaemic administration of volatile anaesthetics is also known to decrease the incidence of post-ischaemic ventricular arrhythmias, particularly in small animals,8 whereas in larger animals (dogs, pigs) this is more controversial.29 Volatile anaesthetics also vasodilate coronary arteries by activation of endothelium KATP channels,16 increase endothelial-dependent and endothelial-independent post-ischaemic basal coronary flow, and promote endothelial NO release.73 Preserved NO generation also prevents leucocyte adhesion and migration (inflammatory response), and blocks expression of adhesion molecules. One study demonstrated improved vascular endothelial protection if volatile anaesthetics were administered during low-flow perfusion for 1 day at 3°C.97 This indicates significant microvascular protection by volatile anaesthetics. Most recently, pretreatment with isoflurane before cytokine exposure increased the survival of human endothelial and smooth muscle cells, an affect that was abrogated by PKC or KATP channel inhibition.20 Importantly, protective effects by endothelial preconditioning appear to be beneficial for up to 1 month and may apply to a wide variety of tissues, including all vital organs.59
Opioids
The existence of - and
-opioid receptors, but not µ-receptors, has been reported in rat atrial and ventricular tissue.48 In addition, cardiomyocytes constantly release opioids into the circulation, particularly during stressful stimuli, and thereby serve as an endocrine organ.65 Activation of opioid receptors results in a potent cardioprotective effect similar to classical and delayed preconditioning. Currently, it is thought that selective activation of
1 opioid agonists exert this protection via interaction with Gi-proteins and activation of PKC, tyrosine kinases (and possibly other kinases, such as MAPK), and ultimately KATP channels.23 Some studies report opioid-induced preconditioning effects, which are independent of direct receptor stimulation and are mediated solely by free radical formation.81 As with ischaemic preconditioning, activation of
-opioid receptors also protects the heart from arrhythmias. Although the
-opioid receptor is the most prominent receptor subtype in opioid-induced cardioprotection,4 some role for
-receptors cannot be dismissed, particularly in protection against ventricular fibrillation.113 Opioid receptor-mediated protection is stereoselective, as protection can be abolished only by the ()-active stereoisomer of naloxone.11 Using a cellular model of simulated ischaemia in chicken cardiomyocytes, Liang and colleagues55 showed that morphine 1 µM elicited the same protection as preconditioning with 5 min of ischaemia. In this study, morphine effects were abolished by 5-hydroxydecanoate (a specific mitochondrial KATP channel blocker), which again emphasizes the dominant role of mitochondrial KATP channels in preconditioning. Interaction of
-opioid agonists with KATP channels was first shown in neuronal tissue, in which analgesia produced by
-opioid receptor activation could be antagonized by glibenclamide.117 Recently, Zaugg and colleagues119 demonstrated that fentanyl enhanced diazoxide-induced mitochondrial KATP channel activity, which was inhibited by the PKC inhibitor chelerythrine. Again, this observation is consistent with a priming effect of fentanyl on mitochondrial KATP channels. Conversely, in an isolated perfused rat heart model, sufentanil did not improve post-ischaemic recovery, but produced an increase in left ventricular end-diastolic pressure during reperfusion.63 The clinical relevance of opioid-induced cardioprotection is not yet clear. This topic will be discussed in Part II of this review.118
Ethanol-based anaesthetics (chloral hydrate, -chloralose) and urethane
Zaugg and colleagues119 recently showed that 2,2,2-trichloroethanol, a halogenated analogue of ethanol and the active metabolite of chloral hydrate and -chloralose, enhanced mitochondrial KATP channel activity via activation of PKC. Though not commonly used clinically, these two anaesthetics are still used extensively in experimental investigations. The cardioprotective role of ethanol in ischaemiareperfusion has been reported previously. In a cellular model of simulated ischaemia, ethanol mimicked preconditioning by activation of PKC.10 Its preconditioning effects could also be demonstrated in dogs fed chronically with ethanol.77 Zaugg and colleagues119 further reported cardiac preconditioning effects by urethane, mediated by mitochondrial KATP channels in a PKC-dependent manner. As many anaesthetics clearly affect KATP channels (Table 2) and thereby modify preconditioning, investigations into the precise mechanisms of preconditioning need to consider the effects of background anaesthesia. Experimental results need to be interpreted in the light of these findings.
