Skip to main content

Advertisement

SpringerLink
Log in

Cyclosporine A at reperfusion fails to reduce infarct size in the in vivo rat heart

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

We examined the effects on infarct size and mitochondrial function of ischemic (Isch), cyclosporine A (CsA) and isoflurane (Iso) preconditioning and postconditioning in the in vivo rat model. Anesthetized open-chest rats underwent 30 min of ischemia followed by either 120 min (protocol 1: infarct size assessment) or 15 min of reperfusion (protocol 2: assessment of mitochondrial function). All treatments administered before the 30-min ischemia (Pre-Isch, Pre-CsA, Pre-Iso) significantly reduced infarct as compared to control. In contrast, only Post-Iso significantly reduced infarct size, while Post-Isch and Post-CsA had no significant protective effect. As for the postconditioning-like interventions, the mitochondrial calcium retention capacity significantly increased only in the Post-Iso group (+58 % vs control) after succinate activation. Only Post-Iso increased state 3 (+177 and +62 %, for G/M and succinate, respectively) when compared to control. Also, Post-Iso reduced the hydrogen peroxide (H2O2) production (−46 % vs control) after complex I activation. This study suggests that isoflurane, but not cyclosporine A, can prevent lethal reperfusion injury in this in vivo rat model. This might be related to the need for a combined effect on cyclophilin D and complex I during the first minutes of reperfusion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Argaud L, Gateau-Roesch O, Muntean D, Chalabreysse L, Loufouat J, Robert D, Ovize M (2005) Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury. J Mol Cell Cardiol 38:367–374. doi:10.1016/j.yjmcc.2004.12.001

    Article  PubMed  CAS  Google Scholar 

  2. Argaud L, Prigent AF, Chalabreysse L, Loufouat J, Lagarde M, Ovize M (2004) Ceramide in the antiapoptotic effect of ischemic preconditioning. Am J Physiol Heart Circ Physiol 286:H246–H251. doi:10.1152/ajpheart.00638.2003

    Article  PubMed  CAS  Google Scholar 

  3. Bhayana V, Alto LE, Dhalla NS (1980) Effects of pentobarbital and pentothal on rat heart contractile force and oxidative phosphorylation activities. Gen Pharmacol 11:375–377

    Article  PubMed  CAS  Google Scholar 

  4. Boengler K, Hilfiker-Kleiner D, Heusch G, Schulz R (2010) Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion. Basic Res Cardiol 105:771–785. doi:10.1007/s00395-010-0124-1

    Article  PubMed  CAS  Google Scholar 

  5. Bopassa JC, Ferrera R, Gateau-Roesch O, Couture-Lepetit E, Ovize M (2006) PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning. Cardiovasc Res 69:178–185. doi:10.1016/j.cardiores.2005.07.014

    Article  PubMed  CAS  Google Scholar 

  6. Boveris A, Cadenas E (1975) Mitochondrial production of superoxide anions and its relationship to the antimycin insensitive respiration. FEBS Lett 54:311–314

    Article  PubMed  CAS  Google Scholar 

  7. Chen Q, Moghaddas S, Hoppel CL, Lesnefsky EJ (2006) Reversible blockade of electron transport during ischemia protects mitochondria and decreases myocardial injury following reperfusion. J Pharmacol Exp Ther 319:1405–1412. doi:10.1124/jpet.106.110262

    Article  PubMed  CAS  Google Scholar 

  8. Chiari PC, Bienengraeber MW, Pagel PS, Krolikowski JG, Kersten JR, Warltier DC (2005) Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol-3-kinase signal transduction: evidence for anesthetic-induced postconditioning in rabbits. Anesthesiology 102:102–109

    Article  PubMed  CAS  Google Scholar 

  9. Dow J, Kloner RA (2007) Postconditioning does not reduce myocardial infarct size in an in vivo regional ischemia rodent model. J Cardiovasc Pharmacol Ther 12:153–163. doi:10.1177/1074248407300897

    Article  PubMed  Google Scholar 

  10. Fabiato A (1982) Calcium release in skinned cardiac cells: variations with species, tissues, and development. Fed Proc 41:2238–2244

    PubMed  CAS  Google Scholar 

  11. Fontaine E, Eriksson O, Ichas F, Bernardi P (1998) Regulation of the permeability transition pore in skeletal muscle mitochondria. Modulation by electron flow through the respiratory chain complex i. J Biol Chem 273:12662–12668

