Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 166.39
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2018, vol. 27, nr 8, August, p. 1069–1073

doi: 10.17219/acem/70192

Publication type: original article

Language: English

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Opioidergic conditioning of the human heart muscle in nitric oxide-dependent mechanism

Marcin Kunecki1,A,B,C,D, Tomasz Roleder2,A,B,C, Jolanta Biernat3,C,E,F, Paweł Kukla4,D,E, Lidia Tomkiewicz-Pająk1,C,E,F, Marek A. Deja5,A,E,F, Piotr Podolec1,E,F, Krzysztof S. Gołba3,A,E,F, Wojciech Płazak1,D,E,F

1 Department of Cardiac and Vascular Diseases, the John Paul II Hospital, Jagiellonian University Medical College, Kraków, Poland

2 Department of Cardiology, Medical University of Silesia in Katowice, Poland

3 Department of Electrocardiology and Heart Failure, Medical University of Silesia in Katowice, Poland

4 Faculty of Health Sciences, Jagiellonian University Medical College, Kraków, Poland

5 Department of Cardiac Surgery, Medical University of Silesia in Katowice, Poland


Background. Opioidergic conditioning is well documented to trigger cardioprotection against ischemia/ reperfusion (I/R) injury. Previous studies on animal models have suggested that nitric oxide (NO) mediates the beneficial effect of opioids, but the role of NO in humans seems to be controversial.
Objectives. The aim of the study was to assess the influence of NO modulators on opioid-induced cardioprotection in the human myocardium.
Material and Methods. Trabeculae of the human right atria were electrically driven in an organ bath and subjected to simulated I/R injury. The non-selective inhibitor of nitric oxide synthase (NOS) – N-methyl-l-arginine (LNMMA), the donor of NO – S-Nitroso-N-acetylpenicillamine (SNAP) or morphine (in the amount of 10−4 M) were used at the time of re-oxygenation. The additional trabecula was subjected to the hypoxia protocol only (control). The contractility 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 the cardiac muscle relaxation – as the rate of decay of the force of a contraction (Slope T).
Results. The application of 100 μM LNMMA resulted in the decrease of Amax, Slope L and Slope T during the re-oxygenation period as compared to control. The application of 10−4 M morphine and/or 100 μM SNAP resulted in a partial reversal of the detrimental influence of LNMMA.
Conclusion. At the re-oxygenation period, the blockade of NO synthesis has a deleterious effect on the systolic and diastolic function of the human myocardium as well as attenuates the beneficial effect of morphine conditioning.

Key words

ischemia, nitric oxide, reperfusion, morphine

References (24)

