Skip to main content
SpringerLink
Log in

Effects of the Inhibition of Late Sodium Current by GS967 on Stretch-Induced Changes in Cardiac Electrophysiology

  • ORIGINAL ARTICLE
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

Mechanical stretch increases sodium and calcium entry into myocytes and activates the late sodium current. GS967, a triazolopyridine derivative, is a sodium channel blocker with preferential effects on the late sodium current. The present study evaluates whether GS967 inhibits or modulates the arrhythmogenic electrophysiological effects of myocardial stretch.

Methods

Atrial and ventricular refractoriness and ventricular fibrillation modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts (n = 28) using epicardial multiple electrodes and high-resolution mapping techniques under control conditions and during the perfusion of GS967 at different concentrations (0.03, 0.1, and 0.3 μM).

Results

On comparing ventricular refractoriness, conduction velocity and wavelength obtained before stretch had no significant changes under each GS967 concentration while atrial refractoriness increased under GS967 0.3 μM. Under GS967, the stretch-induced changes were attenuated, and no significant differences were observed between before and during stretch. GS967 0.3 μM diminished the normal stretch-induced changes resulting in longer (less shortened) atrial refractoriness (138 ± 26 ms vs 95 ± 9 ms; p < 0.01), ventricular refractoriness (155 ± 18 ms vs 124 ± 16 ms; p < 0.01) and increments in spectral concentration (23 ± 5% vs 17 ± 2%; p < 0.01), the fifth percentile of ventricular activation intervals (46 ± 8 ms vs 31 ± 3 ms; p < 0.05), and wavelength of ventricular fibrillation (2.5 ±0.5 cm vs 1.7 ± 0.3 cm; p < 0.05) during stretch. The stretch-induced increments in dominant frequency during ventricular fibrillation (control = 38%, 0.03 μM = 33%, 0.1 μM = 33%, 0.3 μM = 14%; p < 0.01) and the stretch-induced increments in arrhythmia complexity index (control = 62%, 0.03μM = 41%, 0.1 μM = 32%, 0.3 μM = 16%; p < 0.05) progressively decreased on increasing the GS967 concentration.

Conclusions

GS967 attenuates stretch-induced changes in cardiac electrophysiology.

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
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Kondratev D, Christ A, Gallitelli MF. Inhibition of the Na+-H+ exchanger with cariporide abolishes stretch-induced calcium but not sodium accumulation in mouse ventricular myocytes. Cell Calcium. 2005;37:69–80.

    Article  CAS  Google Scholar 

  2. Cingolani HE, Perez NG, Cingolani OH, Ennis IL. The Anrep effect: 100 years later. Am J Physiol Heart Circ Physiol. 2013;304:H175–82.

    Article  CAS  Google Scholar 

  3. Von Lewinski D, Stumme B, Maier LS, Luers C, Bers DM, Pieske B. Stretch-dependent slow force response in isolated rabbit myocardium is Na+ dependent. Cardiovasc Res. 2003;57:1052–61.

    Article  Google Scholar 

  4. Quinn TA, Kohl P. Rabbit models of cardiac mechano-electric and mechano-electric and mechano-mechanical coupling. Prog Biophys Mol Biol. 2016;121:110–22.

    Article  Google Scholar 

  5. Kim D. Novel cation-selective mechanosensitive ion channel in the atrial cell membrane. Circ Res. 1993;72:225–31.

    Article  CAS  Google Scholar 

  6. Beyder A, Rae JL, Bernard C, Strege PR, Sachs F, Farrugia G. Mechanosensitivity of Nav1.5, a voltage-sensitive sodium channel. J Physiol. 2010;588:4969–85.

    Article  CAS  Google Scholar 

  7. Peyronnet R, Nerbonne JM, Kohl P. Cardiac mechano-gated ion channels and arrhythmias. Circ Res. 2016;118:311–29.

    Article  CAS  Google Scholar 

  8. Sag CM, Wagner S, Maier LS. Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes. Free Radic Biol Med. 2013;63:338–49.

    Article  CAS  Google Scholar 

  9. Prosser BL, Ward CW, Lederer WJ. X-ROS signaling is enhanced and graded by cyclic cardiomyocyte stretch. Cardiovasc Res. 2013;98:307–14.

    Article  CAS  Google Scholar 

  10. Patlak JB, Ortiz M. Slow currents through single sodium channels of the adult rat heart. J Gen Physiol. 1985;86:89–104.

    Article  CAS  Google Scholar 

  11. Maltsev VA, Undrovinas A. Late sodium current in failing heart: friend or foe? Prog Biophys Mol Biol. 2008;96:421–51.

