In recent years, there has been increased interest in the mechanisms involved in anaesthetic-induced cardioprotection. It is not thoroughly understood how volatile anaesthetics protect the myocardium from ischaemia or reperfusion injury, but the overall mechanism is likely to be multifactorial. This review examines the recent experimental and clinical research underlying the cellular and molecular mechanisms involved in anaesthetic-induced preconditioning.
A variety of intracellular signalling pathways have been implicated in the protective phenomenon. Ischaemic preconditioning and anaesthetic-induced preconditioning share similar molecular mechanisms, including activation of guanine nucleotide-binding proteins, triggering of second messenger pathways, activation of multiple kinases, mediation of nitric oxide formation and reactive oxygen species release, maintenance of intracellular and/or mitochondrial Ca2+ homeostasis and moderation of the opening of adenosine-triphosphate-sensitive potassium channels.
A more thorough understanding of the multiple signalling steps and the ultimate cytoprotective mechanisms underlying anaesthetic-induced preconditioning may lead to improvements in the management of ischaemia and/or reperfusion injury.
MurryC.E., JenningsR.B., ReimerK.A.Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation1986; 74: 1124–1136.
2.
WarltierD., Al-WathiquiM., KampineJ., SchmellingW.Recovery of contractile function of stunned myocardium in chronically instrumented dogs is enhanced by halothane or isoflurane. Anesthesiology1988; 69: 552–565.
3.
De HertS.G.Cardioprotection with volatile anaesthetics: clinical relevance. Curr Opin Anaesthesiol2004; 17: 57–62.
4.
PrattP.F.Jr., WangC., WeihrauchD., BienengraeberM.W., KerstenJ.R., PagelP.S.Cardioprotection by volatile anesthetics: new applications for old drugs?Curr Opin Anaesthesiol2006; 19: 397–403.
5.
ToyodaY., FriehsI., ParkerR.A., LevitskyS., McCullyJ.D.Differential role of sarcolemmal and mitochondrial K(ATP) channels in adenosine-enhanced ischemic preconditioning. Am J Physiol Heart Circ Physiol2000; 279: H2694–2703.
6.
BienengraeberM., WarltierD.C., BosnjakZ.J., StadnickaA.Mechanism of cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel activation by isoflurane in a heterologous expression system. Anesthesiology2006; 105: 534–540.
7.
KwokW.M., MartinelliA.T., FujimotoK., SuzukiA., StadnickaA., BosnjakZ.J.Differential modulation of the cardiac adenosine triphosphate-sensitive potassium channel by isoflurane and halothane. Anesthesiology2002; 97: 50–56.
8.
ObalD., DettwilerS., FavocciaC., ScharbatkeH., PreckelB., SchlackW.The Influence of mitochondrial KATP-channels in the cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo. Anesth Analg2005; 101: 1252–1260.
9.
LiangB.T., GrossG.J.Direct preconditioning of cardiac myocytes via opioid receptors and KATP channels. Circ Res1999; 84: 1396–1400.
10.
FryerR.M., HsuA.K., EellsJ.T., NagaseH., GrossG.J.Opioid-induced second window of cardioprotection. Potential role of mitochondrial KATP channels. Circ Res1999; 84: 846–851.
11.
ZauggM., LucchinettiE., DonatR.Volatile anaesthetics mimic cardiac preconditioning by priming the activation of mitochondrial KATP channels via multiple signaling pathways. Anesthesiology2002; 97: 4–14.
12.
HanouzJ-L, YvonA., MassettiM., LepageO., BabatasiG., KhayatA.Mechanisms of desflurane-induced preconditioning in isolated human right atria in vitro. Anesthesiology2002; 97: 33–41.
13.
TollerW.G., GrossE.R., KerstenJ.R., PagelP.S., GrossG.J., WarltierD.C.Sarcolemmal and mitochondrial adenosine triphosphate-dependent potassium channels: mechanism of desflurane-induced cardioprotection. Anesthesiology2000; 92: 1731–1739.
14.
