Skip to main content

Advertisement

SpringerLink
Log in

Remote cardioprotection by direct peripheral nerve stimulation and topical capsaicin is mediated by circulating humoral factors

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

We have previously shown that remote ischemic preconditioning by limb ischemia (rIPC) or intra-arterial adenosine releases a dialyzable cardioprotective circulating factor(s), the release of which requires an intact neural connection to the limb and is blocked by pretreatment with S-nitroso-N-acetylpenicillamine (SNAP). Remote cardioprotection can be induced by other forms of peripheral stimulation including topical capsaicin, but the mechanisms of their signal transduction are incompletely understood. Rabbits were anesthetized by intravenous pentobarbital, intubated and ventilated, then randomized (4–7 animals in each group) to receive sham procedure, rIPC (4 cycles of 5 min lower limb ischemia, 5 min reperfusion), direct femoral nerve stimulation, topical capsaicin, pretreatment with intra-arterial SNAP + capsaicin, pretreatment with topical DMSO (a sensory nerve blocker) + topical capsaicin, or pretreatment with intra-arterial SNAP + femoral nerve stimulation, topical DMSO alone, or intra-arterial SNAP alone. Blood was then rapidly drawn from the carotid artery to produce the plasma dialysate which was used to perfuse a naïve heart from an untreated donor rabbit. The infarct size and recovery of LV-developed pressure and end-diastolic pressure were measured after 30 min of global ischemia and 120 min of reperfusion. Compared to sham, dialysate from rIPC, femoral nerve stimulation, and topical capsaicin groups all produced significant cardioprotection with significantly reduced infarct size, and improved the post-ischemic cardiac performance. Cardioprotection was not seen in the topical DMSO-capsaicin, SNAP + capsaicin, and SNAP + FNS groups. These results confirm the central role of peripheral nerves in the local signal transduction of remote cardioprotection. Direct electrical or peripheral neural stimulation evokes the release of cardioprotective substances into the bloodstream, with comparable effects to that of rIPC induced by limb ischemia.

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

Access this article

Log in via an institution

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
Fig. 5

Similar content being viewed by others

References

  1. Birnbaum Y, Hale SL, Kloner RA (1997) Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation 96:1641–1646. doi:10.1161/01.CIR.96.5.1641

    Article  PubMed  CAS  Google Scholar 

  2. Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT (2010) Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 375:727–734. doi:10.1016/S0140-6736(09)62001-8

    Article  PubMed  Google Scholar 

  3. Breivik L, Helgeland E, Aarnes EK, Mrdalj J, Jonassen AK (2011) Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3K/Akt-dependent cell-survival signaling at reperfusion. Basic Res Cardiol 106:135–145. doi:10.1007/s00395-010-0133-0

    Article  PubMed  CAS  Google Scholar 

  4. Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, Holtby HM, Cox PN, Smallhorn JF, Van Arsdell GS, Redington AN (2006) Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol 47:2277–2282. doi:10.1016/j.jacc.2006.01.066

    Article  PubMed  Google Scholar 

  5. Dong JH, Liu YX, Ji ES, He RR (2004) Limb ischemic preconditioning reduces infarct size following myocardial ischemia–reperfusion in rats. Sheng Li Xue Bao 56:41–46

    PubMed  Google Scholar 

  6. Evans MS, Reid KH, Sharp JB Jr (1993) Dimethylsulfoxide (DMSO) blocks conduction in peripheral nerve C fibers: a possible mechanism of analgesia. Neurosci Lett 150:145–148

    Article  PubMed  CAS  Google Scholar 

  7. Gao J, Fu W, Jin Z, Yu X (2006) A preliminary study on the cardioprotection of acupuncture pretreatment in rats with ischemia and reperfusion: involvement of cardiac beta-adrenoceptors. J Physiol Sci 56:275–279. doi:10.2170/physiolsci.RP006606

    Article  PubMed  CAS  Google Scholar 

  8. Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD (1996) Myocardial protection by brief ischemia in noncardiac tissue. Circulation 94:2193–2200. doi:10.1161/01.CIR.94.9.2193

