This Article Abstract Full Text (PDF) All Versions of this Article: 111/2/194    most recent 01.CIR.0000151290.04952.3Bv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Argaud, L. Articles by Ovize, M. Search for Related Content PubMed PubMed Citation Articles by Argaud, L. Articles by Ovize, M. Related Collections Animal models of human disease Ischemic biology - basic studies Acute myocardial infarction Related Article

(Circulation. 2005;111:194-197.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Postconditioning Inhibits Mitochondrial Permeability Transition

Laurent Argaud, MD; Odile Gateau-Roesch, PhD; Olivier Raisky, MD; Joseph Loufouat, PhD; Dominique Robert, MD; Michel Ovize, MD, PhD

From INSERM E 0226, Université Claude Bernard Lyon I (L.A., O.G.-R., O.R., J.L., M.O.), and Département d’Urgence et de Réanimation Médicale, Hospices Civils de Lyon (L.A., D.R.), Lyon, France.

Correspondence to Prof Michel Ovize, INSERM E0226, Laboratoire de Physiologie Lyon-Nord, 8, avenue Rockefeller, 69373 Lyon, France. E-mail ovize{at}sante.univ-lyon1.fr

Received April 21, 2004; revision received September 28, 2004; accepted October 5, 2004.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background— Brief periods of ischemia performed just at the time of reperfusion can reduce infarct size, a phenomenon called "postconditioning." After reflow, opening of the mitochondrial permeability transition pore (mPTP) has been involved in lethal reperfusion injury. We hypothesized that postconditioning may modulate mPTP opening.

Methods and Results— Anesthetized open-chest rabbits underwent 30 minutes of ischemia and 4 hours of reperfusion. Control hearts underwent no additional intervention. Postconditioning consisted of 4 episodes of 1 minute of coronary occlusion and 1 minute of reperfusion performed after 1 minute of reflow after the prolonged ischemia. Preconditioning consisted of 5 minutes of ischemia and 5 minutes of reperfusion before the 30-minute ischemia. An additional group of rabbits received 5 mg/kg IV of NIM811, a specific inhibitor of the mPTP, 1 minute before reperfusion. Infarct size was assessed by triphenyltetrazolium staining. Mitochondria were isolated from the risk region myocardium, and Ca²⁺-induced mPTP opening was assessed by use of a potentiometric method. Postconditioning, preconditioning, and NIM811 significantly limited infarct size, which averaged 29±4%, 18±4%, and 20±4% of the risk region, respectively, versus 61±6% in controls (P0.001 versus control). The Ca²⁺ load required to open the mPTP averaged 41±4, 47±5, and 67±9 µmol/L CaCl₂ per mg of mitochondrial proteins in postconditioning, preconditioning, and NIM811, respectively, significantly higher than the value of 16±4 µmol/L per mg in controls (P0.05).

Conclusions— Postconditioning inhibits opening of the mPTP and provides a powerful antiischemic protection.

Key Words: ischemia • reperfusion • myocardial infarction

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Brief episodes of ischemia render the myocardium more resistant to subsequent prolonged ischemia-reperfusion, a phenomenon called "preconditioning."¹ Recently, Zhao et al^2,3 reported that a similar regimen of brief periods of ischemia applied just after, instead of just before, the sustained ischemia was as protective as preconditioning: they named it "postconditioning." The mechanism of this newly described form of cardioprotection remains unknown.

See p 120

Mitochondrial permeability transition is a key event in cell death after ischemia-reperfusion.^4–6 Opening of the nonspecific mitochondrial permeability transition pore (mPTP) in the inner mitochondrial membrane results in the collapse of the membrane potential (_m), uncoupling of the respiratory chain, and efflux of cytochrome c and other proapoptotic factors that may lead to either apoptosis or necrosis.⁷ Ca²⁺ overload and excessive production of reactive oxygen species in the early minutes of reflow trigger opening of the mPTP and are crucial events in reperfusion injury.^8,9 Griffiths and Halestrap¹⁰ demonstrated in the isolated rat heart that the mPTP remains closed throughout ischemia but opens at the time of reperfusion. We therefore investigated whether postconditioning might inhibit mPTP opening and thereby limit infarct size.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
All animals were treated in compliance with the "Position of the American Heart Association on Research Animal Use," adopted by the American Heart Association on November 11, 1984.

Experimental Protocol
Male New Zealand White rabbits (2.2 to 2.5 kg) were anesthetized with xylazine (5 mg/kg) and ketamine (50 mg/kg) and ventilated with room air.¹¹ A cannula was inserted into the right internal jugular vein for administration of drugs and fluids and into the left carotid artery for measurement of blood pressure. Limb lead II of the ECG was used to measure heart rate. Heart rate and blood pressure were monitored continuously on a Gould recorder (Gould Inc). After a left thoracotomy was performed, the heart was exposed and a snare was passed around a marginal branch of the left circumflex coronary artery to induce regional myocardial ischemia. After the surgical procedure, a 15-minute stabilization period was observed. Animals were then randomly assigned to the experimental groups. All animals underwent 30 minutes of ischemia and 4 hours of reperfusion. They were randomly allocated to the following groups (n=10 per group): (1) the Control group (C): no other intervention; (2) the Preconditioning group (Pre-C): 1 episode of 5 minutes of ischemia and 5 minutes of reperfusion before the prolonged ischemia; (3) the Postconditioning group (Post-C): no intervention before the 30 minute ischemia. After 1 minute of reflow after the release of the 30-minute occlusion, we performed 4 episodes of 1 minute of ischemia each separated by 1 minute of reperfusion; and (4) the NIM811 group (NIM811): 1 minute before reperfusion, rabbits received an IV bolus injection of 5 mg/kg of NIM811, a nonimmunosuppressive derivative of cyclosporin A that specifically inhibits opening of the mPTP.¹²

An additional subset of rabbits underwent a comparable experimental preparation, but the reperfusion period was extended to 72 hours to determine whether postconditioning simply delays or actually limits irreversible myocardial reperfusion injury. Those animals were randomly assigned to either a control or a Post-C group. They underwent an ischemic insult similar to that in the 4-hour reperfusion protocol, had the chest closed, and were returned to the animal facilities until the end of the reperfusion period (n=9 per group).

