Skip to main content
Log in

Optimal intervention time of vagal stimulation attenuating myocardial ischemia/reperfusion injury in rats

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

To determine the optimal intervention time of the vagal stimulation (VS) attenuating myocardial ischemia/reperfusion injury (IRI).

Methods

One hundred and twenty male SD rats were randomly allocated into six groups: sham group, IRI group, the VS performed at 15 min of ischemia (VSI15) group, the VS performed immediately before reperfusion (VSR0) group, the VS performed at 30 min of reperfusion (VSR30) group, and the VS performed at 60 min of reperfusion (VSR60) group. Rats in each group were further allocated into subgroups A and B. In each group, the hemodynamics and ventricular arrhythmias were continuously observed. In the subgroup A, serum inflammatory cytokine levels were tested, and infarct size was assessed. In the subgroup B, myocardial inflammatory cytokine levels in both ischemic and non-ischemic regions were assayed.

Results

As compared to the IRI, VSR0, VSR30 and VSR60 groups, infarct size, serum HMGB-1 and ICAM-1 levels at 120 min of reperfusion, myocardial HMGB-1, IL-1 and IL-6 levels in non-ischemic region, myocardial ICAM-1 level in ischemic region were all significantly decreased in the VSI15 group. Compared with the IRI group, myocardial IL-10 levels in both ischemic and non-ischemic regions were significantly increased in the VSI15 group. Compared to the IRI, VSR0, VSR30 and VSR60 groups, incidence and score of ventricular arrhythmia during initial reperfusion were significantly decreased in the VSI15 group.

Conclusions

The VS performed at 15 min of ischemia provides the best protection against myocardial IRI. Also, early modulation on inflammatory responses caused by myocardial IRI may contribute to this best cardioprotection.

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

Access this article

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

Similar content being viewed by others

References

  1. Miller TD, Christian TF, Hopfenspirger MR, Hodge DO, Gersh BJ, Gibbons RJ. Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality. Circulation. 1995;92(3):334–41.

    Article  CAS  PubMed  Google Scholar 

  2. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357(11):1121–35.

    Article  CAS  PubMed  Google Scholar 

  3. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361(9351):13–20.

    Article  PubMed  Google Scholar 

  4. Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res. 2002;53(1):31–47.

    Article  CAS  PubMed  Google Scholar 

  5. Steffens S, Montecucco F, Mach F. The inflammatory response as a target to reduce myocardial ischaemia and reperfusion injury. Thromb Haemost. 2009;102(2):240–7.

    CAS  PubMed  Google Scholar 

  6. Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A, Takahashi Y, Masumoto J, Koyama J, Hongo M, Noda T, Nakayama J, Sagara J, Taniguchi S, Ikeda U. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation. 2011;123(6):594–604.

    Article  CAS  PubMed  Google Scholar 

  7. Wang Q, Cheng Y, Xue FS, Yuan YJ, Xiong J, Li RP, Liao X, Liu JH. Postconditioning with vagal stimulation attenuates local and systemic inflammatory responses to myocardial ischemia reperfusion injury in rats. Inflamm Res. 2012;61(11):1273–82.

    Article  CAS  PubMed  Google Scholar 

  8. Uemura K, Zheng C, Li M, Kawada T, Sugimachi M. Early short-term vagal nerve stimulation attenuates cardiac remodeling after reperfused myocardial infarction. J Card Fail. 2010;16(8):689–99.

    Article  PubMed  Google Scholar 

  9. Calvillo L, Vanoli E, Andreoli E, Besana A, Omodeo E, Gnecchi M, Zerbi P, Vago G, Busca G, Schwartz PJ. Vagal stimulation, through its nicotinic action, limits infarct size and the inflammatory response to myocardial ischemia and reperfusion. J Cardiovasc Pharmacol. 2011;58(5):500–7.

    Article  CAS  PubMed  Google Scholar 

  10. Tracey KJ. Reflex control of immunity. Nat Rev Immunol. 2009;9(6):418–28.

    Article  CAS  PubMed  Google Scholar 

  11. Zitnik RJ. Treatment of chronic inflammatory diseases with implantable medical devices. Ann Rheum Dis. 2011;70(Suppl 1):i67–70.

    Article  PubMed  Google Scholar 

  12. Howland RH, Shutt LS, Berman SR, Spotts CR, Denko T. The emerging use of technology for the treatment of depression and other neuropsychiatric disorders. Ann Clin Psychiatry. 2011;23(1):48–62.

    PubMed  Google Scholar 

  13. Shuchman M. Approving the vagus-nerve stimulator for depression. N Engl J Med. 2007;356(16):1604–7.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang JQ, Wang Q, Xue FS, Li RP, Cheng Y, Cui XL, Liao X, Meng FM. Ischemic preconditioning produces more powerful anti-inflammatory and cardioprotective effects than limb remote ischemic postconditioning in rats with myocardial ischemia-reperfusion injury. Chin Med J. 2013;126(20):3949–55.