Tonkovic-CapinM., GrossG.J., BosnjakZ.J., TweddellJ.S., FitzpatrickC.M., BakerJ.E.Delayed cardioprotection by isoflurane: role of K(ATP) channels. Am J Physiol Heart Circ Physiol2002; 283: H61–68.
15.
ChiariP.C., BienengraeberM.W., WeihrauchD., KrolikowskiJ.G., KerstenJ.R., WarltierD.C.Role of endothelial nitric oxide synthase as a trigger and mediator of isoflurane-induced delayed preconditioning in rabbit myocardium. Anesthesiology2005; 103: 74–83.
16.
SmulT.M., LangeM., RedelA., BurkhardN., RoewerN., KehlF.Desflurane-induced preconditioning against myocardial infarction is mediated by nitric oxide. Anesthesiology2006; 105: 719–725.
17.
NovalijaE., VaradarajanS.G., CamaraA.K.S., AnJ., ChenQ., RiessM.L.Anesthetic preconditioning: triggering role of reactive oxygen and nitrogen species in isolated hearts. Am J Physiol Heart Circ Physiol2002; 283: H44–52.
18.
NovalijaE., FujitaS., KampineJ.P., StoweD.F.Sevoflurane mimics ischemic preconditioning effects on coronary flow and nitric oxide release in isolated hearts. Anesthesiology1999; 91: 701–712.
19.
FujitaS., RoerigD.L., ChungW.W., BosnjakZ.J., StoweD.F.Volatile anesthetics do not alter bradykinin-induced release of nitric oxide or L-citrulline in crystalloid perfused guinea pig hearts. Anesthesiology1998; 89: 421–433.
20.
PiacentiniL., WainwrightC.L., ParrattJ.R.The antiarrhythmic effect of ischaemic preconditioning in isolated rat heart involves a pertussis toxin sensitive mechanism. Cardiovasc Res1993; 27: 674–680.
21.
ThorntonJ.D., LiuG.S., DowneyJ.M.Pretreatment with pertussis toxin blocks the protective effects of preconditioning: evidence for a G-protein mechanism. J Mol Cell Cardiol1993; 25: 311–320.
22.
TollerW.G., KerstenJ.R., GrossE.R., PagelP.S., WarltierD.C.Isoflurane preconditions myocardium against infarction via activation of inhibitory guanine nucleotide binding proteins. Anesthesiology2000; 92: 1400–1407.
23.
VulliemozY., VeroskyM.Halothane interaction with guanine nucleotide binding proteins in mouse heart. Anesthesiology1989; 69: 876–880.
24.
SchmidtU., SchwingerR.H., BohmM.Interaction of halothane with inhibitory G-proteins in the human myocardium. Anesthesiology1995; 83: 353–360.
25.
YamakuraT., LewohlJ.M., HarrisR.A.Differential effects of general anesthetics on G protein-coupled inwardly rectifying and other potassium channels. Anesthesiology2001; 95: 144–153.
26.
HsuA.K., NagaseH., GrossG.J.TAN-67, a delta 1-opioid receptor agonist, reduces infarct size via activation of Gi/o proteins and KATP channels. Am J Physiol1998; 274: H909–914.
27.
FryerR.M., HsuA.K., EellsJ.T., NagaseH., GrossG.J.Opioid-induced second window of cardioprotection: potential role of mitochondrial KATP channels. Circ Res1999; 84: 846–851.
28.
AllardM.F., FlintJ.D., EnglishJ.C., HenningS.L., SalamancaM.C., KamimuraC.T.Calcium overload during reperfusion is accelerated in isolated hypertrophied rat hearts. J Mol Cell Cardiol1995; 26: 1551–1563.
29.
DaviesL.A., GibsonC.N., BoyettM.R., HopkinsP.M., HarrisonS.M.Effects of isoflurane, sevoflurane, and halothane on myofilament Ca2+ sensitivity and sarcoplasmic reticulum Ca2+ release in rat ventricular myocytes. Anesthesiology2000; 93: 1034–1044.
30.