Infarct Size Studies
At the end of the final reperfusion, the coronary artery was briefly reoccluded, and 0.5 mg/kg Uniperse blue pigment (Ciba-Geigy) was injected intravenously to delineate the in vivo area at risk, as previously described.¹³ Anesthetized rabbits were then euthanized by an intravenous injection of 4 mEq KCl. The heart was excised and cut into 5 to 6 transverse slices, 2 mm thick, parallel to the atrioventricular groove. Each heart slice was weighed, and its basal surface was photographed for later measurement of the area at risk. After incubation for 15 minutes in a 1% solution of triphenyltetrazolium chloride at 37°C to differentiate infarcted (pale) from viable (brick red) myocardial area, the slices were rephotographed. Enlarged projections of these slices were traced for determination of the boundaries of the area at risk and area of necrosis. The extent of the area at risk and area of necrosis was quantified by computerized planimetry and corrected for the weight of the tissue slices. Determination of area at risk and infarct size was performed in a blinded manner. Total weights of the area at risk and the area of necrosis were then calculated and expressed in grams and as percentage of total left ventricular (LV) weight and of the area at risk weight, respectively. We decided prospectively that hearts with a risk region <10% of the LV weight would be excluded from the study.

Detection of mPTP Opening in Isolated Mitochondria
Additional animals (n=7 to 8 per group) were used for this in vitro study. At the end of the protocol, myocardium from the area at risk was excised, and mitochondria were isolated, as previously described.^14–16 An additional set of rabbits (Sham, n=10) underwent no intervention for the whole duration of the experiment.

Opening of the mPTP was assessed after in vitro Ca²⁺ overload.¹⁶ Briefly, the isolated mitochondria suspension (5 mg proteins) was placed in a Teflon chamber equipped with a Ca²⁺-selective microelectrode. Modifications of the medium (ie, extramitochondrial) Ca²⁺ concentration were recorded continuously by use of a custom-made Synchronie software. At the end of the preincubation period, 20 µmol/L CaCl₂ pulses were performed every 60 seconds. Each 20-µmol/L CaCl₂ pulse is recorded as a peak of extramitochondrial Ca²⁺ concentration (Figure 1). Ca²⁺ is then rapidly taken up by the mitochondria, resulting in a return of extramitochondrial Ca²⁺ concentration to near baseline levels. After sufficient Ca²⁺ loading, extramitochondrial Ca²⁺ concentration increases abruptly, indicating a massive release of Ca²⁺ by mitochondria as a result of mPTP opening (Figure 1A).¹⁶ The amount of Ca²⁺ necessary to trigger this massive Ca²⁺ release is used here as an indicator of the susceptibility of mPTP to Ca²⁺ overload.

View larger version (24K): [in this window] [in a new window]   Figure 1. Postconditioning delays Ca2+-induced mPTP opening. A, Typical example of Ca2+-induced mPTP opening recordings in mitochondria isolated from control (C), Pre-C, and Post-C animals. mPTP opening was defined as massive release of Ca2+ by mitochondria after progressive Ca2+ overload of suspension medium. B, Ca2+ required for mPTP opening was significantly reduced vs shams in C group. Post-C, Pre-C, and NIM811 equally inhibited mPTP opening (n=7 to 8 per group). *P<0.0001 vs sham; P0.01 vs C.

Statistical Analysis
All values are expressed as mean±SEM. Differences in the relationship between infarct size and area at risk were evaluated by ANCOVA and post hoc Tukey’s test, with infarct size as the dependent variable and area at risk as the covariate. Hemodynamics were analyzed by use of 2-way ANOVA with repeated measures on one factor.¹⁷ Mitochondrial Ca²⁺ loads required for mPTP opening were analyzed by 1-way ANOVA. Means were compared by the Fisher test. Statistical significance was defined at a value of P<0.05.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Postconditioning Delays mPTP Opening
The mean amount of Ca²⁺ required to trigger mPTP opening averaged 99±7 µmol/L CaCl₂ per mg mitochondrial proteins in shams (Figure 1B). Ischemia-reperfusion resulted in a significant reduction of Ca²⁺ load necessary to open mPTPs: 16±4 µmol/L per mg in controls (P<0.0001 versus sham). The Ca²⁺ load that induced mPTP opening in Post-C averaged 41±4 µmol/L per mg, ie, significantly higher than in controls (P=0.01 versus control). Pre-C and NIM811 affected mPTP opening to an extent comparable to that in Post-C, with Ca²⁺ load averaging 47±5 and 67±9 µmol/L per mg, respectively (P<0.001 versus control).