    Article  PubMed  CAS  Google Scholar 

  12. Ge ZD, Pravdic D, Bienengraeber M, Pratt PF Jr, Auchampach JA, Gross GJ, Kersten JR, Warltier DC (2010) Isoflurane postconditioning protects against reperfusion injury by preventing mitochondrial permeability transition by an endothelial nitric oxide synthase-dependent mechanism. Anesthesiology 112:73–85. doi:10.1097/ALN.0b013e3181c4a607

    Article  PubMed  CAS  Google Scholar 

  13. Gomez L, Paillard M, Price M, Chen Q, Teixeira G, Spiegel S, Lesnefsky EJ (2011) A novel role for mitochondrial sphingosine-1-phosphate produced by sphingosine kinase-2 in PTP-mediated cell survival during cardioprotection. Basic Res Cardiol 106:1341–1353. doi:10.1007/s00395-011-0223-7

    Article  PubMed  CAS  Google Scholar 

  14. Gomez L, Thibault H, Gharib A, Dumont JM, Vuagniaux G, Scalfaro P, Derumeaux G, Ovize M (2007) Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice. Am J Physiol Heart Circ Physiol 293:H1654–H1661. doi:10.1152/ajpheart.01378.2006

    Article  PubMed  CAS  Google Scholar 

  15. Hanley PJ, Ray J, Brandt U, Daut J (2002) Halothane, isoflurane and sevoflurane inhibit NADH:ubiquinone oxidoreductase (complex I) of cardiac mitochondria. J Physiol 544:687–693

    Article  PubMed  CAS  Google Scholar 

  16. Hausenloy DJ, Lim SY, Ong SG, Davidson SM, Yellon DM (2010) Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning. Cardiovasc Res 88:67–74. doi:10.1093/cvr/cvq113

    Article  PubMed  CAS  Google Scholar 

  17. Hausenloy DJ, Yellon DM (2007) Preconditioning and postconditioning: united at reperfusion. Pharmacol Ther 116:173–191. doi:10.1016/j.pharmthera.2007.06.005

    Article  PubMed  CAS  Google Scholar 

  18. Heusch G, Boengler K, Schulz R (2008) Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 118:1915–1919. doi:10.1161/CIRCULATIONAHA.108.805242

    Article  PubMed  Google Scholar 

  19. Heusch G, Boengler K, Schulz R (2010) Inhibition of mitochondrial permeability transition pore opening: the Holy Grail of cardioprotection. Basic Res Cardiol 105:151–154. doi:10.1007/s00395-009-0080-9

    Article  PubMed  Google Scholar 

  20. Heusch G, Musiolik J, Gedik N, Skyschally A (2011) Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ Res 109:1302–1308. doi:10.1161/CIRCRESAHA.111.255604

    Article  PubMed  CAS  Google Scholar 

  21. Hirata N, Shim YH, Pravdic D, Lohr NL, Pratt PF Jr, Weihrauch D, Kersten JR, Warltier DC, Bosnjak ZJ, Bienengraeber M (2011) Isoflurane differentially modulates mitochondrial reactive oxygen species production via forward versus reverse electron transport flow: implications for preconditioning. Anesthesiology 115:531–540. doi:10.1097/ALN.0b013e31822a2316

    Article  PubMed  CAS  Google Scholar 

  22. Ichas F, Mazat JP (1998) From calcium signaling to cell death: two conformations for the mitochondrial permeability transition pore. Switching from low- to high-conductance state. Biochim Biophys Acta 1366:33–50

    Article  PubMed  CAS  Google Scholar 

  23. Iliodromitis EK, Georgiadis M, Cohen MV, Downey JM, Bofilis E, Kremastinos DT (2006) Protection from post-conditioning depends on the number of short ischemic insults in anesthetized pigs. Basic Res Cardiol 101:502–507. doi:10.1007/s00395-006-0606-3

    Article  PubMed  Google Scholar 

  24. Janssen M, van der Meer P, de Jong JW (1993) Antioxidant defences in rat, pig, guinea pig, and human hearts: comparison with xanthine oxidoreductase activity. Cardiovasc Res 27:2052–2057

    Article  PubMed  CAS  Google Scholar 

  25. Kaljusto ML, Mori T, Mohammad Husain Rizvi S, Galagudza M, Frantzen ML, Valen G, Vaage J (2006) Postconditioning in rats and mice. Scand Cardiovasc J 40:334–341. doi:10.1080/14017430601007587

    Article  PubMed  Google Scholar 

  26. Kersten JR, Schmeling TJ, Pagel PS, Gross GJ, Warltier DC (1997) Isoflurane mimics ischemic preconditioning via activation of K(ATP) channels: reduction of myocardial infarct size with an acute memory phase. Anesthesiology 87:361–370