  1. Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: New strategies for cardioprotection. Diabetes Obes Metab. 2008;10(6):451–459.
  2. Meybohm P; RIPHeart Study Collaborators. A multicenter trial of remote ischemic preconditioning for heart surgery. NEJM. 2015;373(15):1397–1407. doi:10.1056/ NEJMoa1413579
  3. Hausenloy DJ, Yellon DM; ERICCA Trial Investigators. Remote ischemic preconditioning and outcomes of cardiac surgery. NEJM. 2015;373(15):1408–1417. doi:10.1056/NEJMoa1413534
  4. Hahn JY, Yu CW, Park HS, et al. Long-term effects of ischemic postconditioning on clinical outcomes: 1-year follow-up of the POST randomized trial. Am Heart J. 2015;169(5):639–646. doi:10.1016/j.ahj.2015.01.015
  5. Lu XH, Ran K, Xiao YY, et al. Protective effects of morphine preconditioning in delayed phase on myocardial ischemia – reperfusion injury in rabbits. Gen Mol Res. 2015;14(3):8947–8954. doi:10.4238/2015
  6. Roleder T, Gołba KS, Kunecki M, et al. The co-application of hypoxic preconditioning and postconditioning abolishes their own protective effect on systolic function in human myocardium. Cardiol J. 2013;20:472–477. doi:10.5603/CJ.2013.0131
  7. Kunecki M, Roleder T, Biernat J, et al. Ochronne działanie układu opioidowego na czynność niedotlenionego ludzkiego mięśnia sercowego w warunkach in vitro. Folia Med Cracov. 2015;55(Suppl 1):48–49.
  8. Valtchanova-Matchouganska A, Ojewole JA. Mechanisms of opioid delta and kappa receptors’ cardioprotection in ischaemic preconditioning in a rat model of myocardial infarction. Cardiovasc J S Afr. 2003;14:73–80.
  9. Chen Z, Li T, Zhang B. Morphine postconditioning protects against reperfusion injury in the isolated rat hearts. J Surg Res. 2008;145:287–294.
  10. Headrick JP, See Hoe LE, Du Toit EF, Peart JN. Opioid receptors and cardioprotection: ‘Opioidergic conditioning’ of the heart. Brit J Pharm. 2015;172:2026–2050. doi:10.1111/bph.13042
  11. Wong GT, Huang Z, Ji S, Irwin MG. 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.
  12. Araszkiewicz A, Grygier M, Pyda M, Rajewska J, Lesiak M, Grajek S. Postconditioning attenuates early ventricular arrhythmias in patients with high-risk ST-segment elevation myocardial infarction. J Cardiol. 2015;65(6):459–465. doi:10.1016/j.jjcc.2015.02.010
  13. Hayashida K, Takeuchi T, Shimizu H, Ando K, Harada E. Lactoferrin enhances opioid-mediated analgesia via nitric oxide in the rat spinal cord. Am J Physiol. 2003;285:R302.
  14. Nagasaka Y, Fernandez BO, Garcia-Saura MF, et al. Brief periods of nitric oxide inhalation protect against myocardial ischemia – reperfusion injury. Anesthesiology. 2008;109:675–682.
  15. Neye N, Enigk F, Shiva S, et al. Inhalation of NO during myocardial ischemia reduces infarct size and improves cardiac function. Intensive Care Med. 2012;38:1381–1391.
  16. Lu Y, Hu J, Zhang Y, Dong C. Spinal neuronal NOS activation mediates intrathecal fentanyl preconditioning induced remote cardioprotection in rats. Int Immunopharmacol. 2014;19:127. doi:10.1016/j.intimp.2014.01.013
  17. Correa F, Buelna-Chontal M, Chagoya V, et al. Inhibition of the nitric oxide/cyclic guanosine monophosphate pathway limited the cardioprotective effect of post-conditioning in hearts with apical myocardial infarction. Eur J Pharmacol. 2015;765:472–481. doi:10.1016/j.ejphar.2015.09.018
  18. Takano H, Manchikalapudi S, Tang XL, et al. Nitric oxide synthase is the mediator of late preconditioning against myocardial infarction in conscious rabbits. Circulation. 1998;98:441–449.
  19. Liang F, Gao E, Tao L, et al. Critical timing of L-arginine treatment in post-ischemic myocardial apoptosis-role of NOS isoforms. Cardiovasc Res. 2004;62(3):568–577.
  20. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. NEJM. 2007;357:1121–1135.
  21. Hattori Y, Kasai K, Gross SS. NO suppresses while peroxynitrite sustains NF-kappaB: A paradigm to rationalize cytoprotective and cytotoxic actions attributed to NO. Cardiovasc Res. 2004;63(1):31–40.
  22. Beręsewicz A, Maczewski M, Duda M. Effect of classic preconditioning and diazoxide on endothelial function and O2− and NO generation in the post-ischemic guinea-pig heart. Cardiovasc Res. 2004;63(1):118–129.
  23. Ohtani H, Katoh H, Tanaka T, et al. Effects of nitric oxide on mitochondrial permeability transition pore and thiol-mediated responses in cardiac myocytes. Nitric Oxide. 2012;26(2):95–101. doi:10.1016/j.niox.2011.12.007
  24. Folino A, Losano G, Rastaldo. Balance of nitric oxide and reactive oxygen species in myocardial reperfusion injury and protection. J Cardiovasc Pharmacol. 2013;62:567–575.