Cardiovascular Drugs and Therapy

, Volume 23, Issue 4, pp 263–270 | Cite as

Pharmacological Preconditioning in Type 2 Diabetic Rat Hearts: The Roles of Mitochondrial ATP-Sensitive Potassium Channels and the Phosphatidylinositol 3-Kinase-Akt Pathway

  • Shuhei Matsumoto
  • Sungsam Cho
  • Shinya Tosaka
  • Hiroyuki Ureshino
  • Takuji Maekawa
  • Tetsuya Hara
  • Koji Sumikawa



The authors examined whether olprinone, a phosphodiesterase type 3 inhibitor, or isoflurane, a volatile anesthetic, could protect the heart against myocardial infarction in type 2 diabetic rats and whether the underlying mechanisms involve protein kinase C (PKC), mitochondrial ATP-sensitive potassium (m-KATP) channels, or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway.


All rats underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion. Wistar rats received isoflurane or olprinone before ischemia with or without the PKC inhibitor chelerythrine (CHE), the m-KATP channel blocker 5-hydroxydecanoic acid (5HD), or the PI3K-Akt inhibitor LY294002 (LY). Goto-Kakizaki (GK) rats were randomly assigned to receive isoflurane or olprinone. In another group, GK rats received LY before the olprinone.


In the Wistar rats, both isoflurane (38 ± 11%) and olprinone (40 ± 11%) reduced infarct size as compared to the control group (59 ± 8%). In the GK rats, olprinone (41 ± 9%) but not isoflurane (53 ± 11%) reduced infarct size as compared to the GK control group (58 ± 14%). The beneficial effects of olprinone were blocked by LY (58 ± 14%). In the Wistar rats, CHE, 5HD, and LY prevented isoflurane-induced reductions of infarct size. On the other hand, LY but not CHE or 5HD prevented olprinone-induced reductions of infarct size.


Olprinone but not isoflurane protects the heart against myocardial infarction in type 2 diabetic rats. The olprinone-induced cardioprotective effect is mediated by the PI3K-Akt pathway but not PKC or m-KATP channels.

Key words

Olprinone Isoflurane Diabetes Mitochondrial ATP-sensitive potassium channels Phosphatidylinositol 3-kinase-Akt 



This work was supported in part by Grants-In-Aid 90325655 (to Dr. Cho) and 60028660 (to Dr. Sumikawa) for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. This work was presented in part at the annual meeting of the American Society of Anesthesiologists, Orlando, Florida, October 18–22, 2008.