    Article  PubMed  CAS  Google Scholar 

  27. Kin H, Zhao ZQ, Sun HY, Wang NP, Corvera JS, Halkos ME, Kerendi F, Guyton RA, Vinten-Johansen J (2004) Postconditioning attenuates myocardial ischemia-reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res 62:74–85. doi:10.1016/j.cardiores.2004.01.006

    Article  PubMed  CAS  Google Scholar 

  28. Kottenberg E, Thielmann M, Bergmann L, Heine T, Jakob H, Heusch G, Peters J (2012) Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol—a clinical trial. Acta Anaesthesiol Scand 56:30–38. doi:10.1111/j.1399-6576.2011.02585.x

    Article  PubMed  CAS  Google Scholar 

  29. Kuznetsov AV, Veksler V, Gellerich FN, Saks V, Margreiter R, Kunz WS (2008) Analysis of mitochondrial function in situ in permeabilized muscle fibers, tissues and cells. Nat Protoc 3:965–976. doi:10.1038/nprot.2008.61

    Article  PubMed  CAS  Google Scholar 

  30. Li B, Chauvin C, De Paulis D, De Oliveira F, Gharib A, Vial G, Lablanche S, Leverve X, Bernardi P, Ovize M, Fontaine E (2012) Inhibition of complex I regulates the mitochondrial permeability transition through a phosphate-sensitive inhibitory site masked by cyclophilin D. Biochim Biophys Acta 1817:1628–1634. doi:10.1016/j.bbabio.2012.05.011

    Article  PubMed  CAS  Google Scholar 

  31. Liu L, Zhu J, Brink PR, Glass PS, Rebecchi MJ (2011) Age-associated differences in the inhibition of mitochondrial permeability transition pore opening by cyclosporine A. Acta Anaesthesiol Scand 55:622–630. doi:10.1111/j.1399-6576.2011.02421.x

    Article  PubMed  CAS  Google Scholar 

  32. Loschen G, Azzi A, Richter C, Flohe L (1974) Superoxide radicals as precursors of mitochondrial hydrogen peroxide. FEBS Lett 42:68–72

    Article  PubMed  CAS  Google Scholar 

  33. Paillard M, Gomez L, Augeul L, Loufouat J, Lesnefsky EJ, Ovize M (2009) Postconditioning inhibits mPTP opening independent of oxidative phosphorylation and membrane potential. J Mol Cell Cardiol 46:902–909. doi:10.1016/j.yjmcc.2009.02.017

    Article  PubMed  CAS  Google Scholar 

  34. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, Andre-Fouet X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M (2008) Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med 359:473–481. doi:10.1056/NEJMoa071142

    Article  PubMed  CAS  Google Scholar 

  35. Piriou V, Chiari P, Gateau-Roesch O, Argaud L, Muntean D, Salles D, Loufouat J, Gueugniaud PY, Lehot JJ, Ovize M (2004) Desflurane-induced preconditioning alters calcium-induced mitochondrial permeability transition. Anesthesiology 100:581–588

    Article  PubMed  CAS  Google Scholar 

  36. Pratt PF Jr, Wang C, Weihrauch D, Bienengraeber MW, Kersten JR, Pagel PS, Warltier DC (2006) Cardioprotection by volatile anesthetics: new applications for old drugs? Curr Opin Anaesthesiol 19:397–403. doi:10.1097/01.aco.0000236139.31099.b5

    Article  PubMed  Google Scholar 

  37. Pravdic D, Sedlic F, Mio Y, Vladic N, Bienengraeber M, Bosnjak ZJ (2009) Anesthetic-induced preconditioning delays opening of mitochondrial permeability transition pore via protein kinase C-epsilon-mediated pathway. Anesthesiology 111:267–274. doi:10.1097/ALN.0b013e3181a91957

    Article  PubMed  CAS  Google Scholar 

  38. Sedlic F, Pravdic D, Hirata N, Mio Y, Sepac A, Camara AK, Wakatsuki T, Bosnjak ZJ, Bienengraeber M (2010) Monitoring mitochondrial electron fluxes using NAD(P)H-flavoprotein fluorometry reveals complex action of isoflurane on cardiomyocytes. Biochim Biophys Acta 1797:1749–1758. doi:10.1016/j.bbabio.2010.07.009

    Article  PubMed  CAS  Google Scholar 

  39. Skyschally A, Schulz R, Heusch G (2010) Cyclosporine A at reperfusion reduces infarct size in pigs. Cardiovasc Drugs Ther 24:85–87. doi:10.1007/s10557-010-6219-y

