Skip to main content
Log in

Postconditioning with vagal stimulation attenuates local and systemic inflammatory responses to myocardial ischemia reperfusion injury in rats

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

Abstract

Objective

To assess effects of postconditioning with the vagal stimulation (VS) on the local and systematic inflammatory responses to acute myocardial ischemia reperfusion injury (IRI).

Methods

Sixty male Sprague–Dawley rats were randomly allocated into three groups: sham group, ischemia reperfusion group (IR group), and postconditioning with the VS group (POVS group). Serum levels of inflammatory cytokines during reperfusion and myocardial levels of inflammatory cytokines in both ischemic and non-ischemic regions at the end of the experiment were assayed. The infarct size was assessed by Evans blue and triphenyltetrazolium chloride staining.

Results

The infarct size was significantly reduced in the POVS group compared to the IR group. Serum levels of TNF-α at 30, 60, and 120 min of reperfusion and serum levels of HMGB-1, ICAM-1, IL-1, and IL-6 at 120 min of reperfusion were significantly lower in the POVS group than in the IR group. Myocardial levels of TNF-α, HMGB-1, ICAM-1, IL-1, and IL-6 in both ischemic and non-ischemic regions were also significantly reduced in the POVS group compared with the IR group.

Conclusions

Postconditioning with the VS can significantly attenuate the local and systemic inflammatory responses to myocardial IRI, and provide an obvious 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.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. De Ferrari GM, Schwartz PJ. Vagus nerve stimulation: from pre-clinical to clinical application: challenges and future directions. Heart Fail Rev. 2011;16(2):195–203.

    Article  PubMed  Google Scholar 

  2. 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 Psychiatr. 2011;23(1):48–62.

    Google Scholar 

  3. Schwartz PJ, Vanoli E, Stramba-Badiale M, De Ferrari GM, Billman GE, Foreman RD. Autonomic mechanisms and sudden death. New insights from analysis of baroreceptor reflexes in conscious dogs with and without a myocardial infarction. Circulation. 1988;78(4):969–79.

    Article  PubMed  CAS  Google Scholar 

  4. La Rovere MT, Bigger JT, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic tone and reflexes after myocardial infarction) investigators. Lancet. 1998;351(9101):478–84.

    Article  PubMed  Google Scholar 

  5. Schwartz PJ, De Ferrari GM, Sanzo A, Landolina M, Rordorf R, Raineri C, Campana C, Revera M, Ajmone-Marsan N, Tavazzi L, Odero A. Long term vagal stimulation in patients with advanced heart failure: first experience in man. Eur J Heart Fail. 2008;10(9):884–91.

    Article  PubMed  Google Scholar 

  6. De Ferrari GM, Crijns HJ, Borggrefe M, Milasinovic G, Smid J, Zabel M, Gavazzi A, Sanzo A, Dennert R, Kuschyk J, Raspopovic S, Klein H, Swedberg K. Cardiofit multicenter trial investigators. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J. 2011;32(7):847–55.

    Article  PubMed  Google Scholar 

  7. 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  9. 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.

    PubMed  CAS  Google Scholar 

  10. Ottani A, Giuliani D, Galantucci M, Spaccapelo L, Novellino E, Grieco P, Jochem J, Guarini S. Melanocortins counteract inflammatory and apoptotic responses to prolonged myocardial ischemia/reperfusion through a vagus nerve-mediated mechanism. Eur J Pharmacol. 2010;637(1–3):124–30.

    Article  PubMed  CAS  Google Scholar 

  11. Pavlov VA. Cholinergic modulation of inflammation. Int J Clin Exp Med. 2008;1(3):203–12.

    PubMed  CAS  Google Scholar 

  12. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458–62.

    Article  PubMed  CAS  Google Scholar 

  13. Xiong J, Wang Q, Xue FS, Yuan YJ, Li S, Liu JH, Liao X, Zhang YM. Comparison of cardioprotective and anti-inflammatory effects of ischemia pre and postconditioning in rats with myocardial ischemia-reperfusion injury. Inflamm Res. 2011;60(6):547–54.

    Article  PubMed  CAS  Google Scholar 

  14. 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  PubMed  CAS  Google Scholar 

  15. 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  PubMed  CAS  Google Scholar 

  16. 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 

  17. 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  PubMed  CAS  Google Scholar 

  18. 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  PubMed  CAS  Google Scholar 

  19. Jolly SR, Kane WJ, Hook BG, Abrams GD, Kunkel SL, Lucchesi BR. Reduction of myocardial infarct size by neutrophil depletion: effect of duration of occlusion. Am Heart J. 1986;112(4):682–90.

    Article  PubMed  CAS  Google Scholar 

  20. Birdsall HH, Green DM, Trial J, Youker KA, Burns AR, MacKay CR, LaRosa GJ, Hawkins HK, Smith CW, Michael LH, Entman ML, Rossen RD. Complement C5a, TGF-β1, and MCP-1, in sequence, induce migration of monocytes into ischemic canine myocardium within the first one to five hours after reperfusion. Circulation. 1997;95(3):684–92.

