Vol 24, No 4 (2017)
Original articles — Basic science and experimental cardiology
Published online: 2016-10-11

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‘Opioidergic postconditioning’ of heart muscle during ischemia/reperfusion injury

Marcin Kunecki, Wojciech Płazak, Tomasz Roleder, Jolanta Biernat, Tomasz Oleksy, Piotr Podolec, Krzysztof S. Gołba
Pubmed: 27734456
Cardiol J 2017;24(4):419-426.


Background: Ischemic preconditioning and postconditioning are the novel strategies of attaining cardioprotection against ischemia/reperfusion (I/R) injury. Previous studies suggested the role of opioid pathway, however the class of opioid receptors responsible for this effect in humans remains unknown. The aim of the study was to assess the influence of opioids on simulated I/R injury outcomes in the hu­man myocardium.

Methods: Trabeculae of the human right atrium were electrically driven in organ bath and subjected to simulated I/R injury. Morphine (10–4M, 10–5M, 10–6M) or d-opioid receptor agonist DADLE (10–8M, 10–7M, 10–6M) was used at the time of re-oxygenation. Additional trabecula was subjected to hypoxia protocol only (Control). Contractive force of the myocardium was assessed as the maximal force of a contraction (Amax), the rate of rise of the force of a contraction (Slope L) and relaxation as the rate of decay of the force of a contraction (Slope T).

Results: Application of morphine 10–4M resulted in increase of Amax, Slope L and Slope T during re-oxygenation period as compared to Control (77.99 ± 1.5% vs. 68.8 ± 2.2%, p < 0.05; 45.72 ± 2.9% vs. 34.12 ± 5.1%, p < 0.05; 40.95 ± 2.5% vs. 32.37 ± 4.3%, p < 0.05). Parameters were not significantly different in the lower morphine concentrations. Application of DADLE 10–6M resulted in decrease of Amax and Slope L as compared to Control (68.13 ± 5.5% vs. 76.62 ± 6.6%, p < 0.05; 28.29 ± 2.2 vs. 34.80 ± 3.9%, p < 0.05).

Conclusions: At re-oxygenation, morphine improves systolic and diastolic function of the human myo­cardium in the dose-dependent manner. Delta-opioid receptor stimulation attenuates systolic function of human heart muscle which remains in contrast to previous reports with animal models of I/R injury. (Cardiol J 2017; 24, 4: 419–425)