    Article  PubMed  Google Scholar 

  40. Skyschally A, van Caster P, Iliodromitis EK, Schulz R, Kremastinos DT, Heusch G (2009) Ischemic postconditioning: experimental models and protocol algorithms. Basic Res Cardiol 104:469–483. doi:10.1007/s00395-009-0040-4

    Article  PubMed  Google Scholar 

  41. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L’Huillier I, Aupetit JF, Bonnefoy E, Finet G, Andre-Fouet X, Ovize M (2005) Postconditioning the human heart. Circulation 112:2143–2148. doi:10.1161/CIRCULATIONAHA.105.558122

    Article  PubMed  Google Scholar 

  42. Stewart S, Lesnefsky EJ, Chen Q (2009) Reversible blockade of electron transport with amobarbital at the onset of reperfusion attenuates cardiac injury. Transl Res 153:224–231. doi:10.1016/j.trsl.2009.02.003

    Article  PubMed  CAS  Google Scholar 

  43. Tanaka K, Weihrauch D, Kehl F, Ludwig LM, LaDisa JF Jr, Kersten JR, Pagel PS, Warltier DC (2002) Mechanism of preconditioning by isoflurane in rabbits: a direct role for reactive oxygen species. Anesthesiology 97:1485–1490

    Article  PubMed  CAS  Google Scholar 

  44. Tang XL, Sato H, Tiwari S, Dawn B, Bi Q, Li Q, Shirk G, Bolli R (2006) Cardioprotection by postconditioning in conscious rats is limited to coronary occlusions <45 min. Am J Physiol Heart Circ Physiol 291:H2308–H2317. doi:10.1152/ajpheart.00479.2006

    Article  PubMed  CAS  Google Scholar 

  45. Teixeira G, Abrial M, Portier K, Chiari P, Couture-Lepetit E, Tourneur Y, Ovize M, Gharib A (2013) Synergistic protective effect of cyclosporin A and rotenone against hypoxia-reoxygenation in cardiomyocytes. J Mol Cell Cardiol 56:55–62. doi:10.1016/j.yjmcc.2012.11.023

    Article  PubMed  CAS  Google Scholar 

  46. Tsutsumi YM, Yokoyama T, Horikawa Y, Roth DM, Patel HH (2007) Reactive oxygen species trigger ischemic and pharmacological postconditioning: in vivo and in vitro characterization. Life Sci 81:1223–1227. doi:10.1016/j.lfs.2007.08.031

    Article  PubMed  CAS  Google Scholar 

  47. Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357:1121–1135. doi:10.1056/NEJMra071667

    Article  PubMed  CAS  Google Scholar 

  48. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285:H579–H588. doi:10.1152/ajpheart.01064.2002

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work was supported by the Institut National de la Santé et de la Recherche Médicale (Inserm U1060) and by a Grant No. ASE09027CSA from the Inserm/DHOS program (to Dr. Chiari). Damien De Paulis was a recipient of a grant from the Ministère de l’Enseignement Supérieur et de la Recherche, France.

Conflict of interest

None declared.

Author information

Authors and Affiliations

  1. Inserm U1060, CarMeN Laboratoire, Laboratoire de Physiologie Lyon Nord, Lyon University, Univ Lyon-1, 8 Av Rockefeller, 69373, Lyon, France

    Damien De Paulis, Pascal Chiari, Geoffrey Teixeira, Elisabeth Couture-Lepetit, Maryline Abrial, Laurent Argaud, Abdallah Gharib & Michel Ovize

  2. Service d’Anesthésie Réanimation, Hôpital Louis Pradel, Hospices Civils de Lyon, 69677, Lyon, France

    Pascal Chiari

  3. Service de Réanimation Médicale, Hôpital Edouard Herriot, Hospices Civils de Lyon, 69373, Lyon, France

    Laurent Argaud

  4. Service d’Explorations Fonctionnelles Cardiovasculaires et CIC de Lyon, Hôpital Louis Pradel, Hospices Civils de Lyon, 69677, Lyon, France

    Michel Ovize

Authors
  1. Damien De Paulis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pascal Chiari
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Geoffrey Teixeira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elisabeth Couture-Lepetit
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maryline Abrial
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Laurent Argaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Abdallah Gharib
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michel Ovize
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abdallah Gharib.

Rights and permissions

Reprints and permissions

About this article

Cite this article

De Paulis, D., Chiari, P., Teixeira, G. et al. Cyclosporine A at reperfusion fails to reduce infarct size in the in vivo rat heart. Basic Res Cardiol 108, 379 (2013). https://doi.org/10.1007/s00395-013-0379-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-013-0379-4

Keywords

Search

Navigation