Basic Research in Cardiology

, Volume 102, Issue 4, pp 341–349 | Cite as

GSK3β inhibition and KATP channel opening mediate acute opioid-induced cardioprotection at reperfusion

ORIGINAL CONTRIBUTION

Abstract

Both glycogen synthase kinase 3β (GSK3β) and the ATP-dependant potassium channel (KATP) mediate opioid-induced cardioprotection (OIC). However, whether direct KATP channel openers induce cardioprotection prior to reperfusion and their signaling cascade position with respect to GSK3β inhibition is unknown. Therefore, we investigated the role of KATP channel opening at reperfusion in OIC, and the interaction between the GSK signaling axis and KATP channels in cardioprotection.Male Sprague-Dawley rats underwent 30 minutes ischemia with 2 hours of reperfusion and infarct size was determined. Rats given the nonselective opioid agonist, morphine (0.3 mg/kg), or the selective delta opioid agonist, BW373U86 (1.0 mg/kg), 5 minutes prior to reperfusion reduced infarct size (40.3±1.6*, 39.7±1.9* versus 60.0±1.1%, respectively, * P<0.001%). This protection was abrogated with prior administration of the putative sarcolemmal KATP antagonist, HMR-1098 (6 mg/kg), or the putative mitochondrial KATP antagonist, 5-HD (10 mg/kg). The putative sKATP channel opener, P-1075 (1μg/kg) or the putative mKATP channel opener, BMS-191095 (1 mg/kg) given 5 minutes prior to reperfusion also reduced infarct size (41.8±2.4*, 43.4±1.4*) and protection was abrogated by prior administration of the PI3k inhibitor wortmannin (60.0±1.7, 64.0±2.6%, respectively, * P<0.001). Cardioprotection afforded by the GSK inhibitor SB216763 (0.6 mg/kg) given 5 minutes prior to reperfusion was also partially blocked by either HMR or 5-HD and completely blocked when HMR and 5-HD were given in combination (40.8±1.6*, 50.4±1.6^; 49.4±1.7^, 61.6±1.6%, respectively, * or ^ P<0.001). These data indicate that both the sKATP and mKATP channel are involved in acute OIC and the GSK signaling axis regulates cardioprotection via KATP channel opening.