    Article  CAS  Google Scholar 

  12. Wei XH, Yu SD, Ren L, Huang SH, Yang QM, Wang P, et al. Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions. Sci Rep. 2017;7:981.

    Article  Google Scholar 

  13. Yao L, Fan P, Jiang Z, Viatchenko-Karpinski S, Wu Y, Kornyeyev D, et al. Nav1.5-dependent persistent Na+ influx activates CaMKII in rat ventricular myocytes and N1325S mice. Am J Physiol Cell Physiol. 2011;301:C577–86.

    Article  CAS  Google Scholar 

  14. Ma J, Luo A, Wu L, Wan W, Zhang P, Ren Z, et al. Calmodulin kinase II and protein kinase C mediate the effect of increased intracellular calcium to augment late sodium current in rabbit ventricular myocytes. Am J Physiol Cell Physiol. 2012;302:C1141–51.

    Article  CAS  Google Scholar 

  15. Antzelevitch C, Burashnikov A, Sicouri S, Belardinelli L. Electrophysiological basis for the antiarrhythmic actions of ranolazine. Heart Rhythm. 2011;8:1281–90.

    Article  Google Scholar 

  16. Verrier RL, Kumar K, Nieminen T, Belardinelli L. Mechanisms of ranolazine’s dual protection against atrial and ventricular fibrillation. Europace. 2013;15:317–24.

    Article  Google Scholar 

  17. Chorro FJ, del Canto I, Brines L, Such-Miquel L, Calvo C, Soler C, et al. Ranolazine attenuates the electrophysiological effects of myocardial stretch in Langendorff perfused rabbit hearts. Cardiovasc Drugs Ther. 2015;29:231–41.

    Article  CAS  Google Scholar 

  18. Belardinelli L, Liu G, Smith-Maxwell C, Wang WQ, el-Bizri N, Hirakawa R, et al. A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias. J Pharmacol Exp Ther. 2013;344:23–32.

    Article  CAS  Google Scholar 

  19. Sicouri S, Belardinelli L, Antzelevitch C. Antiarrhytmic effects of the highly selective late sodium channel current blocker GS-458967. Heart Rhyhm. 2013;10:1036–43.

    Article  Google Scholar 

  20. Koltun DO, Parkhill EQ, Elzein E, Kobayashi T, Notte GT, Kalla R, et al. Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine. Bioorg Med Chem Lett. 2016;26:3202–6.

    Article  CAS  Google Scholar 

  21. Bonatti R, Silva AF, Batatinha JA, Sobrado LF, Machado AD, Varone BB, et al. Selective late sodium current blockade with GS-458967 markedly reduces ischemia-induced atrial and ventricular repolarization alternans and ECG heterogeneity. Heart Rhythm. 2014;11:1827–35.

    Article  Google Scholar 

  22. Alves Bento AS, Bacic D, Saran Carneiro J, Nearing BD, Fuller H, Justo FA, et al. Selective late INa inhibition by GS-458967 exerts parallel suppression of catecholamine-induced hemodynamically significant ventricular tachycardia and T-wave alternans in an intact porcine model. Heart Rhyhm. 2015;12:2508–14.

    Article  Google Scholar 

  23. Carneiro JS, Bento AS, Bacic D, Nearing BD, Rajamani S, Belardinelli L, et al. The selective cardiac late sodium current inhibitor GS-458967 suppresses autonomically triggered atrial fibrillation in an intact porcine model. J Cardiovasc Electrophysiol. 2015;26:1364–9.

    Article  Google Scholar 

  24. Chorro FJ, Trapero I, Guerrero J, Such LM, Canoves J, Mainar L, et al. Modification of ventricular fibrillation activation patterns induced by local stretching. J Cardiovasc Electrophysiol. 2005;16:1087–96.

    Article  Google Scholar 

  25. Chorro FJ, Trapero I, Such-Miquel L, Pelechano F, Mainar L, Cánoves J, et al. Pharmacological modifications of the stretch-induced effects of ventricular fibrillation in perfused rabbit-hearts. Am J Physiol Heart Circ Physiol. 2009;297:H1860–9.

    Article  CAS  Google Scholar 

  26. Such-Miquel L, Chorro FJ, Guerrero J, Trapero I, Brines L, Zarzoso M, et al. Evaluation of the complexity of myocardial activation during ventricular fibrillation. An experimental study. Rev Esp Cardiol. 2013;66:177–84.

    Article  Google Scholar 

  27. Burashnikov A, Di Diego JM, Robert J, Goodrow RJ, Belardinelli L, Antzelevitch C. Atria are more sensitive than ventricles to GS-458967-induced inhibition of late sodium current. J Cardiovasc Pharmacol Ther. 2015;20:501–8.