    Article  PubMed  CAS  Google Scholar 

  9. Heusch G, Boengler K, Schulz R (2008) Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 118:1915–1919. doi:10.1161/CIRCULATIONAHA.108.805242

    Article  PubMed  Google Scholar 

  10. Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M (2012) STAT5 activation and cardioprotection by remote ischemic preconditioning in humans. Circ Res 110. doi:10.1161/CIRCRESAHA.111.259556

  11. Jones WK, Fan GC, Liao S, Zhang JM, Wang Y, Weintraub NL, Kranias EG, Schultz JE, Lorenz J, Ren X (2009) Peripheral nociception associated with surgical incision elicits remote nonischemic cardioprotection via neurogenic activation of protein kinase C signaling. Circulation 120:S1–S9. doi:10.1161/CIRCULATIONAHA.108.843938

    Article  PubMed  CAS  Google Scholar 

  12. Karuppasamy P, Chaubey S, Dew T, Musto R, Sherwood R, Desai J, John L, Shah AM, Marber MS, Kunst G (2011) Remote intermittent ischemia before coronary artery bypass graft surgery: a strategy to reduce injury and inflammation? Basic Res Cardiol 106:511–519. doi:10.1007/s00395-011-0185-9

    Article  PubMed  CAS  Google Scholar 

  13. Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, Vogel M, Sorensen K, Redington AN, MacAllister R (2002) Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation 106:2881–2883. doi:10.1161/01.CIR.0000043806.51912.9B

    Article  PubMed  CAS  Google Scholar 

  14. Kharbanda RK, Nielsen TT, Redington AN (2009) Translation of remote ischaemic preconditioning into clinical practice. Lancet 374:1557–1565. doi:10.1016/S0140-6736(09)61421-5

    Article  PubMed  Google Scholar 

  15. Kong SZ, Fan MX, Zhang BH, Wang ZY, Wang Y (2009) Nitric oxide inhibits excitatory vagal afferent input to nucleus tractus solitarius neurons in anaesthetized rats. Neurosci Bull 25:325–334. doi:10.1007/S12264-009-0624-x

    Article  PubMed  CAS  Google Scholar 

  16. Konstantinov IE, Li J, Cheung MM, Shimizu M, Stokoe J, Kharbanda RK, Redington AN (2005) Remote ischemic preconditioning of the recipient reduces myocardial ischemia–reperfusion injury of the denervated donor heart via a Katp channel-dependent mechanism. Transplantation 79:1691–1695. doi:10.1097/01.TP.0000159137.76400.5D

    Article  PubMed  Google Scholar 

  17. Kottenberg E, Thielmann M, Bergmann L, Heine T, Jakob H, Heusch G, Peters J (2012) Protection by remote ischemic preconditioning during coronary artery bypass graft surgery with isoflurane but not propofol—a clinical trial. Acta Anaesthesiol Scand 56:30–38. doi:10.1111/j.1399-6576.2011.02585.x

    Article  PubMed  CAS  Google Scholar 

  18. Li J, Xuan W, Yan R, Tropak MB, Jean-St-Michel E, Liang W, Gladstone R, Backx PH, Kharbanda RK, Redington AN (2011) Remote preconditioning provides potent cardioprotection via PI3K/Akt activation and is associated with nuclear accumulation of beta-catenin. Clin Sci (Lond) 120:451–462. doi:10.1042/CS20100466

    Article  CAS  Google Scholar 

  19. Lim SY, Yellon DM, Hausenloy DJ (2010) The neural and humoral pathways in remote limb ischemic preconditioning. Basic Res Cardiol 105:651–655. doi:10.1007/s00395-010-0099-y

    Article  PubMed  Google Scholar 

  20. Ma HJ, Liu YX, Wu YM, He RR (2003) Intrarenal artery injection of l-arginine inhibits spontaneous activity of renal afferent nerve fibers. Sheng Li Xue Bao 55:225–231

    PubMed  CAS  Google Scholar 

  21. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136. doi:10.1161/01.CIR.74.5.1124