Key words

glycogen synthase kinase KATP channel morphine infarct size reperfusion 

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References

  1. 1.
    Baukrowitz T, Schulte U, Oliver D, Herlitze S, Krauter T, Tucker SJ, Ruppersberg JP, Fakler B (1998) PIP2 and PIP as determinants for ATP inhibition of KATP channels. Science 282(5391):1141–1144PubMedCrossRefGoogle Scholar
  2. 2.
    Cohen MV,Yang XM, Liu GS,Heusch G, Downey JM (2001) Acetylcholine, bradykinin, opioids, and phenylephrine, but not adenosine, trigger preconditioning by generating free radicals and opening mitochondrial K(ATP) channels. Circ Res 89(3):273–278PubMedGoogle Scholar
  3. 3.
    Das B, Sarkar C (2003) Cardiomyocyte mitochondrial KATP channels participate in the antiarrhythmic and antiinfarct effects of KATP activators during ischemia and reperfusion in an intact anesthetized rabbit model. Pol J Pharmacol 55(5):771–786PubMedGoogle Scholar
  4. 4.
    Das M, Parker JE, Halestrap AP (2003) Matrix volume measurements challenge the existence of diazoxide/glibencamide- sensitive KATP channels in rat mitochondria. J Physiol 547:893–902PubMedCrossRefGoogle Scholar
  5. 5.
    Doble BW,Woodgett JR (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116:1175–1186PubMedCrossRefGoogle Scholar
  6. 6.
    Frame S, Cohen P (2001) GSK3 takes centre stage more than 20 years after its discovery. Biochem J 359:1–16PubMedCrossRefGoogle Scholar
  7. 7.
    Fryer RM, Hsu AK, Nagase H, Gross GJ (2000) Opioid-induced cardioprotection against myocardial infarction and arrhythmias: mitochondrial versus sarcolemmal ATP-sensitive potassium channels. J Pharmacol Exp Ther 294(2):451–457PubMedGoogle Scholar
  8. 8.
    Gross ER, Nithipatikom K, Hsu AK, Peart JN, Falck JR, Campbell WB,Gross GJ (2004) Cytochrome P450 omega-hydroxylase inhibition reduces infarct size during reperfusion via the sarcolemmal KATP channel. J Mol Cell Cardiol 37(6):1245–1249PubMedGoogle Scholar
  9. 9.
    Gross ER,Hsu AK,Gross GJ (2004) Opioid- induced cardioprotection occurs via glycogen synthase kinase beta inhibition during reperfusion in intact rat hearts. Circ Res 94(7):960–966PubMedCrossRefGoogle Scholar
  10. 10.
    Gross ER, Peart JN, Hsu AK, Grover GJ, Gross GJ (2003) K(ATP) opener-induced delayed cardioprotection: involvement of sarcolemmal and mitochondrial K(ATP) channels, free radicals and MEK1/2. J Mol Cell Cardiol 35(8):985–992PubMedCrossRefGoogle Scholar
  11. 11.
    Grover GJ, D’Alonzo AJ, Darbenzio RB, Parham CS,Hess TA,Bathala MS (2002) In vivo characterization of the mitochondrial selective K(ATP) opener (3R)-trans-4-((4-chlorophenyl)-N- (1H-imidazol-2-ylmethyl)dimethyl- 2H-1-ben zopyran-6-carbonitril monohydrochloride (BMS-191095): cardioprotective, hemodynamic, and electrophysiological effects. J Pharmacol Exp Ther 303(1):132–140PubMedCrossRefGoogle Scholar
  12. 12.
    Hanley PJ, Drose S, Brandt U, Lareau RA, Banerjee AL, Srivastava DK, Banaszak LJ,Barycki JJ,Van Veldhoven PP, Daut J (2005) 5-Hydroxydecanoate is metabolised in mitochondria and creates a rate-limiting bottleneck for betaoxidation of fatty acids. J Physiol 562:307–318PubMedCrossRefGoogle Scholar
  13. 13.
    Harvey J, Hardy SC, Irving AJ, Ashford ML (2000) Leptin activation of ATPsensitive K+ (KATP) channels in rat CRIG1 insulinoma cells involves disruption of the actin cytoskeleton. J Physiol 527:95–107PubMedCrossRefGoogle Scholar
  14. 14.
    Huh J, Gross GJ, Nagase H, Liang BT (2001) Protection of cardiac myocytes via delta(1)-opioid receptors, protein kinase C, and mitochondrial K(ATP) channels. Am J Physiol Heart Circ Physiol 280(1):H377–H383PubMedGoogle Scholar
  15. 15.
    Jope RS, Johnson GV (2004) The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29(2):95–102PubMedCrossRefGoogle Scholar
  16. 16.
    Juhaszova M,Zorov DB,Kim SH,Pepe S, Fu Q, Fishbein KW, Ziman BD,Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ (2004) Glycogen synthase kinase- 3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 113(11):1535–1549PubMedCrossRefGoogle Scholar
  17. 17.
    Kato R, Ross S, Foex P (2000) Fentanyl protects the heart against ischaemic injury via opioid receptors, adenosine A1 receptors and KATP channel linked mechanisms in rats. Br J Anaesth 84(2): 204–214PubMedGoogle Scholar
  18. 18.
    Liang BT, Gross GJ (1999) Direct preconditioning of cardiac myocytes via opioid receptors and KATP channels. Circ Res 84(12):1396–1400CrossRefGoogle Scholar
  19. 19.
    Light PE, Kanji HD, Fox JE, French RJ (2001) Distinct myoprotective roles of cardiac sarcolemmal and mitochondrial KATP channels during metabolic inhibition and recovery. Faseb J 15(14):2586–2594PubMedCrossRefGoogle Scholar
  20. 20.
    Lim KH, Javadov SA, Das M, Clarke SJ, Suleiman MS, Halestrap AP (2002) The effects of ischaemic preconditioning, diazoxide and 5-hydroxydecanoate on rat heart mitochondrial volume and respiration. J Physiol 545:961–974PubMedCrossRefGoogle Scholar