    Article  CAS  Google Scholar 

  28. Weiss JN, Chen PS, Qu Z, Karagueuzian HS, Garfinkel A. Ventricular fibrillation: how do we stop the waves from breaking? Circ Res. 2000;87:1103–7.

    Article  CAS  Google Scholar 

  29. Del Canto I, Such-Miquel L, Brines L, Soler C, Zarzoso M, Calvo C, et al. Effects of JTV-519 on stretch-induced manifestations of mechanoelectric feedback. Clin Exp Pharmacol Physiol. 2016;43:1062–70.

    Article  CAS  Google Scholar 

  30. Pezhouman A, Madahian S, Stepanyan H, Ghukasyan H, Qu Z, Belardinelli L, et al. Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts. Heart Rhythm. 2014;11:492–501.

    Article  Google Scholar 

  31. Potet F, Vanoye CG, George AL. Use-dependent block of human cardiac sodium channels by GS967. Mol Pharmacol. 2016;90:52–60.

    Article  CAS  Google Scholar 

  32. Chorro FJ, Canto ID, Brines L, Such-Miquel L, Calvo C, Soler C, et al. Experimental study of the effects of EIPA, losartan, and BQ-123 on electrophysiological changes induced by myocardial stretch. Rev Esp Cardiol. 2015;68:1101–10.

    Article  Google Scholar 

  33. Ravelli F, Allessie MA. Effects of atrial dilatation on refractory period and vulnerability to atrial fibrillation in the isolated Langendorff-perfused rabbit heart. Circulation. 1997;96:1686–95.

    Article  CAS  Google Scholar 

  34. Reiter MJ, Synhorst DP, Mann DE. Electrophysiological effects of acute ventricular dilatation in the isolated rabbit heart. Circ Res. 1988;62:554–62.

    Article  CAS  Google Scholar 

  35. Chorro FJ, Egea S, Mainar L, Cánoves J, Sanchis J, Llavador E, et al. Acute modifications in the wavelength of the atrial excitation process induced by stretching. An experimental study. Rev Esp Cardiol. 1998;51:874–83.

    Article  CAS  Google Scholar 

  36. Iribe G, Jin H, Kaihara K, Naruse K. Effects of axial stretch on sarcolemmal BKCa channels in post-hatch chick ventricular myocytes. Exp Physiol. 2010;95:699–711.

    Article  CAS  Google Scholar 

  37. Calaghan SC, Belus A, White E. Do stretch-induced changes in intracellular calcium modify the electrical activity of cardiac muscle? Progr Biophys Mol Biol. 2003;82:81–95.

    Article  CAS  Google Scholar 

  38. Zhao HC, Agula H, Zhang W, Wang F, Sokabe M, Li LM. Membrane stretch and cytoplasmic Ca2+ independently modulate stretch-activated BK channel activity. J. Biomechanics. 2010;43:3015–9.

    Article  Google Scholar 

  39. Isenberg G, Kazanski V, Kondratev D, Gallitelli MF, Kiseleva I, Kamkin A. Differential effects of stretch and compression on membrane currents and [Na+]c in ventricular myocytes. Progr Biophys. Mol Biol. 2003;82:43–56.

    CAS  Google Scholar 

  40. Kelly D, Mackenzie L, Hunter P, Smaill B, Saint DA. Gene expression of stretch-activated channels and mechanoelectric feedback in the heart. Clin Exp Pharmacol Physiol. 2006;33:642–8.

    Article  CAS  Google Scholar 

  41. Decher N, Kiper AK, Rinné S. Stretch-activated potassium currents in the heart: focus on TREK-1 and arrhythmias. Progr Biophys Mol Biol. 2017;130:223–32.

    Article  CAS  Google Scholar 

  42. Carmeliet E. Action potential duration, rate of stimulation, and intracellular sodium. J Cariovasc Electrophysiol. 2006;17(Suppl. I):S2–7.

    Article  Google Scholar 

  43. Wu L, Ma J, Li H, Wang C, Grandi E, Zhang P, et al. Late sodium current contributes to the reverse rate-dependent effect of Ikr inhibition on ventricular repolarization. Circulation. 2011;123:1713–20.

    Article  CAS  Google Scholar 

  44. Despa S, Bers DM. Na+ transport in the normal and failing heart—remember the balance. J Mol Cell Cardiol. 2013;61:2–10.

    Article  CAS  Google Scholar 

  45. Burashnikov A. Late INa inhibition as an antiarrhythmic strategy. J Cardiovasc Pharmacol. 2017;70:159–67.

    Article  CAS  Google Scholar 

  46. Zygmunt AC, Nesterenko VV, Rajamani S, Hu D, Barajas-Martinez H, Belardinelli L, et al. Mechanisms of atrial-selective block of Na+ channels by ranolazine: I. Experimental analysis of the use-dependent block. Am J Physiol Heart Circ Physiol. 2011;301:H1606–14.