    Article  PubMed  CAS  Google Scholar 

  22. Ockaili R, Salloum F, Hawkins J, Kukreja RC (2002) Sildenafil (Viagra) induces powerful cardioprotective effect via opening of mitochondrial K(ATP) channels in rabbits. Am J Physiol 283:H1263–H1269. doi:10.1152/ajpheart.00324.2002

    CAS  Google Scholar 

  23. Peters J (2011) Remote ischaemic preconditioning of the heart: remote questions, remote importance, or remote preconditions? Basic Res Cardiol 106:507–509. doi:10.1007/s00395-011-0187-7

    Article  PubMed  Google Scholar 

  24. Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P (1993) Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87:893–899. doi:10.1161/01.CIR.87.3.893

    Article  PubMed  CAS  Google Scholar 

  25. Shimizu M, Tropak M, Diaz RJ, Suto F, Surendra H, Kuzmin E, Li J, Gross G, Wilson GJ, Callahan J, Redington AN (2009) Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clin Sci 117:191–200. doi:10.1042/CS20080523

    Article  PubMed  CAS  Google Scholar 

  26. Steensrud T, Li J, Dai X, Manlhiot C, Kharbanda RK, Tropak M, Redington A (2010) Pretreatment with the nitric oxide donor SNAP or nerve transection blocks humoral preconditioning by remote limb ischemia or intra-arterial adenosine. Am J Physiol Heart Circ Physiol 299:H1598–H1603. doi:10.1152/ajpheart.00396.2010

    Article  PubMed  CAS  Google Scholar 

  27. Thielmann M, Kottenberg E, Boengler K, Raffelsieper C, Neuhaeuser M, Peters J, Jakob H, Heusch G (2010) Remote ischemic preconditioning reduces myocardial injury after coronary artery bypass surgery with crystalloid cardioplegic arrest. Basic Res Cardiol 105:657–664. doi:10.1007/s00395-010-0104-5

    Article  PubMed  CAS  Google Scholar 

  28. Todorov S, Pozzoli C, Zamfirova R, Poli E (2003) Prejunctional modulation of non-adrenergic non-cholinergic (NANC) inhibitory responses in the isolated guinea-pig gastric fundus. Neurogastroenterol Motil 15:299–306. doi:10.1124/pr.57.3.4

    Article  PubMed  CAS  Google Scholar 

  29. Wardle KA, Ranson J, Sanger GJ (1997) Pharmacological characterization of the vanilloid receptor in the rat dorsal spinal cord. Br J Pharmacol 121:1012–1016. doi:10.1038/sj.bjp.0701199

    Article  PubMed  CAS  Google Scholar 

  30. Zhu GQ, Gao XY, Zhang F, Wang W (2004) Reduced nitric oxide in the rostral ventrolateral medulla enhances cardiac sympathetic afferent reflex in rats with chronic heart failure. Sheng Li Xue Bao 56:47–53

    PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Canadian Institutes of Health Research and a Transatlantic Network of Research Excellence grant from the Leducq Foundation.

Author information

Authors and Affiliations

  1. Division of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X 8, Canada

    Kathrine L. Redington, Tara Disenhouse, Rachel Gladstone, Can Wei, Xiaojing Dai, Cedric Manlhiot, Jing Li & Andrew N. Redington

  2. Division of Neurology, Hospital for Sick Children, Toronto, Canada

    Samuel C. Strantzas

  3. Genetic and Metabolic Laboratory Medicine, Hospital for Sick Children, Toronto, Canada

    Michael B. Tropak

Authors
  1. Kathrine L. Redington
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tara Disenhouse
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samuel C. Strantzas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rachel Gladstone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Can Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael B. Tropak
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaojing Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cedric Manlhiot
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Andrew N. Redington
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew N. Redington.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Redington, K.L., Disenhouse, T., Strantzas, S.C. et al. Remote cardioprotection by direct peripheral nerve stimulation and topical capsaicin is mediated by circulating humoral factors. Basic Res Cardiol 107, 241 (2012). https://doi.org/10.1007/s00395-011-0241-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-011-0241-5

Keywords

Search

Navigation