  1. 1.
    Aguilar D, Solomon SD, Kober L, et al. Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the Valsartan in Acute Myocardial Infarction (VALIANT) Trial. Circulation 2004;110:1572–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Kersten JR, Toller WG, Gross ER, Pagel PS, Warltier DC. Diabetes abolishes ischemic preconditioning: role of glucose, insulin, and osmolality. Am J Physiol Heart Circ Physiol. 2000;278:H1218–24.PubMedGoogle Scholar
  3. 3.
    Tosaki A, Engelman DT, Engelman RM, Das DK. The evolution of diabetic response to ischemia/reperfusion and preconditioning in isolated working rat hearts. Cardiovasc Res. 1996;31:526–36.PubMedGoogle Scholar
  4. 4.
    del Valle HF, Lascano EC, Negroni JA. Ischemic preconditioning protection against stunning in conscious diabetic sheep: role of glucose, insulin, sarcolemmal and mitochondrial KATP channels. Cardiovasc Res. 2002;55:642–59.PubMedCrossRefGoogle Scholar
  5. 5.
    Tanaka K, Kehl F, Gu W, et al. Isofurane-induced preconditioning is attenuated by diabetes. Am J Physiol Heart Circ Physiol. 2002;282:H2018–23.PubMedGoogle Scholar
  6. 6.
    Kersten JR, Montgomery MW, Ghassemi T, et al. Diabetes and hyperglycemia impair activation of mitochondrial KATP channels. Am J Physiol Heart Circ Physiol. 2001;280:H1744–50.PubMedGoogle Scholar
  7. 7.
    Ghosh S, Standen NB, Galiñanes M. Failure to precondition pathological human myocardium. J Am Coll Cardiol. 2001;37:711–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Hassouna A, Loubani M, Matata BM, Fowler A, Standen NB, Galinanes M. Mitochondrial dysfunction as the cause of the failure to precondition the diabetic human myocardium. Cardiovasc Res. 2006;69:450–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Katakam PV, Jordan JE, Snipes JA, Tulbert CD, Miller AW, Busija DW. Myocardial preconditioning against ischemia-reperfusion injury is abolished in Zucker obese rats with insulin resistance. Am J Physiol Regul Integr Comp Physiol. 2007;292:R920–6.PubMedGoogle Scholar
  10. 10.
    Ghosh S, Standen NB, Galiñanes M. Evidence for mitochondrial K channels as effectors of human ATP myocardial preconditioning. Cardiovasc Res. 2000;45:934–40.PubMedCrossRefGoogle Scholar
  11. 11.
    Lebuffe G, Schumacker PT, Shao ZH, Anderson T, Iwase H, Vanden Hoek TL. ROS and NO trigger early preconditioning: relationship to mitochondrial KATP channel. Am J Physiol Heart Circ Physiol. 2003;284:H299–308.PubMedGoogle Scholar
  12. 12.
    Obal D, Dettwiler S, Favoccia C, Scharbatke H, Preckel B, Schlack W. The influence of mitochondrial KATP-Channels in the cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo. Anesth Analg. 2005;101:1252–60.PubMedCrossRefGoogle Scholar
  13. 13.
    Tanaka K, Weihrauch D, Ludwig LM, Kersten JR, Pagel PS, Warltier DC. Mitochondrial adenosine triphosphate-regulated potassium channel opening acts as a trigger for isoflurane-induced preconditioning by generating reactive oxygen species. Anesthesiology 2003;98:935–43.PubMedCrossRefGoogle Scholar
  14. 14.
    Wang Y, Ashraf M. Role of protein kinase C in mitochondrial KATP channel-mediated protection against Ca2+ overload injury in rat myocardium. Circ Res. 1999;84:1156–65.PubMedGoogle Scholar
  15. 15.
    Sato T, O’Rourke B, Marban E. Modulation of mitochondrial ATP dependent K+ channels by protein kinase C. Circ Res. 1998;83:110–4.PubMedGoogle Scholar
  16. 16.
    Satoh H, Endoh M. Effects of a new cardiotonic agent 1, 2-dihydro-6-methyl-2-oxo-5-[imidazo (1, 2-a) pyridine-6-yl]-3- pyridine carbonitrile hydrochloride monohydrate (E-1020) on contractile force and cyclic AMP metabolism in canine ventricular muscle. Jpn J Pharmacol. 1990;52:215–24.PubMedCrossRefGoogle Scholar
  17. 17.
    Goyal RK, McNeill JH. Effects of chronic streptozotocin-induced diabetes on the cardiac responses to milrinone. Can J Physiol Pharmacol. 1985;63:1620–3.PubMedGoogle Scholar
  18. 18.
    Sanada S, Asanuma H, Tsukamoto O, et al. Protein kinase A as another mediator of ischemic preconditioning independent of protein kinase C. Circulation 2001;104:705–10.PubMedCrossRefGoogle Scholar
  19. 19.
    Goto Y, Kakizaki M, Masaki N. Production of spontaneous diabetic rats by repetition of selective breeding. Tohoku J Exp Med. 1976;119:85–90.PubMedCrossRefGoogle Scholar
  20. 20.
    Goto Y, Suzuki K, Ono T, Sasaki M, Toyota T. Development of diabetes in the non-obese NIDDM rat (GK rat). Adv Exp Med Biol. 1988;246:29–31.PubMedGoogle Scholar
  21. 21.
    Janssen U, Phillips AO, Floege J. Rodent models of nephropathy associated with type II diabetes. J Nephrol. 1999;12:159–72.PubMedGoogle Scholar
  22. 22.
    King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998;21:1414–31.PubMedCrossRefGoogle Scholar
  23. 23.
    Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM. Preconditioning the Diabetic Heart: The Importance of Akt Phosphorylation. Diabetes 2005;54:2360–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Kristiansen SB, Løfgren B, Støttrup NB, et al. Ischaemic preconditioning does not protect the heart in obese and lean animal models of type 2 diabetes. Diabetologia 2004;47:1716–21.PubMedCrossRefGoogle Scholar
  25. 25.
    Ludwig LM, Weihrauch D, Kersten JR, Pagel PS, Warltier DC. 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. Anesthesiology 2004;100:532–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Raphael J, Abedat S, Rivo J, et al. Volatile anesthetic preconditioning attenuates myocardial apoptosis in rabbits after regional ischemia and reperfusion via Akt signaling and modulation of Bcl-2 family proteins. J Pharmacol Exp Ther. 2006;318:186–94.PubMedCrossRefGoogle Scholar
  27. 27.
    Tosaka S, Makita T, Tosaka R, et al. Cardioprotection induced by olprinone, a phosphodiesterase III inhibitor, involves phosphatidylinositol-3-OH kinase-Akt and a mitochondrial permeability transition pore during early reperfusion. J Anesth. 2007;21:176–80.PubMedCrossRefGoogle Scholar
  28. 28.
    Ravingerová T, Matejíková J, Neckár J. Differential role of PI3K/Akt pathway in the infarct size limitation and antiarrhythmic protection in the rat heart. Mol Cell Biochem. 2007;297:111–20.PubMedCrossRefGoogle Scholar
  29. 29.
    Kehl F, Krolikowski JG, Mraovic B, Pagel PS, Warltier DC, Kersten JR. Hyperglycemia prevents isoflurane-induced preconditioning against myocardial infarction. Anesthesiology 2002;96:183–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Sanada S, Kitakaze M, Papst PJ, et al. Cardioprotective effect afforded by transient exposure to phosphodiesterase III inhibitors. Circulation 2001;104:705–10.PubMedCrossRefGoogle Scholar
  31. 31.
    Wolfrum S, Dendorfer A, Rikitake Y, et al. Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection. Arterioscler Thromb Vasc Biol. 2004;24:1842–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Downey JM, Davis AM, Cohen MV. Signaling pathways in ischemic preconditioning. Heart Fail Rev. 2007;12:181–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Jaffe JR, Nag SS, Landsman PB, Alexander CM. Reassessment of cardiovascular risk in diabetes. Curr Opin Lipidol. 2006;17:644–52.PubMedCrossRefGoogle Scholar
  34. 34.
    Sato F, Isoyama S, Takishima T. Normalization of impaired coronary circulation in hypertrophied rat hearts. Hypertension 1990;16:26–34.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Shuhei Matsumoto
    • 1
  • Sungsam Cho
    • 1
  • Shinya Tosaka
    • 1
  • Hiroyuki Ureshino
    • 1
  • Takuji Maekawa
    • 1
  • Tetsuya Hara
    • 1
  • Koji Sumikawa
    • 1
  1. 1.Department of AnesthesiologyNagasaki University School of MedicineNagasakiJapan

Personalised recommendations