    Article  CAS  Google Scholar 

  47. Kornyeyev D, El-Bizri N, Hirakawa R, Nguyen S, Viatchenko-Karpinski S, Yao L, et al. Contribution of the late sodium current to intracellular sodium and calcium overload in rabbit ventricular myocytes treated by anemone toxin. Am J Physiol Heart Circ Physiol. 2016;310:H426–35.

    Article  Google Scholar 

  48. Janvier NC, Boyett MR. The role of Na-Ca exchange current in the cardiac action potential. Cardiovasc Res. 1996;32:69–84.

    Article  CAS  Google Scholar 

  49. Karagueuzian HS, Pezhouman A, Angelini M, Olcese R. Enhanced late Na and Ca currents as effective antiarrhythmic drug targets. Front Pharmacol. 2017;8

  50. Remme CA, Bezzina CR. Sodium channel (Dys) function and cardiac arrhythmias. Cardiovasc Ther. 2010;28:287–94.

    Article  Google Scholar 

  51. Scirica BM, Morrow DA, Hod H, Murphy SA, Belardinelli L, Hedgepeth CM, et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the metabolic efficiency with ranolazine for less ischemia in non ST-elevation acute coronary syndrome thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation. 2007;116:1647–52.

    Article  CAS  Google Scholar 

  52. Shenasa M, Assadi H, Heidary S, Ranolazine SH. Electrophysiologic effect, efficacy, and safety in patients with cardiac arrhythmias. Card Electrophysiol Clin. 2016;8:467–79.

    Article  Google Scholar 

  53. Yu S, Li G, Huang CLH, Lei M, Wu L. Late sodium current associated cardiac electrophysiological and mechanical dysfunction. Pflugers Arch - Eur J Physiol. 2018;470:461–9.

    Article  CAS  Google Scholar 

  54. Gong M, Zhang Z, Fragakis N, Korantzopoulos P, Letsas KP, Li G, et al. Role of ranolazine in the prevention and treatment of atrial fibrillation: a meta-analysis of randomized clinical trials. Heart Rhythm. 2017;14:3–11.

    Article  Google Scholar 

Download references

Funding

This work was supported by the Spanish Ministry of Economy and Competiveness (Carlos III Health Institute)/European Regional Development Fund (FEDER) (Grants FIS PI12/00407, PI15/01408, PIE15/00013, CB16/11/00486) and by the Generalitat Valenciana (Grant PROMETEO FASE II 2014/037).

Author information

Authors and Affiliations

  1. CIBER CV. Carlos III Health Institute, Madrid, Spain

    Irene del Canto, Patricia Genovés, Luis Such-Miquel, Oscar Arias-Mutis, Álvaro Tormos, Antonio Alberola, Luis Such & Francisco J. Chorro

  2. Department of Electronics, Universitat Politècnica de València, Valencia, Spain

    Irene del Canto & Álvaro Tormos

  3. Department of Physiology, Valencia University - Estudi General, Valencia, Spain

    Laura Santamaría, Carlos Soler, Germán Parra, Antonio Alberola & Luis Such

  4. Department of Physiotherapy, Valencia University - Estudi General, Valencia, Spain

    Luis Such-Miquel & Manuel Zarzoso

  5. Service of Cardiology, Valencia University Clinic Hospital, INCLIVA, Valencia, Spain

    Francisco J. Chorro

  6. Department of Medicine, Valencia University - Estudi General, Valencia, Spain

    Francisco J. Chorro

  7. Servicio de Cardiología, Hospital Clínico Universitario, Avda. Blasco Ibañez 17, 46010, Valencia, Spain

    Francisco J. Chorro

Authors
  1. Irene del Canto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura Santamaría
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patricia Genovés
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luis Such-Miquel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Oscar Arias-Mutis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Manuel Zarzoso
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carlos Soler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Germán Parra
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Álvaro Tormos
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Antonio Alberola
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Luis Such
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Francisco J. Chorro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francisco J. Chorro.

Ethics declarations

Conflicts of Interest

The authors declare that they have no competing interests.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

del Canto, I., Santamaría, L., Genovés, P. et al. Effects of the Inhibition of Late Sodium Current by GS967 on Stretch-Induced Changes in Cardiac Electrophysiology. Cardiovasc Drugs Ther 32, 413–425 (2018). https://doi.org/10.1007/s10557-018-6822-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-018-6822-x

Keywords

Search

Navigation