    CAS  PubMed  Google Scholar 

  15. Stumpner J, Redel A, Kellermann A, Lotz CA, Blomeyer CA, Smul TM, Kehl F, Roewer N, Lange M. Differential role of Pim-1 kinase in anesthetic-induced and ischemic preconditioning against myocardial infarction. Anesthesiology. 2009;111(6):1257–64.

    Article  CAS  PubMed  Google Scholar 

  16. Kakinuma Y, Ando M, Kuwabara M, Katare RG, Okudela K, Kobayashi M, Sato T. Acetylcholine from vagal stimulation protects cardiomyocytes against ischemia and hypoxia involving additive non-hypoxic induction of HIF-1α. FEBS Lett. 2005;579(10):2111–8.

    Article  CAS  PubMed  Google Scholar 

  17. Ravingerová T, Pancza D, Ziegelholffer A, Styk J. Preconditioning modulates susceptibility to ischemia-induced arrhythmias in the rat heart: The role of α-adrenergic stimulation and K +ATP channels. Physiol Res. 2002;51(2):109–19.

    PubMed  Google Scholar 

  18. Kawada T, Yamazaki T, Akiyama T, Kitagawa H, Shimizu S, Mizuno M, Li M, Sugimachi M. Vagal stimulation suppresses ischemia-induced myocardial interstitial myoglobin release. Life Sci. 2008;83(13–14):490–5.

    Article  CAS  PubMed  Google Scholar 

  19. Dai AL, Fan LH, Zhang FJ, Yang MJ, Yu J, Wang JK, Fang T, Chen G, Yu LN, Yan M. Effects of sevoflurane preconditioning and postconditioning on rat myocardial stunning in ischemic reperfusion injury. J Zhejiang Univ Sci B. 2010;11(4):267–74.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Zipes DP, Wellens HJ. Sudden cardiac death. Circulation. 1998;98(21):2334–51.

    Article  CAS  PubMed  Google Scholar 

  21. Zuanetti G, De Ferrari GM, Priori SG, Schwartz PJ. Protective effect of vagal stimulation on reperfusion arrhythmias in cats. Circ Res. 1987;61(3):429–35.

    Article  CAS  PubMed  Google Scholar 

  22. Mioni C, Bazzani C, Giuliani D, Altavilla D, Leone S, Ferrari A, Minutoli L, Bitto A, Marini H, Zaffe D, Botticelli AR, Iannone A, Tomasi A, Bigiani A, Bertolini A, Squadrito F, Guarini S. Activation of an efferent cholinergic pathway produces strong protection against myocardial ischemia/reperfusion injury in rats. Crit Care Med. 2005;33(11):2621–8.

    Article  CAS  PubMed  Google Scholar 

  23. Ando M, Katare RG, Kakinuma Y, Zhang D, Yamasaki F, Muramoto K, Sato T. Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein. Circulation. 2005;112(2):164–70.

    Article  CAS  PubMed  Google Scholar 

  24. Pourkhalili K, Hajizadeh S, Tiraihi T, Akbari Z, Esmailidehaj M, Bigdeli MR, Khoshbaten A. Ischemia and reperfusion-induced arrhythmias: role of hyperoxic preconditioning. J Cardiovasc Med (Hagerstown). 2009;10(8):635–42.

    Article  Google Scholar 

  25. Andrassy M, Volz HC, Igwe JC, Funke B, Eichberger SN, Kaya Z, Buss S, Autschbach F, Pleger ST, Lukic IK, Bea F, Hardt SE, Humpert PM, Bianchi ME, Mairbäurl H, Nawroth PP, Remppis A, Katus HA, Bierhaus A. High-mobility group box-1 in ischemia-reperfusion injury of the heart. Circulation. 2008;117(25):3216–26.

    Article  CAS  PubMed  Google Scholar 

  26. Xiong J, Xue FS, Yuan YJ, Wang Q, Liao X, Wang WL. Cholinergic anti-inflammatory pathway: a possible approach to protect against myocardial ischemia reperfusion injury. Chin Med J. 2010;123(19):2720–6.

    CAS  PubMed  Google Scholar 

  27. Martelli D, McKinley MJ, McAllen RM. The cholinergic anti-inflammatory pathway: a critical review. Auton Neurosci. 2014;182:65–9.

    Article  CAS  PubMed  Google Scholar 

  28. Lataro RM, Silva CA, Fazan R Jr, Rossi MA, Prado CM, Godinho RO, Salgado HC. Increase in parasympathetic tone by pyridostigmine prevents ventricular dysfunction during the onset of heart failure. Am J Physiol Regul Integr Physiol. 2013;305(8):R908–16.

    Article  CAS  Google Scholar 

  29. Huston JM, Gallowitsch-Puerta M, Ochani M, Ochani K, Yuan R, Rosas-Ballina M, Ashok M, Goldstein RS, Chavan S, Pavlov VA, Metz CN, Yang H, Czura CJ, Wang H, Tracey KJ. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Crit Care Med. 2007;35(12):2762–8.