Postconditioning Protects the In Vivo Rabbit Heart
Heart rate and blood pressure were comparable among groups throughout the experiment: blood pressure decreased significantly in all groups after the ischemic insult (Table). Similar pattern of hemodynamics were observed in the 72-hour reperfusion groups, but blood pressure had returned to near baseline at the end of the experiment. Area at risk averaged 0.93±0.07 g (29±3% of LV weight), 0.91±0.06 g (28±3%), 0.94±0.06 g (37±2%), and 1.11±0.09 g (38±3%) in the C, Pre-C, Post-C, and NIM811 groups, respectively (P=NS among groups). Preconditioning reduced infarct size to 18±4% of area at risk versus 61±6% in controls (P<0.0001). Both postconditioning and NIM811 significantly limited infarct size, which averaged 29±4% and 20±4% of the risk region, respectively (P<0.0001 versus control, P=NS versus Pre-C) (Figure 2A). For animals with a 72-hour reperfusion period, area at risk averaged 1.00±0.15 g (31±4% of LV weight) and 1.04±0.16 g (35±4%) in C and Post-C, respectively. Infarct size averaged 20±5% of the risk region in the Post-C group versus 48±6% in the C group (P<0.005) (Figure 2B). These differences were confirmed by ANCOVA.

View this table: [in this window] [in a new window]   Heart Rate and Blood Pressure Variations

View larger version (29K): [in this window] [in a new window]   Figure 2. Postconditioning reduces infarct size. A, At 4 hours of reperfusion. Area at risk (AR) and area of necrosis (AN) are presented for each group (n=10 per group). Area of necrosis was reduced to a comparable extent in Pre-C, Post-C, and NIM811 groups. *P<0.05 vs control. B, At 72 hours of reperfusion. When reperfusion was extended to 72 hours, infarct size-limiting effect of postconditioning was maintained (n=9 per group). *P<0.05 vs control.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
We report for the first time that postconditioning modifies mPTP opening and reduces infarct size in the rabbit heart.

Zhao et al² first described that brief episodes of ischemia performed at the onset of reperfusion after a prolonged ischemia provided a powerful antinecrotic protection. Kin et al³ proposed that postconditioning might be related to an attenuation of oxygen-derived free radical production in the early minutes of reflow.

The rationale for the present investigation was based on 3 observations. First, the report by Zhao et al indicates that preconditioning and postconditioning are approximately equally protective and that a significant amount of infarct after ischemia-reperfusion is because of reperfusion-induced lethal injury. Second, Griffiths and Halestrap¹⁰ demonstrated that the mPTP remains closed during ischemia but opens in early reperfusion. Third, recent reports demonstrated that mitochondrial permeability transition is involved in preconditioning and that blockade of the mPTP at reflow by cyclosporin A is cardioprotective.^16,18,19 We therefore investigated whether mPTP opening may play a role in postconditioning.

We report that in the in vivo rabbit heart model, postconditioning significantly reduced infarct size and that this protection was preserved after 72 hours of reperfusion, indicating that irreversible myocardial injury was not simply delayed but actually limited. The magnitude of the protective effect of postconditioning was similar to that obtained with NIM811, which specifically inhibited mPTP opening at the time of reperfusion. This is in agreement with previous studies by Hausenloy et al¹⁸ and Javadov et al¹⁹ that demonstrated, using cyclosporin A in the isolated rat heart model, that mPTP is important in myocardial lethal reperfusion injury.

We demonstrated here that mitochondria isolated from postconditioned myocardium display an increased resistance to Ca²⁺ loading. In other words, postconditioning delays Ca²⁺-induced mPTP opening. This pattern of Ca²⁺-induced mPTP opening is very similar to that of preconditioned hearts and mimics those recorded in rabbit hearts treated at the time of reperfusion by the specific mPTP inhibitor NIM811. Although a full demonstration of a causal relation between postconditioning and inhibition of the mPTP will require additional investigations, the present data strongly suggest that mitochondrial permeability transition is an important mediator of this cardioprotection. How postconditioning modulates mPTP opening will need further investigations. On the basis of the initial studies by Zhao et al and Kin et al, it would be worth determining whether the reduced production of reactive oxygen species after postconditioning may be responsible for delaying mPTP opening.^2,3 One could hypothesize that postconditioning may alter the production of oxygen-derived free radicals by the respiratory chain and thereby delay opening of the mPTP; this, however, remains to be determined. Tsang et al²⁰ recently reported that postconditioning activates the phosphatidylinositol 3 kinase (PI3K)–Akt pathway and its downstream target, endothelial nitric oxide synthase (eNOS). Yang et al²¹ demonstrated that pharmacological inhibition of eNOS and blockade of the mitochondrial K⁺_ATP channels prevent infarct size limitation by postconditioning. Whether activation of the PI3K-Akt-eNOS cascade may inhibit mPTP opening and be responsible for the protective effect of postconditioning remains to be determined.²² Recent preconditioning studies also prompt us to investigate matrix Ca²⁺ accumulation and pH variations in the influence of postconditioning on mPTP opening.^23–25

Postconditioning seems to be a fairly simple strategy to apply during coronary angioplasty in patients with ongoing acute myocardial infarction. It is still unknown, however, whether postconditioning is feasible, safe, and efficient in those patients. Although clear evidence that lethal myocardial reperfusion injury exists in humans is lacking, the potential of postconditioning (ie, limitation of infarct size and improvement in prognosis) must be tested in clinical trials. As an alternative in those patients who cannot undergo coronary angioplasty, pharmacological inhibition of the mPTP at the time of reperfusion may be of major interest as an adjunct therapy to thrombolysis. Clinical investigations are needed to determine the potential benefit of the inhibition of mPTP opening in patients with acute myocardial infarction.

	Acknowledgments

 
The authors are grateful to La Fondation de France for supporting this work.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986; 74: 1124–1136.[Abstract/Free Full Text]

2. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol. 2003; 285: H579–H588.

3. Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, Guyton RA, Vinten-Johansen J. Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res. 2004; 62: 74–85.[Abstract/Free Full Text]

4. Nazareth W, Yafei N, Crompton M. Inhibition of anoxia-induced injury in heart myocytes by cyclosporin A. J Mol Cell Cardiol. 1991; 23: 1351–1354.[CrossRef][Medline] [Order article via Infotrieve]

5. Duchen MR, McGuiness O, Brown LA, Crompton M. On the involvement of a cyclosporin A sensitive mitochondrial pore in myocardial reperfusion injury. Cardiovasc Res. 1993; 27: 1790–1794.[Free Full Text]

6. Griffiths EJ, Halestrap AP. Protection by cyclosporin A of ischemia/reperfusion induced damage in isolated rat hearts. J Mol Cell Cardiol. 1993; 25: 1461–1469.[CrossRef][Medline] [Order article via Infotrieve]

7. Bernardi P, Petronelli V. The permeability transition pore as a mitochondrial calcium release channel: a critical appraisal. J Bioenerg Biomembr. 1996; 28: 129–136.

8. Piper HM, Meuter K, Schafer C. Cellular mechanisms of ischemia-reperfusion injury. Ann Thorac Surg. 2003; 75: S644–S6448.[Abstract/Free Full Text]

9. Di Lisa F, Menabo R, Canton M, Barile M, Bernardi P. Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart. J Biol Chem. 2001; 276: 2571–2575.[Abstract/Free Full Text]

10. Griffiths EJ, Halestrap AP. Mitochondrial non-specific pores remain closed during cardiac ischaemia but open upon reperfusion. Biochem J. 1995; 307: 93–98.[Medline] [Order article via Infotrieve]

11. Piriou V, Chiari P, Gateau-Roesch O, Argaud L, Muntean D, Salles D, Loufouat J, Gueugniaud PY, Lehot JJ, Ovize M. Desflurane-induced preconditioning alters calcium-induced mitochondrial permeability transition. Anesthesiology. 2004; 100: 581–588.[CrossRef][Medline] [Order article via Infotrieve]

12. Waldmeier PC, Feldtrauer JJ, Qian T, Lemasters JJ. Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM 811. Mol Pharmacol. 2002; 62: 22–29.[Abstract/Free Full Text]

13. Argaud L, Prigent AF, Chalabreysse L, Loufouat J, Lagarde M, Ovize M. Ceramide in the antiapoptotic effect of ischemic preconditioning. Am J Physiol. 2004; 286: H246–H251.

14. Gateau-Roesch O, Pavlov E, Lazareva AV, Limarenko EA, Levrat C, Saris NE, Louisot P, Mironova GD. Calcium-binding properties of the mitochondrial channel-forming hydrophobic component. J Bioenerg Biomembr. 2000; 32: 105–110.[CrossRef][Medline] [Order article via Infotrieve]

15. Kristian T, Gertsch J, Bates TE, Siesjo BK. Characteristics of the calcium-triggered mitochondrial permeability transition in nonsynaptic brain mitochondria: effects of cyclosporin A and ubiquinone O. J Neurochem. 2000; 74: 1999–2009.[CrossRef][Medline] [Order article via Infotrieve]

16. Argaud L, Gateau-Roesch O, Chalabreysse L, Gomez L, Loufouat J, Thivolet-Bejui F, Robert D, Ovize M. Preconditioning delays Ca²⁺-induced mitochondrial permeability transition. Cardiovasc Res. 2004; 61: 115–122.[Abstract/Free Full Text]

17. Wallenstein S, Zucker CL, Fleiss JL. Some statistical methods useful in circulation research. Circ Res. 1980; 47: 1–9.[Abstract/Free Full Text]

18. Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM. Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning? Cardiovasc Res. 2002; 55: 534–543.[Abstract/Free Full Text]

19. Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KH, Halestrap AP. Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol. 2003; 549: 513–524.[Abstract/Free Full Text]

20. Tsang A, Hausenloy DJ, Mocanu MM, Yellon DM. Postconditioning: a form of modified reperfusion protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway. Circ Res. 2004; 95: 230–232.[Abstract/Free Full Text]

21. Yang XM, Proctor JB, Cui L, Krieg T, Downey JM, Cohen MV. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. J Am Coll Cardiol. 2004; 44: 1103–1110.[Abstract/Free Full Text]

22. Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the reperfusion injury salvage kinase (RISK)-pathway. Cardiovasc Res. 2004; 61: 448–460.[Abstract/Free Full Text]

23. Holmuhamedov EL, Jovanovic S, Dzeja PP, Jovanovic A, Terzic A. Mitochondrial ATP-sensitive K⁺ channels modulate cardiac mitochondrial function. Am J Physiol. 1998; 275: H1567–H1576.[Medline] [Order article via Infotrieve]

24. Wang L, Cherednichenko G, Hernandez L, Halow J, Camacho SA, Figueredo V, Schaefer S. Preconditioning limits mitochondrial Ca²⁺ during ischemia in rat hearts: role of K_ATP channels. Am J Physiol. 2001; 280: H2321–H2328.

25. Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion: a target for cardioprotection. Cardiovasc Res. 2004; 61: 372–385.[Abstract/Free Full Text]

Related Article:

We Think We See a Pattern Emerging Here

James M. Downey and Michael V. Cohen
Circulation 2005 111: 120-121. [Extract] [Full Text]

This article has been cited by other articles:

				E. K. Iliodromitis, J. M. Downey, G. Heusch, and D. T. Kremastinos What Is the Optimal Postconditioning Algorithm? Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2009; 14(4): 269 - 273. [Abstract] [PDF]

				S. Javadov, M. Karmazyn, and N. Escobales Mitochondrial Permeability Transition Pore Opening as a Promising Therapeutic Target in Cardiac Diseases J. Pharmacol. Exp. Ther., September 1, 2009; 330(3): 670 - 678. [Abstract] [Full Text] [PDF]

				R. Tissier, N. Couvreur, B. Ghaleh, P. Bruneval, F. Lidouren, D. Morin, R. Zini, A. Bize, M. Chenoune, M.-F. Belair, et al. Rapid cooling preserves the ischaemic myocardium against mitochondrial damage and left ventricular dysfunction Cardiovasc Res, July 15, 2009; 83(2): 345 - 353. [Abstract] [Full Text] [PDF]

				L. Gomez, B. Li, N. Mewton, I. Sanchez, C. Piot, M. Elbaz, and M. Ovize Inhibition of mitochondrial permeability transition pore opening: translation to patients Cardiovasc Res, July 15, 2009; 83(2): 226 - 233. [Abstract] [Full Text] [PDF]

				A. Granfeldt, D. J. Lefer, and J. Vinten-Johansen Protective ischaemia in patients: preconditioning and postconditioning Cardiovasc Res, July 15, 2009; 83(2): 234 - 246. [Abstract] [Full Text] [PDF]

				I. Szwarc, G. Mourad, and A. Argiles Post-conditioning to reduce renal ischaemia/reperfusion injury Nephrol. Dial. Transplant., July 1, 2009; 24(7): 2288 - 2289. [Full Text] [PDF]

				G. J. Gross, K. M. Gauthier, J. Moore, W. B. Campbell, J. R. Falck, and K. Nithipatikom Evidence for role of epoxyeicosatrienoic acids in mediating ischemic preconditioning and postconditioning in dog Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H47 - H52. [Abstract] [Full Text] [PDF]

				M. Juhaszova, D. B. Zorov, Y. Yaniv, H. B. Nuss, S. Wang, and S. J. Sollott Role of Glycogen Synthase Kinase-3{beta} in Cardioprotection Circ. Res., June 5, 2009; 104(11): 1240 - 1252. [Abstract] [Full Text] [PDF]

				N. Couvreur, R. Tissier, S. Pons, M. Chenoune, X. Waintraub, A. Berdeaux, and B. Ghaleh The Ceiling Effect of Pharmacological Postconditioning with the Phytoestrogen Genistein Is Reversed by the GSK3{beta} Inhibitor SB 216763 [3-(2,4-Dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione] through Mitochondrial ATP-Dependent Potassium Channel Opening J. Pharmacol. Exp. Ther., June 1, 2009; 329(3): 1134 - 1141. [Abstract] [Full Text] [PDF]

				P. S. Pagel and J. G. Krolikowski Transient Metabolic Alkalosis During Early Reperfusion Abolishes Helium Preconditioning Against Myocardial Infarction: Restoration of Cardioprotection by Cyclosporin A in Rabbits Anesth. Analg., April 1, 2009; 108(4): 1076 - 1082. [Abstract] [Full Text] [PDF]

				J. Huffmyer and J. Raphael Physiology and Pharmacology of Myocardial Preconditioning and Postconditioning Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2009; 13(1): 5 - 18. [Abstract] [PDF]

				K. Zhou, L. Zhang, J. Xi, W. Tian, and Z. Xu Ethanol Prevents Oxidant-Induced Mitochondrial Permeability Transition Pore Opening in Cardiac Cells Alcohol Alcohol., January 1, 2009; 44(1): 20 - 24. [Abstract] [Full Text] [PDF]

				H. Ishii, T. Amano, T. Matsubara, and T. Murohara Pharmacological Intervention for Prevention of Left Ventricular Remodeling and Improving Prognosis in Myocardial Infarction Circulation, December 16, 2008; 118(25): 2710 - 2718. [Full Text] [PDF]

				B. G. Leshnower, S. Kanemoto, M. Matsubara, H. Sakamoto, R. Hinmon, J. H. Gorman III, and R. C. Gorman Cyclosporine Preserves Mitochondrial Morphology After Myocardial Ischemia/Reperfusion Independent of Calcineurin Inhibition Ann. Thorac. Surg., October 1, 2008; 86(4): 1286 - 1292. [Abstract] [Full Text] [PDF]

				O. Bouhidel, S. Pons, R. Souktani, R. Zini, A. Berdeaux, and B. Ghaleh Myocardial ischemic postconditioning against ischemia-reperfusion is impaired in ob/ob mice Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1580 - H1586. [Abstract] [Full Text] [PDF]

				L. Xi, A. Das, Z.-Q. Zhao, V. F. Merino, M. Bader, and R. C. Kukreja Loss of Myocardial Ischemic Postconditioning in Adenosine A1 and Bradykinin B2 Receptors Gene Knockout Mice Circulation, September 30, 2008; 118(14_suppl_1): S32 - S37. [Abstract] [Full Text] [PDF]

				S. E. McAllister, H. Ashrafpour, N. Cahoon, N. Huang, M. A. Moses, P. C. Neligan, C. R. Forrest, J. E. Lipa, and C. Y. Pang Postconditioning for salvage of ischemic skeletal muscle from reperfusion injury: efficacy and mechanism Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2008; 295(2): R681 - R689. [Abstract] [Full Text] [PDF]

				A. D. T. Costa and K. D. Garlid Intramitochondrial signaling: interactions among mitoKATP, PKC{varepsilon}, ROS, and MPT Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H874 - H882. [Abstract] [Full Text] [PDF]

				C. Piot, P. Croisille, P. Staat, H. Thibault, G. Rioufol, N. Mewton, R. Elbelghiti, T. T. Cung, E. Bonnefoy, D. Angoulvant, et al. Effect of Cyclosporine on Reperfusion Injury in Acute Myocardial Infarction N. Engl. J. Med., July 31, 2008; 359(5): 473 - 481. [Abstract] [Full Text] [PDF]