    Article  PubMed  CAS  Google Scholar 

  21. Kloner RA, Giacomelli F, Alker KJ, Hale SL, Matthews R, Bellows S. Influx of neutrophils into the walls of large epicardial coronary arteries in response to ischemia/reperfusion. Circulation. 1991;84(4):1758–72.

    Article  PubMed  CAS  Google Scholar 

  22. Dhalla NS, Elmoselhi AB, Hata T, Makino N. Status of myocardial antioxidants in ischemia-reperfusion injury. Cardiovasc Res. 2000;47(3):446–56.

    Article  PubMed  CAS  Google Scholar 

  23. Zhang C, Xu X, Potter BJ, Wang W, Kuo L, Michael L, Bagby GJ, Chilian WM. TNF-α contributes to endothelial dysfunction in ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol. 2006;26(3):475–80.

    Article  PubMed  CAS  Google Scholar 

  24. 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  PubMed  CAS  Google Scholar 

  25. Bernik TR, Friedman SG, Ochani M, DiRaimo R, Susarla S, Czura CJ, Tracey KJ. Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion. J Vasc Surg. 2002;36(6):1231–6.

    Article  PubMed  Google Scholar 

  26. Bernik TR, Friedman SG, Ochani M, DiRaimo R, Ulloa L, Yang H, Sudan S, Czura CJ, Ivanova SM, Tracey KJ. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J Exp Med. 2002;195(6):781–8.

    Article  PubMed  CAS  Google Scholar 

  27. de Jonge WJ, van der Zanden EP, The FO, Bijlsma MF, van Westerloo DJ, Bennink RJ, Berthoud HR, Uematsu S, Akira S, van den Wijngaard RM, Boeckxstaens GE. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol. 2005;6(8):844–51.

    Article  PubMed  Google Scholar 

  28. van Westerloo DJ, Giebelen IA, Florquin S, Bruno MJ, Larosa GJ, Ulloa L, Tracey KJ, van der Poll T. The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology. 2006;130(6):1822–30.

    Article  PubMed  Google Scholar 

  29. Leib C, Göser S, Lüthje D, Öttl R, Tretter T, Lasitschka F, Zittrich S, Pfitzer G, Katus HA, Kaya Z. Role of the cholinergic antiinflammatory pathway in murine autoimmune myocarditis. Circ Res. 2011;109(2):130–40.

    Article  PubMed  CAS  Google Scholar 

  30. Fallen EL. Vagal afferent stimulation as a cardioprotective strategy? Introducing the concept. Ann Noninvasive Electrocardiol. 2005;10(4):441–6.

    Article  PubMed  Google Scholar 

  31. Watkins LR, Maier SF. Implications of immune-to-brain communication for sickness and pain. Proc Natl Acad Sci USA. 1999;96(14):7710–3.

    Article  PubMed  CAS  Google Scholar 

  32. 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  PubMed  CAS  Google Scholar 

  33. Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res. 1991;68(5):1471–81.

    Article  PubMed  CAS  Google Scholar 

  34. Frangogiannis NG, Lindsey ML, Michael LH, Youker KA, Bressler RB, Mendoza LH, Spengler RN, Smith CW, Entman ML. Resident cardiac mast cells degranulate and release preformed TNF-α, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion. Circulation. 1998;98(7):699–710.

    Article  PubMed  CAS  Google Scholar 

  35. Niederbichler AD, Papst S, Claassen L, Jokuszies A, Steinstraesser L, Hirsch T, Altintas MA, Ipaktchi KR, Reimers K, Kraft T, Vogt PM. Burn-induced organ dysfunction: vagus nerve stimulation attenuates organ and serum cytokine levels. Burns. 2009;35(6):783–9.

    Article  PubMed  Google Scholar 

  36. Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991;147:3815–22.

    PubMed  CAS  Google Scholar 

  37. Jenkins JK, Malyak M, Arend WP. The effects of interleukin-10 on interleukin-1 receptor antagonist and interleukin-1 β production in human monocytes and neutrophils. Lymphokine Cytokine Res. 1994;13(1):47–54.

    PubMed  CAS  Google Scholar 

  38. Liu X, Xie W, Liu P, Duan M, Jia Z, Li W, Xu J. Mechanism of the cardioprotection of rhEPO pretreatment on suppressing the inflammatory response in ischemia-reperfusion. Life Sci. 2006;78(19):2255–64.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  40. Kawada T, Yamazaki T, Akiyama T, Mori H, Uemura K, Miyamoto T, Sugimachi M, Sunagawa K. Disruption of vagal efferent axon and nerve terminal function in the postischemic myocardium. Am J Physiol Heart Circ Physiol. 2002;283(6):H2687–91.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study is supported by the National Natural Science Foundation of China (Grant 81170128) and the Peking Union Medical College Fund for Young Scholars. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

All authors have no potential conflicts of interest for this work.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fu-Shan Xue.

Additional information

Responsible Editor: Michael Parnham.

Q. Wang and Y. Cheng contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, Q., Cheng, Y., Xue, FS. et al. Postconditioning with vagal stimulation attenuates local and systemic inflammatory responses to myocardial ischemia reperfusion injury in rats. Inflamm. Res. 61, 1273–1282 (2012). https://doi.org/10.1007/s00011-012-0527-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-012-0527-6

Keywords

Navigation