    Article  PubMed  Google Scholar 

  30. Sabat R, Grütz G, Warszawska K, Kirsch S, Witte E, Wolk K, Geginat J. Biology of interleukin-10. Cytokine Growth Factor Rev. 2010;21(5):331–44.

    Article  CAS  PubMed  Google Scholar 

  31. Yang Z, Zingarelli B, Szabo C. Crucial role of endogenous interleukin-10 production in myocardial ischemia/reperfusion injury. Circulation. 2000;101(9):1019–26.

    Article  CAS  PubMed  Google Scholar 

  32. Pasqui AL, Di Renzo M, Maffei S, Pastorelli M, Pompella G, Auteri A, Puccetti L. Pro/Anti-inflammatory cytokine imbalance in postischemic left ventricular remodeling. Mediat Inflamm. 2010;2010:974694.

    Article  Google Scholar 

  33. Velasco CE, Turner M, Inagami T, Atkinson JB, Virmani R, Jackson EK, Murray JJ, Forman MB. Reperfusion enhances the local release of endothelin after regional myocardial ischemia. Am Heart J. 1994;128(3):441–51.

    Article  CAS  PubMed  Google Scholar 

  34. Engler RL, Dahlgren MD, Morris DD, Peterson MA, Schmid-Schönbein GW. Role of leukocytes in response to acute myocardial ischemia and reflow in dogs. Am J Physiol. 1986;251(2Pt 2):H314–23.

    CAS  PubMed  Google Scholar 

  35. Babior BM. The respiratory burst of phagocytes. J Clin Invest. 1984;73(3):599–601.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Abdel-Rahman U, Margraf S, Aybek T, Lögters T, Bitu-Moreno J, Francischetti I, Kranert T, Grünwald F, Windolf J, Moritz A, Scholz M. Inhibition of neutrophil activity improves cardiac function after cardiopulmonary bypass. J Inflamm Lond. 2007;4:21.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature. 1997;385(6618):729–33.

    Article  CAS  PubMed  Google Scholar 

  38. Sack MN, Smith RM, Opie LH. Tumor necrosis factor in myocardial hypertrophy and ischaemia-an anti-apoptotic perspective. Cardiovasc Res. 2000;45(3):688–95.

    Article  CAS  PubMed  Google Scholar 

  39. Kimura H, Shintani-Ishida K, Nakajima M, Liu S, Matsumoto K, Yoshida K. Ischemic preconditioning or p38 MAP kinase inhibition attenuates myocardial TNF α production and mitochondria damage in brief myocardial ischemia. Life Sci. 2006;78(17):1901–10.

    Article  CAS  PubMed  Google Scholar 

  40. Park SY, Kim DJ, Aldohayan A, Ahmed I, Husain S. Al Rikabi A, Aldawlatly A, Al Obied O, Hajjar W, Al Nassar S. Immune response after systematic lymph node dissection in lung cancer surgery: changes of interleukin-6 level in serum, pleural lavage fluid, and lung supernatant in a dog model. World J Surg Oncol. 2013;11:270.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Li J, Mathieu SL, Harris R, Ji J, Anderson DJ, Malysz J, Bunnelle WH, Waring JF, Marsh KC, Murtaza A, Olson LM, Gopalakrishnan M. Role of α7 nicotinic acetylcholine receptors in regulating tumor necrosis factor-α (TNF-α) as revealed by subtype selective agonists. J Neuroimmunol. 2011;239(1–2):37–43.

    Article  CAS  PubMed  Google Scholar 

  42. Frangogiannis NG. Regulation of the inflammatory response in cardiac repair. Circ Res. 2012;110(1):159–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Kawada T, Yamazaki T, Akiyama T. Vagal stimulation suppresses ischemia-induced myocardial interstitial norepinephrine release. Life Sci. 2006;78(8):882–7.

    Article  CAS  PubMed  Google Scholar 

  44. Uemura K, Li M, Tsutsumi T, Yamazaki T, Kawada T, Kamiya A, Inagaki M, Sunagawa K, Sugimachi M. Efferent vagal nerve stimulation induces tissue inhibitor of metalloproteinase-1 in myocardial ischemia-reperfusion injury in rabbit. Am J Physiol Heart Circ Physiol. 2007;293(4):H2254–61.

    Article  CAS  PubMed  Google Scholar 

  45. Katare RG, Ando M, Kakinuma Y, Arikawa M, Handa T, Yamasaki F, Sato T. Vagal nerve stimulation prevents reperfusion injury through inhibition of opening of mitochondrial permeability transition pore independent of the bradycardiac effect. J Thorac Cardiovasc Surg. 2009;137(1):223–31.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was funded by the National Natural Science Foundation of China (No. 81170128). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

None declared.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fu-Shan Xue.

Additional information

Responsible editor: Andrew Roberts.

Q. Wang and R.-P. Li contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Q., Li, RP., Xue, FS. et al. Optimal intervention time of vagal stimulation attenuating myocardial ischemia/reperfusion injury in rats. Inflamm. Res. 63, 987–999 (2014). https://doi.org/10.1007/s00011-014-0775-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-014-0775-8

Keywords

Navigation