				F. N. Obame, C. Plin-Mercier, R. Assaly, R. Zini, J. L. Dubois-Rande, A. Berdeaux, and D. Morin Cardioprotective Effect of Morphine and a Blocker of Glycogen Synthase Kinase 3{beta}, SB216763 [3-(2,4-Dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione], via Inhibition of the Mitochondrial Permeability Transition Pore J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 252 - 258. [Abstract] [Full Text] [PDF]

				L. Gomez, M. Paillard, H. Thibault, G. Derumeaux, and M. Ovize Inhibition of GSK3{beta} by Postconditioning Is Required to Prevent Opening of the Mitochondrial Permeability Transition Pore During Reperfusion Circulation, May 27, 2008; 117(21): 2761 - 2768. [Abstract] [Full Text] [PDF]

				G. Serviddio, A. D. Romano, L. Gesualdo, R. Tamborra, A. M. Di Palma, T. Rollo, E. Altomare, and G. Vendemiale Postconditioning is an effective strategy to reduce renal ischaemia/reperfusion injury Nephrol. Dial. Transplant., May 1, 2008; 23(5): 1504 - 1512. [Abstract] [Full Text] [PDF]

				J.-y. Wang, J. Shen, Q. Gao, Z.-g. Ye, S.-y. Yang, H.-w. Liang, I. C. Bruce, B.-y. Luo, and Q. Xia Ischemic Postconditioning Protects Against Global Cerebral Ischemia/Reperfusion-Induced Injury in Rats Stroke, March 1, 2008; 39(3): 983 - 990. [Abstract] [Full Text] [PDF]

				A. J. Zatta, H. Kin, D. Yoshishige, R. Jiang, N. Wang, J. G. Reeves, J. Mykytenko, R. A. Guyton, Z.-Q. Zhao, J. L. Caffrey, et al. Evidence that cardioprotection by postconditioning involves preservation of myocardial opioid content and selective opioid receptor activation Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1444 - H1451. [Abstract] [Full Text] [PDF]

				H. Thibault, C. Piot, P. Staat, L. Bontemps, C. Sportouch, G. Rioufol, T. T. Cung, E. Bonnefoy, D. Angoulvant, J.-F. Aupetit, et al. Long-Term Benefit of Postconditioning Circulation, February 26, 2008; 117(8): 1037 - 1044. [Abstract] [Full Text] [PDF]

				A. B. Gustafsson and R. A. Gottlieb Heart mitochondria: gates of life and death Cardiovasc Res, January 15, 2008; 77(2): 334 - 343. [Abstract] [Full Text] [PDF]

				A. D.T. Costa, S. V. Pierre, M. V. Cohen, J. M. Downey, and K. D. Garlid cGMP signalling in pre- and post-conditioning: the role of mitochondria Cardiovasc Res, January 15, 2008; 77(2): 344 - 352. [Abstract] [Full Text] [PDF]

				N. Oka, L. Wang, W. Mi, W. Zhu, O. Honjo, and C. A. Caldarone Cyclosporine A prevents apoptosis-related mitochondrial dysfunction after neonatal cardioplegic arrest J. Thorac. Cardiovasc. Surg., January 1, 2008; 135(1): 123 - 130. [Abstract] [Full Text] [PDF]

				L. Argaud, O. Gateau-Roesch, L. Augeul, E. Couture-Lepetit, J. Loufouat, L. Gomez, D. Robert, and M. Ovize Increased mitochondrial calcium coexists with decreased reperfusion injury in postconditioned (but not preconditioned) hearts Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H386 - H391. [Abstract] [Full Text] [PDF]

				S. L. Hale, A. Mehra, J. Leeka, and R. A. Kloner Postconditioning fails to improve no reflow or alter infarct size in an open-chest rabbit model of myocardial ischemia-reperfusion Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H421 - H425. [Abstract] [Full Text] [PDF]

				D. A. Liem, H. M. Honda, J. Zhang, D. Woo, and P. Ping Past and present course of cardioprotection against ischemia- reperfusion injury J Appl Physiol, December 1, 2007; 103(6): 2129 - 2136. [Abstract] [Full Text] [PDF]

				P. Ferdinandy, R. Schulz, and G. F. Baxter Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning Pharmacol. Rev., December 1, 2007; 59(4): 418 - 458. [Abstract] [Full Text] [PDF]

				G.-X. Zhang, X.-M. Lu, S. Kimura, and A. Nishiyama Role of mitochondria in angiotensin II-induced reactive oxygen species and mitogen-activated protein kinase activation Cardiovasc Res, November 1, 2007; 76(2): 204 - 212. [Abstract] [Full Text] [PDF]

				F. N. Obame, R. Zini, R. Souktani, A. Berdeaux, and D. Morin Peripheral Benzodiazepine Receptor-Induced Myocardial Protection is Mediated by Inhibition of Mitochondrial Membrane Permeabilization J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 336 - 345. [Abstract] [Full Text] [PDF]

				H. Sato, R. Bolli, G. D. Rokosh, Q. Bi, S. Dai, G. Shirk, and X.-L. Tang The cardioprotection of the late phase of ischemic preconditioning is enhanced by postconditioning via a COX-2-mediated mechanism in conscious rats Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2557 - H2564. [Abstract] [Full Text] [PDF]

				S. P. Loukogeorgakis, R. Williams, A. T. Panagiotidou, S. K. Kolvekar, A. Donald, T. J. Cole, D. M. Yellon, J. E. Deanfield, and R. J. MacAllister Transient Limb Ischemia Induces Remote Preconditioning and Remote Postconditioning in Humans by a KATP Channel Dependent Mechanism Circulation, September 18, 2007; 116(12): 1386 - 1395. [Abstract] [Full Text] [PDF]