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  1. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986; 74(5): 1124–1136.
  2. Yellon DM, Alkhulaifi AM, Pugsley WB. Preconditioning the human myocardium. Lancet. 1993; 342(8866): 276–277.
  3. Granfeldt A, Lefer DJ, Vinten-Johansen J. Protective ischaemia in patients: preconditioning and postconditioning. Cardiovasc Res. 2009; 83(2): 234–246.
  4. Vinten-Johansen J. Postconditioning: a mechanical maneuver that triggers biological and molecular cardioprotective responses to reperfusion. Heart Fail Rev. 2007; 12(3-4): 235–244.
  5. Lu XH, Ran K, Xiao YY, et al. Protective effects of morphine preconditioning in delayed phase on myocardial ischemia-reperfusion injury in rabbits. Genet Mol Res. 2015; 14(3): 8947–8954.
  6. Schultz JE, Hsu AK, Gross GJ. Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart. Circ Res. 1996; 78(6): 1100–1104.
  7. Peart JN, Gross GJ. Exogenous activation of delta- and kappa-opioid receptors affords cardioprotection in isolated murine heart. Basic Res Cardiol. 2004; 99(1): 29–37.
  8. Fuardo M, Lemoine S, Lo Coco C, et al. [D-Ala2,D-Leu5]-enkephalin (DADLE) and morphine-induced postconditioning by inhibition of mitochondrial permeability transition pore, in human myocardium. Exp Biol Med (Maywood). 2013; 238(4): 426–432.
  9. Jang Y, Xi J, Wang H, et al. Postconditioning prevents reperfusion injury by activating delta-opioid receptors. Anesthesiology. 2008; 108(2): 243–250.
  10. Tanaka K, Kersten JR, Riess ML. Opioid-induced cardioprotection. Curr Pharm Des. 2014; 20(36): 5696–5705.
  11. Bell SP, Sack MN, Patel A, et al. Delta opioid receptor stimulation mimics ischemic preconditioning in human heart muscle. J Am Coll Cardiol. 2000; 36(7): 2296–2302.
  12. Steg PG, James SK, Atar D, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J. 2012; 33(20): 2569–2619.
  13. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 130(25): 2354–2394.
  14. Ellingsrud C, Agewall S. Morphine in the treatment of acute pulmonary oedema. Tidsskr Nor Laegeforen. 2014; 134(23-24): 2272–2275.
  15. Lemoine S, Zhu L, Massetti M, et al. Continuous administration of remifentanil and sufentanil induces cardioprotection in human myocardium, in vitro. Acta Anaesthesiol Scand. 2011; 55(6): 758–764.
  16. Shen H, Ben Q, Zhang Y, et al. Role of δ2 opioid receptor in cardioprotection against hypoxia-reoxygenation injury. J Cardiovasc Pharmacol. 2012; 60(3): 253–261.
  17. Gross ER, Hsu AK, Gross GJ. Opioid-induced cardioprotection occurs via glycogen synthase kinase beta inhibition during reperfusion in intact rat hearts. Circ Res. 2004; 94(7): 960–966.
  18. Peart JN, Gross GJ. Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors. Am J Physiol Heart Circ Physiol. 2003; 285(1): H81–H89.
  19. Peart JN, Patel HH, Gross GJ. Delta-opioid receptor activation mimics ischemic preconditioning in the canine heart. J Cardiovasc Pharmacol. 2003; 42(1): 78–81.
  20. Wang G, Wu S, Pei J, et al. Kappa- but not delta-opioid receptors mediate effects of ischaemic preconditioning on both infarct and arrhythmia in rats. Am J Physiol Heart Circ Physiol. 2001; 280: H384–H391.
  21. Cheng L, Ma S, Wei LX, et al. Cardioprotective and antiarrhythmic effect of U50,488H in ischemia/reperfusion rat heart. Heart Vessels. 2007; 22(5): 335–344.
  22. Tsai HJ, Huang SS, Tsou MT, et al. Role of Opioid Receptors Signaling in Remote Electrostimulation--Induced Protection against Ischemia/Reperfusion Injury in Rat Hearts. PLoS One. 2015; 10(10): e0138108.
  23. Aitchison KA, Baxter GF, Awan MM, et al. Opposing effects on infarction of delta and kappa opioid receptor activation in the isolated rat heart: implications for ischemic preconditioning. Basic Res Cardiol. 2000; 95(1): 1–10; discussion 11.
  24. Sobanski P, Krajnik M, Shaqura M, et al. The presence of mu-, delta-, and kappa-opioid receptors in human heart tissue. Heart Vessels. 2014; 29(6): 855–863.
  25. Zhang Ye, Irwin MG, Wong TM. Remifentanil preconditioning protects against ischemic injury in the intact rat heart. Anesthesiology. 2004; 101(4): 918–923.
  26. Wong GTC, Huang Z, Ji S, et al. Remifentanil reduces the release of biochemical markers of myocardial damage after coronary artery bypass surgery: a randomized trial. J Cardiothorac Vasc Anesth. 2010; 24(5): 790–796.
  27. Ela C, Barg J, Vogel Z, et al. Distinct components of morphine effects on cardiac myocytes are mediated by the kappa and delta opioid receptors. J Mol Cell Cardiol. 1997; 29(2): 711–720.
  28. Pagel PS, Krolikowski JG, Amour J, et al. Morphine reduces the threshold of helium preconditioning against myocardial infarction: the role of opioid receptors in rabbits. J Cardiothorac Vasc Anesth. 2009; 23(5): 619–624.
  29. Lucchinetti E, da Silva R, Pasch T, et al. Anaesthetic preconditioning but not postconditioning prevents early activation of the deleterious cardiac remodelling programme: evidence of opposing genomic responses in cardioprotection by pre- and postconditioning. Br J Anaesth. 2005; 95(2): 140–152.
  30. Obal D, Dettwiler S, Favoccia C, et al. The influence of mitochondrial KATP-channels in the cardioprotection of preconditioning and postconditioning by sevoflurane in the rat in vivo. Anesth Analg. 2005; 101(5): 1252–1260.
  31. Weber TP, Stypmann J, Meissner A, et al. Naloxone improves functional recovery of myocardial stunning in conscious dogs through its action on the central nervous system. Br J Anaesth. 2001; 86(4): 545–549.
  32. Ling Ling J, Wong GTC, Yao L, et al. Remote pharmacological post-conditioning by intrathecal morphine: cardiac protection from spinal opioid receptor activation. Acta Anaesthesiol Scand. 2010; 54(9): 1097–1104.
  33. Wong GTC, Ling Ling J, Irwin MG. Activation of central opioid receptors induces cardioprotection against ischemia-reperfusion injury. Anesth Analg. 2010; 111(1): 24–28.
  34. Peart JN, Pepe S, Reichelt ME, et al. Dysfunctional survival-signaling and stress-intolerance in aged murine and human myocardium. Exp Gerontol. 2014; 50: 72–81.
  35. Headrick JP, See Hoe LE, Du Toit EF, et al. Opioid receptors and cardioprotection - 'opioidergic conditioning' of the heart. Br J Pharmacol. 2015; 172(8): 2026–2050.
  36. Cao Z, Liu L, Packwood W, et al. Met5-enkephalin-induced cardioprotection occurs via transactivation of EGFR and activation of PI3K. Am J Physiol Heart Circ Physiol. 2005; 288(4): H1955–H1964.
  37. Pepe S, van den Brink OWV, Lakatta EG, et al. Cross-talk of opioid peptide receptor and beta-adrenergic receptor signalling in the heart. Cardiovasc Res. 2004; 63(3): 414–422.
  38. Pfeiffer M, Koch T, Schröder H, et al. Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization. J Biol Chem. 2002; 277(22): 19762–19772.