  21. 21.
    Minami K, Miki T, Kadowaki T, Seino S (2004) Roles of ATP-sensitive K+ channels as metabolic sensors: studies of Kir6.x null mice. Diabetes 53:S176–S180PubMedCrossRefGoogle Scholar
  22. 22.
    Mizumura TK, Nithipatikom K, Gross GJ (1995) Bimakalim, an ATP-sensitive potassium channel opener, mimics the effects of ischemic preconditioning to reduce infarct size, adenosine release, and neutrophil function in dogs. Circulation 92(5):1236–1245PubMedGoogle Scholar
  23. 23.
    Moritani K, Miyazaki T, Miyoshi S, Asanagi M, Zhao LS, Mitamura H, Ogawa S (1994) Blockade of ATP-sensitive potassium channels by 5-hydroxydecanoate suppresses monophasic action potential shortening during regional myocardial ischemia. Cardiovasc Drugs Ther 8(5):749–756PubMedCrossRefGoogle Scholar
  24. 24.
    Oldenburg O, Yang XM, Krieg T, Garlid KD, Cohen MV, Grover GJ, Downey JM (2003) P1075 opens mitochondrial K(ATP) channels and generates reactive oxygen species resulting in cardioprotection of rabbit hearts. J Mol Cell Cardiol 35(9):1035–1042PubMedCrossRefGoogle Scholar
  25. 25.
    Ozcan C, Bienengraeber M, Dzeja PP, Terzic A (2002) Potassium channel openers protect cardiac mitochondria by attenuating oxidant stress at reoxygenation. Am J Physiol Heart Circ Physiol 282(2):H531–H539PubMedGoogle Scholar
  26. 26.
    Patel HH, Hsu AK, Peart JN, Gross GJ (2002) Sarcolemmal K(ATP) channel triggers opioid-induced delayed cardioprotection in the rat. Circ Res 96(3):186–188CrossRefGoogle Scholar
  27. 27.
    Peart JN, Gross ER, Gross GJ (2004) Effect of exogenous kappa-opioid receptor activation in rat model of myocardial infarction. J Cardiovasc Pharmacol 43(3):410–415PubMedCrossRefGoogle Scholar
  28. 28.
    Rajashree R, Koster JC, Markova KP, Nichols CG, Hofmann PA (2002) Contractility and ischemic response of hearts from transgenic mice with altered sarcolemmal K(ATP) channels. Am J Physiol Heart Circ Physiol 283(2):H584–H590PubMedGoogle Scholar
  29. 29.
    Sargent CA, Sleph PG, Dzwonczyk S, Normandin D, Antonaccio MJ, Grover GJ (1993) Cardioprotective effects of the cyanoguanidine potassium channel opener P-1075. J Cardiovasc Pharmacol 22(4):564–570PubMedCrossRefGoogle Scholar
  30. 30.
    Sato T, Sasaki N, Seharaseyon J, O’Rourke B, Marban E et al. (2000) Selective pharmacological agents implicate mitochondrial but not sarcolemmal K(ATP) channels in ischemic cardioprotection. Circulation 101(20):2418–2423PubMedGoogle Scholar
  31. 31.
    Schultz J el-J, Hsu AK, Nagase H, Gross GJ (1998) TAN-67, a delta 1-opioid receptor agonist, reduces infarct size via activation of Gi/o proteins and KATP channels. Am J Physiol 274(3): H909–H914Google Scholar
  32. 32.
    Schultz JJ, Hsu AK, GrossGJ (1997) Ischemic preconditioning and morphine- induced cardioprotection involve the delta (delta)-opioid receptor in the intact rat heart. J Mol Cell Cardiol 29(8):2187–2195PubMedCrossRefGoogle Scholar
  33. 33.
    Schulze D, Rapedius M, Krauter T, Baukrowitz T (2003) Long-chain acyl- CoA esters and phosphatidylinositol phosphates modulate ATP inhibition of KATP channels by the same mechanism. J Physiol 552:357–367PubMedCrossRefGoogle Scholar
  34. 34.
    Shyng SL,Nichols CG (1998) Membrane phospholipid control of nucleotide sensitivity of KATP channels. Science 282(5391):1138–1141PubMedCrossRefGoogle Scholar
  35. 35.
    Suzuki M, Saito T, Sato T, Tamagawa M, Miki T, Seino S, Nakaya H (2003) Cardioprotective effect of diazoxide is mediated by activation of sarcolemmal but not mitochondrial ATP-sensitive potassium channels in mice. Circulation 107(5):682–685PubMedCrossRefGoogle Scholar
  36. 36.
    Suzuki M, Sasaki N, Miki T, Sakamoto N, Ohmoto-Sekine Y, Tamagawa M, Seino S, Marban E, Nakaya H (2002) Role of sarcolemmal K(ATP) channels in cardioprotection against ischemia/ reperfusion injury in mice. J Clin Invest 109(4):509–516PubMedCrossRefGoogle Scholar
  37. 37.
    Vanden Hoek T, Becker LB, Shao ZH, Li CQ, Schumacker PT (2000) Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion. Circ Res 86(5):541–548Google Scholar
  38. 38.
    Xie LH, Takano M, Kakei M, Okamura M, Noma A (1999) Wortmannin, an inhibitor of phosphatidylinositol kinases, blocks the MgATP-dependent recovery of Kir6.2/SUR2A channels. J Physiol 514:655–665PubMedCrossRefGoogle Scholar
  39. 39.
    Yang XM, Proctor JB, Cui L, Krieg T, Downey JM, Cohen MV (2004) Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. J Am Coll Cardiol 44(5):1103–1110PubMedCrossRefGoogle Scholar
  40. 40.
    Zweier JL, Kuppusamy P, Thompson- Gorman S, Klunk D, Lutty GA (1994) Measurement and characterization of free radical generation in reoxygenated human endothelial cells. Am J Physiol 266(3):C700–C708PubMedGoogle Scholar

Copyright information

© Steinkopff-Verlag 2007

Authors and Affiliations

  1. 1.Medical College of WisconsinDept. of Pharmacology and ToxicologyMilwaukee (WI)USA

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