				P. S. Pagel, J. G. Krolikowski, Y. H. Shim, S. Venkatapuram, J. R. Kersten, D. Weihrauch, D. C. Warltier, and P. F. Pratt Jr Noble Gases Without Anesthetic Properties Protect Myocardium Against Infarction by Activating Prosurvival Signaling Kinases and Inhibiting Mitochondrial Permeability Transition In Vivo Anesth. Analg., September 1, 2007; 105(3): 562 - 569. [Abstract] [Full Text] [PDF]

				L. Gomez, H. Thibault, A. Gharib, J.-M. Dumont, G. Vuagniaux, P. Scalfaro, G. Derumeaux, and M. Ovize Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1654 - H1661. [Abstract] [Full Text] [PDF]

				S. Y. Lim, S. M. Davidson, D. J. Hausenloy, and D. M. Yellon Preconditioning and postconditioning: The essential role of the mitochondrial permeability transition pore Cardiovasc Res, August 1, 2007; 75(3): 530 - 535. [Abstract] [Full Text] [PDF]

				C. Penna, D. Mancardi, R. Rastaldo, G. Losano, and P. Pagliaro Intermittent activation of bradykinin B2 receptors and mitochondrial KATP channels trigger cardiac postconditioning through redox signaling Cardiovasc Res, July 1, 2007; 75(1): 168 - 177. [Abstract] [Full Text] [PDF]

				E. Robin, R. D. Guzy, G. Loor, H. Iwase, G. B. Waypa, J. D. Marks, T. L. V. Hoek, and P. T. Schumacker Oxidant Stress during Simulated Ischemia Primes Cardiomyocytes for Cell Death during Reperfusion J. Biol. Chem., June 29, 2007; 282(26): 19133 - 19143. [Abstract] [Full Text] [PDF]

				W. Y. Vanagt, R. N. Cornelussen, T. C. Baynham, A. Van Hunnik, Q. P. Poulina, F. Babiker, J. Spinelli, T. Delhaas, and F. W. Prinzen Pacing-Induced Dyssynchrony During Early Reperfusion Reduces Infarct Size J. Am. Coll. Cardiol., May 1, 2007; 49(17): 1813 - 1819. [Abstract] [Full Text] [PDF]

				J. F. Spear, S. K. Prabu, D. Galati, H. Raza, H. K. Anandatheerthavarada, and N. G. Avadhani beta1-Adrenoreceptor activation contributes to ischemia-reperfusion damage as well as playing a role in ischemic preconditioning Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2459 - H2466. [Abstract] [Full Text] [PDF]

				M. V. Cohen, X.-M. Yang, and J. M. Downey The pH Hypothesis of Postconditioning: Staccato Reperfusion Reintroduces Oxygen and Perpetuates Myocardial Acidosis Circulation, April 10, 2007; 115(14): 1895 - 1903. [Abstract] [Full Text] [PDF]

				E. Shi, X. Jiang, T. Kazui, N. Washiyama, K. Yamashita, H. Terada, and A. H. M. Bashar Controlled low-pressure perfusion at the beginning of reperfusion attenuates neurologic injury after spinal cord ischemia J. Thorac. Cardiovasc. Surg., April 1, 2007; 133(4): 942 - 948. [Abstract] [Full Text] [PDF]

				J. C. Bopassa, D. Vandroux, M. Ovize, and R. Ferrera Controlled reperfusion after hypothermic heart preservation inhibits mitochondrial permeability transition-pore opening and enhances functional recovery Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2265 - H2271. [Abstract] [Full Text] [PDF]

				X.-L. Tang, H. Sato, S. Tiwari, B. Dawn, Q. Bi, Q. Li, G. Shirk, and R. Bolli Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions <45 min Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2308 - H2317. [Abstract] [Full Text] [PDF]

				N. Couvreur, L. Lucats, R. Tissier, A. Bize, A. Berdeaux, and B. Ghaleh Differential effects of postconditioning on myocardial stunning and infarction: a study in conscious dogs and anesthetized rabbits Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1345 - H1350. [Abstract] [Full Text] [PDF]

				S.-S. Park, H. Zhao, Y. Jang, R. A. Mueller, and Z. Xu N6-(3-Iodobenzyl)-adenosine-5'-N-methylcarboxamide Confers Cardioprotection at Reperfusion by Inhibiting Mitochondrial Permeability Transition Pore Opening via Glycogen Synthase Kinase 3beta J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 124 - 131. [Abstract] [Full Text] [PDF]

				K. Ueda, H. Takano, H. Hasegawa, Y. Niitsuma, Y. Qin, M. Ohtsuka, and I. Komuro Granulocyte Colony Stimulating Factor Directly Inhibits Myocardial Ischemia-Reperfusion Injury Through Akt-Endothelial NO Synthase Pathway Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): e108 - e113. [Abstract] [Full Text] [PDF]

				P. S. Pagel, J. G. Krolikowski, D. A. Neff, D. Weihrauch, M. Bienengraeber, J. R. Kersten, and D. C. Warltier Inhibition of glycogen synthase kinase enhances isoflurane-induced protection against myocardial infarction during early reperfusion in vivo. Anesth. Analg., May 1, 2006; 102(5): 1348 - 1354. [Abstract] [Full Text] [PDF]