Conclusions
This review summarizes current knowledge about the key cellular events involved in ischaemic and anaesthetic preconditioning. Although many characteristics of anaesthetic preconditioning are similar to ischaemic preconditioning, there may be fundamental differences with respect to signal intensity and the potential to concomitantly harm cardiac tissue. Understanding of the multiple signalling steps and the ultimate cytoprotective mechanisms is an important prerequisite for both the design of future basic research studies and the evaluation of the clinical effects of ischaemic and anaesthetic-induced preconditioning.
Acknowledgements
This work was supported by a grant from the Swiss Society of Anaesthesiology and Resuscitation, Berne, Switzerland, the Myron B. Laver Grant of the Department of Anaesthesia, University of Basle, Switzerland, Grant 3200-063417.00 of the Swiss National Science Foundation, Berne, Switzerland, a grant from the Hartmann-Müller Foundation, Zurich, Switzerland, and a grant from the Swiss Heart Foundation, Berne, Switzerland.
Addendum
During the review process for this article, important studies on basic principles underlying cardiac preconditioning and, in particular, anaesthetic preconditioning were published. The most salient findings of these are briefly summarized here.
Controversy surrounding the main end-effector in early preconditioning: mitochondrial vs sarcolemmal KATP channelsa never-ending story
A recent study by Suzuki and colleagues121 demonstrated loss of diazoxide-mediated post-ischaemic functional improvement in mice lacking the sarcolemmal KATP channels. This study has the following important implications. First, although it cannot be totally excluded that knockout of sarcolemmal KATP channels may artificially increase ischaemic damage and thereby cancel the effect of ischaemic preconditioning, the results of this study reinforce the importance of sarcolemmal KATP channels in the development of cardioprotection in the murine model. Secondly, the findings of this study provide evidence that diazoxide may have significant effects on sarcolemmal KATP channels, questioning its mitochondrial selectivity in some species (mouse vs rat). Finally, results obtained from mouse hearts should not be extrapolated directly to larger animal models. In another recent study,122 a mixed agonist/antagonist (MCC-134) with opposing effects on sarcolemmal and mitochondrial KATP channels was identified. MCC-134 inhibited diazoxide-induced flavoprotein oxidation and at the same time opened sarcolemmal KATP channels in mouse and rabbit cardiomyocytes. In the in vivo mouse model, MCC-134 abolished the effect of ischaemic preconditioning against infarction, suggesting that, even in mice, mitochondrial KATP channels are the key players in cardioprotection. In accordance with this concept, several recent publications suggest that mitochondrial KATP channels may be more important than sarcolemmal KATP channels in anaesthetic-induced preconditioning.123125
The metabolic concept of cardiac preconditioning
This concept provides an alternative explanation for the preconditioning process without assuming the existence of mitochondrial KATP channels, which have not yet been cloned. According to this model, agents such as pinacidil, nicorandil and volatile anaesthetics would target enzymes of the respiratory chain directly. A recent report by Hanley and colleagues126 showed that diazoxide and 5-hydroxydecanoate have KATP channel-independent targets in the heart, diazoxide inhibiting succinate dehydrogenase and 5-hy droxydecanoate serving as a substrate for acyl-CoA synthetase (fatty acid oxidation). These observations raise the possibility that inhibition of key enzymes in the tricarboxylic acid cycle and the respiratory chain may initially lead to a reduction in ROS formation and mitochondrial ATPase activity and subsequently (at the time of washout of the agent) induce a burst of free radicals. The sequence of these events would mimic the preconditioning process and ultimately induce protection.127 128 In this scenario, 5-hydroxydecanoate would abrogate preconditioning by increasing the electron flow to the respiratory chain, thereby circumventing the inhibitory effects of diazoxide on succinate dehydrogenase. In fact, 5-hydroxydecanoate is metabolized by acyl-CoA-dehydrogenase and may thus increase the supply of electrons to the respiratory chain.
Lack of delayed protection in volatile anaesthetic-induced preconditioning?
Kehl and colleagues129 showed that isoflurane (1 MAC, corresponding to 1.28 vol%) administered for 6 h in dogs does not produce a second window of protection (SWOP) against coronary occlusion 24 h later. However, other temporal relationships for the occurrence of a SWOP were not tested. Also, this study failed to show effective delayed preconditioning by ischaemia as an important positive control in the experimental setting used.
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