HousmansP.R., WanekL.A., CartonE.G., BartunekA.E.Effects of halothane and isoflurane on the intracellular Ca2+ transient in ferret cardiac muscle. Anesthesiology2000; 93: 189–201.
31.
AnJ., VaradarajanS.G., NovalijaE., StoweD.F.Ischemic and anesthetic preconditioning reduces cytosolic [Ca2+] and improves Ca(2+) responses in intact hearts. Am J Physiol Heart Circ Physiol2001; 281: H1508–1523.
32.
TavernierB.M., AdnetP.J., ImbenotteM., EtchriviT.S., ReyfordH., HaudecoeurG., ScherpereelP., Krivosic-HorberR.M.Halothane and isoflurane decrease calcium sensitivity and maximal force in human skinned cardiac fibers. Anesthesiology1994; 80: 625–633.
KokitaN., HaraA., AbikoY., ArakawaJ., HashizumeH., NamikiA.Propofol improves functional and metabolic recovery in ischemic reperfused isolated rat hearts. Anesth Analg1998; 86: 252–258.
35.
NakaeY., FujitaS., NamikiA.Propofol inhibits Ca(2+) transients but not contraction in intact beating guinea-pig hearts. Anesth Analg2000; 90: 1286–1292.
36.
LudwigL.M., WeihrauchD., KerstenJ.R., PagelP.S., WarltierD.C.Protein kinase C translocation and Src protein tyrosine kinase activation mediate isoflurane-induced preconditioning in vivo: potential downstream targets of mitochondrial adenosine triphosphate-sensitive potassium channels and reactive oxygen species. Anesthesiology2004; 100: 532–539.
37.
UeckerM., Da SilvaR., GramppT., PaschT., SchaubM.C., ZauggM.Translocation of protein kinase C isoforms to sub-cellular targets in ischemic and anesthetic preconditioning. Anesthesiology2003; 99: 138–147.
38.
MarinovicJ., BosnjakZ.J., StadnickaA.Preconditioning by isoflurane induces lasting sensitization of the cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel by a protein kinase C-delta-mediated mechanism. Anesthesiology2005; 103: 540–547.
39.
AizawaK., TurnerL.A., WeihrauchD., BosnjakZ.J., KwokW-MProtein kinase C-epsilon primes the cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel to modulation by isoflurane. Anesthesiology2004; 101: 381–389.
40.
JulierK., da SilvaR., GarciaC., BestmannL., FrascaroloP., ZollingerA.Preconditioning by sevoflurane decreases biochemical markers for myocardial and renal dysfunction in coronary artery bypass graft surgery: a double-blinded, placebo-controlled, multicenter study. Anesthesiology2003; 98: 1315–1327.
41.
EbelD., MullenheimJ., SudkampH., BohlenT., FerrariJ., FluhnR.Role of tyrosine kinase in desflurane-induced preconditioning. Anesthesiology2004; 100: 555–561.
42.
da SilvaR., GramppT., PaschT., SchaubM.C., ZauggM.Differential activation of mitogen-activated protein kinases in ischemic and anesthetic preconditioning. Anesthesiology2003; 100: 59–69.
43.
WangC., WeihrauchD., SchwabeD.A., BienengraeberM., WarltierD.C., KerstenJ.R.Extracellular signal-regulated kinases trigger isoflurane preconditioning concomitant with upregulation of hypoxia-inducible factor-1 alpha and vascular endothelial growth factor expression in rats. Anesth Analg2006; 103: 281–288.
44.
FryerR.M., PrattP.F., HsuA.K., GrossG.J.Differential activation of extracellular signal regulated kinase isoforms in preconditioning and opioid-induced cardioprotection. J Pharmacol Exp Ther2001; 296: 642–649.
45.
ZauggM., LucchinettiE., SpahnD.R., PaschT., GarciaC., SchaubM.C.Differential effects of anesthetics on mitochondrial K(ATP) channel activity and cardiomyocyte protection. Anesthesiology2002; 97: 15–23.
46.
KatoR., FoexP.Fentanyl reduces infarction but not stunning via delta-opioid receptors and protein kinase C in rats. Br J Anaesth2000; 84: 608–614.