				C. Wang, D. A. Neff, J. G. Krolikowski, D. Weihrauch, M. Bienengraeber, D. C. Warltier, J. R. Kersten, and P. S. Pagel The influence of B-cell lymphoma 2 protein, an antiapoptotic regulator of mitochondrial permeability transition, on isoflurane-induced and ischemic postconditioning in rabbits. Anesth. Analg., May 1, 2006; 102(5): 1355 - 1360. [Abstract] [Full Text] [PDF]

				F. Di Lisa and P. Bernardi Mitochondria and ischemia-reperfusion injury of the heart: Fixing a hole Cardiovasc Res, May 1, 2006; 70(2): 191 - 199. [Abstract] [Full Text] [PDF]

				Z.-Q. Zhao and J. Vinten-Johansen Postconditioning: Reduction of reperfusion-induced injury Cardiovasc Res, May 1, 2006; 70(2): 200 - 211. [Abstract] [Full Text] [PDF]

				D. J. Hausenloy and D. M. Yellon Survival kinases in ischemic preconditioning and postconditioning Cardiovasc Res, May 1, 2006; 70(2): 240 - 253. [Abstract] [Full Text] [PDF]

				O. Gateau-Roesch, L. Argaud, and M. Ovize Mitochondrial permeability transition pore and postconditioning Cardiovasc Res, May 1, 2006; 70(2): 264 - 273. [Abstract] [Full Text] [PDF]

				A. J. Zatta, H. Kin, G. Lee, N. Wang, R. Jiang, R. Lust, J. G. Reeves, J. Mykytenko, R. A. Guyton, Z.-Q. Zhao, et al. Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signalling Cardiovasc Res, May 1, 2006; 70(2): 315 - 324. [Abstract] [Full Text] [PDF]

				L. M. Schwartz and C. J. Lagranha Ischemic postconditioning during reperfusion activates Akt and ERK without protecting against lethal myocardial ischemia-reperfusion injury in pigs Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1011 - H1018. [Abstract] [Full Text] [PDF]

				S. P. Loukogeorgakis, A. T. Panagiotidou, D. M. Yellon, J. E. Deanfield, and R. J. MacAllister Postconditioning Protects Against Endothelial Ischemia-Reperfusion Injury in the Human Forearm Circulation, February 21, 2006; 113(7): 1015 - 1019. [Abstract] [Full Text] [PDF]

				J.-C. Bopassa, R. Ferrera, O. Gateau-Roesch, E. Couture-Lepetit, and M. Ovize PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning Cardiovasc Res, January 1, 2006; 69(1): 178 - 185. [Abstract] [Full Text] [PDF]

				J. G. Krolikowski, M. Bienengraeber, D. Weihrauch, D. C. Warltier, J. R. Kersten, and P. S. Pagel Inhibition of Mitochondrial Permeability Transition Enhances Isoflurane-Induced Cardioprotection During Early Reperfusion: The Role of Mitochondrial KATP Channels Anesth. Analg., December 1, 2005; 101(6): 1590 - 1596. [Abstract] [Full Text] [PDF]

				J. Vinten-Johansen, D. M. Yellon, and L. H. Opie Postconditioning: A Simple, Clinically Applicable Procedure to Improve Revascularization in Acute Myocardial Infarction Circulation, October 4, 2005; 112(14): 2085 - 2088. [Full Text] [PDF]

				P. Staat, G. Rioufol, C. Piot, Y. Cottin, T. T. Cung, I. L'Huillier, J.-F. Aupetit, E. Bonnefoy, G. Finet, X. Andre-Fouet, et al. Postconditioning the Human Heart Circulation, October 4, 2005; 112(14): 2143 - 2148. [Abstract] [Full Text] [PDF]

				J. E. Davies, S. B. Digerness, C. R. Killingsworth, C. Zaragoza, C. R. Katholi, R. K. Justice, S. P. Goldberg, and W. L. Holman Multiple Treatment Approach to Limit Cardiac Ischemia-Reperfusion Injury Ann. Thorac. Surg., October 1, 2005; 80(4): 1408 - 1416. [Abstract] [Full Text] [PDF]

				C. E. Darling, R. Jiang, M. Maynard, P. Whittaker, J. Vinten-Johansen, and K. Przyklenk Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts: role of ERK1/2 Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1618 - H1626. [Abstract] [Full Text] [PDF]

				G. W. Booz Growing Old, Angiotensin II, Cardiac Hypertrophy, and Death: Making the Connection With p66Shc Hypertension, August 1, 2005; 46(2): 259 - 260. [Full Text] [PDF]

				A. Tsang, D. J. Hausenloy, and D. M. Yellon Myocardial postconditioning: reperfusion injury revisited Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H2 - H7. [Full Text] [PDF]

				H. T.F. Facundo, A. J. Kowaltowski, L. Argaud, O. Gateau-Roesch, O. Raisky, J. Loufouat, M. Ovize, and D. Robert Letter Regarding Article by Argaud et al, "Postconditioning Inhibits Mitochondrial Permeability Transition" Circulation, June 21, 2005; 111(24): e442 - e442. [Full Text] [PDF]

				J. C. Bopassa, P. Michel, O. Gateau-Roesch, M. Ovize, and R. Ferrera Low-pressure reperfusion alters mitochondrial permeability transition Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2750 - H2755. [Abstract] [Full Text] [PDF]

				J. M. Downey and M. V. Cohen We Think We See a Pattern Emerging Here Circulation, January 18, 2005; 111(2): 120 - 121. [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 111/2/194    most recent 01.CIR.0000151290.04952.3Bv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Argaud, L. Articles by Ovize, M. Search for Related Content PubMed PubMed Citation Articles by Argaud, L. Articles by Ovize, M. Related Collections Animal models of human disease Ischemic biology - basic studies Acute myocardial infarction Related Article