47.
ZweierJ.L., FlahertyJ.T., WeisfeldtM.L.Direct measurement of free radical generation following reperfusion of ischemic myocardium. Proc Natl Acad Sei U S A1987; 84: 1404–1407.
48.
AmbrosioG., TrittoI., ChiarielloM.The role of oxygen free radicals in preconditioning. J Mol Cell Cardiol1995; 27: 1035–1039.
49.
NakamuraT., KashimotoS., OguchiT., KumazawaT.Hydroxyl radical formation during inhalation anesthesia in the reperfused working rat heart. Can J Anaesth1999; 46: 470–475.
50.
MullenheimJ., EbelD., FrassdorfJ., PreckelB., ThamerV., SchlackW.Isoflurane preconditions myocardium against infarction via release of free radicals. Anesthesiology2002; 96: 934–940.
51.
GopalakrishnaR., JakenS.Protein kinase C signaling and oxidative stress. Free Radic Biol Med2000; 28: 1349–1361.
52.
KonishiH., YamauchiE., TaniguchiH., YamamotoT., MatsuzakiH., TakemuraY.Phosphorylation sites of protein kinase C delta in H2O2-treated cells and its activation by tyrosine kinase in vitro. Proc Natl Acad Sci U S A2001; 98: 6587–6592.
53.
BouwmanR.A., MustersR.J.P., van Beek-HarmsenB.J., de LangeJ.J., BoerC.Reactive oxygen species precede protein kinase C-delta activation independent of adenosine triphosphate-sensitive mitochondrial channel opening in sevoflurane-induced cardioprotection. Anesthesiology2004; 100: 506–514.
54.
KuliszA., ChenN., ChandelN.S., ShaoZ., SchumackerP.T.Mitochondrial ROS initiate phosphorylation of p38 MAP kinase during hypoxia in cardiomyocytes. Am J Physiol Lung Cell Mol Physiol2002; 282: L1324–1329.
55.
TanakaK., WeihrauchD., LudwigL.M., KerstenJ.R., PagelP.S., WarltierD.C.Mitochondrial adenosine triphosphate-regulated potassium channel opening acts as a trigger for isoflurane-induced preconditioning by generating reactive oxygen species. Anesthesiology2003; 98: 935–943.
56.
LebuffeG., SchumackerP.T., ShaoZ-H, AndersonT., IwaseH., Vanden HoekT.L.ROS and NO trigger early preconditioning: relationship to mitochondrial KATP channel. Am J Physiol Heart Cire Physiol2002; 284: H299–308.
57.
KowaltowskiA.J., SeetharamanS., PaucekP., GarlidK.D.Bioenergetic consequences of opening the ATP-sensitive K(+) channel of heart mitochondria. Am J Physiol Heart Circ Physiol2001; 280: H649–657.
58.
ConradieS., CoetzeeA., CoetzeeJ.Anesthetic modulation of myocardial ischemia and reperfusion injury in pigs: comparison between halothane and sevoflurane. Can J Anaesth1999; 46: 71–81.
59.
PreckelB., SchlackW., ComfereT., ObalD., BarthelH., ThamerV.Effects of enflurane, isoflurane, sevoflurane and desflurane on reperfusion injury after regional myocardial ischaemia in the rabbit heart in vivo. Br J Anaesth1999; 81: 905–912.
60.
HofbauerR., FrassM., GmeinerB., SandorN., SchumannR., WagnerO.Effects of remifentanil on neutrophil adhesion, transmigration, and intercellular adhesion molecule expression. Acta Anaesthesiol Scand2001; 44: 1232–1237.
61.
CopeD.K., ImpastatoW.K., CohenM.V., DowneyJ.M.Volatile anesthetics protect the ischemic rabbit myocardium from infarction. Anesthesiology1997; 86: 699–709.
62.
HaesslerR., KuzumeK., ChienG L., WolffR.A., DavisR.F., Van WinkleD.M.Anaesthetics alter the magnitude of infarct limitation by ischaemic preconditioning. Cardiovasc Res1995; 28: 1574–1580.
