Skip to main content
SpringerLink
Log in

Multiple effects of 4-aminopyridine on feline and rabbit sinoatrial node myocytes and multicellular preparations

  • Cardiovascular Physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

4-aminopyridine (4-AP) is commonly used to block the transient outward potassium current, Ito, in cardiac and noncardiac tissues. In the present work, we found that 4-AP inhibited the rapid component of the delayed rectifier potassium current, IKr, in rabbit-isolated sinoatrial node myocytes by 25% (1 mM) and 51% (5 mM) and inhibited the slow component of the delayed rectifier potassium current, IKs, in cat- isolated sinoatrial node myocytes by 39% (1 mM) and 62% (5 mM). In cat- and rabbit-isolated sinoatrial node myocytes, 4-AP activated muscarinic receptors in a voltage-dependent manner to increase the acetylcholine-activated potassium current, IKACh. In multicellular preparations of the central region of the sinoatrial node from nonreserpinized rabbits, 4-AP produced an increase in action potential overshoot, frequency, and rate of diastolic depolarization. In the presence of the β-adrenergic antagonist propranolol, 4-AP produced a marked increase in duration and a marked decrease in maximum diastolic potential and eventually, cessation of the spontaneous activity in preparations from the sinoatrial central region. In multicellular preparations from reserpinized rabbits, 4-AP produced similar effects to those observed in the presence of propranolol. We conclude that 4-AP inhibits multiple cardiac K+ currents, including Ito, IKr, and IKs, and that these activities mask IKACh activation. In addition, in multicellular preparations, 4-AP produces neurotransmitter release from the autonomic nerve terminals. These multiple effects need to be considered when using 4-AP as a “specific” Ito blocker.

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

Similar content being viewed by others

References

  1. Nerbonne JM, Kass RS (2005) Molecular physiology of cardiac repolarization. Physiol Rev 85:1205–1253

    Article  CAS  PubMed  Google Scholar 

  2. Mangoni ME, Nargeot J (2008) Genesis and regulation of the heart automaticity. Physiol Rev 88:919–982

    Article  CAS  PubMed  Google Scholar 

  3. Honjo H, Lei M, Boyett MR, Kodama I (1999) Heterogeneity of 4-aminopyridine-sensitive current in rabbit sinoatrial node cells. Am J Physiol 276:H1295–H1304

    CAS  PubMed  Google Scholar 

  4. Boyett MR, Honjo H, Yamamoto M, Nikmaram MR, Niwa R, Kodama I (1998) Regional differences in effects of 4-aminopyridine within the sinoatrial node. Am J Physiol 275:H1158–H1168

    CAS  PubMed  Google Scholar 

  5. Navarro-Polanco RA, Sanchez-Chapula JA (1997) 4-aminopyridine activates potassium currents by activation of a muscarinic receptor in feline atrial myocytes. J Physiol 498:663–678

    CAS  PubMed  Google Scholar 

  6. Mitcheson JS, Hancox JC (1999) Characteristics of a transient outward current (sensitive to 4-aminopyridine) in Ca2+-tolerant myocytes isolated from the rabbit atrioventricular node. Pflugers Arch 438:68–78

    Article  CAS  PubMed  Google Scholar 

  7. Ridley JM, Milnes JT, Zhang YH, Witchel HJ, Hancox JC (2003) Inhibition of HERG K+ current and prolongation of the guinea-pig ventricular action potential by 4-aminopyridine. J Physiol 549:667–672

    Article  CAS  PubMed  Google Scholar 

  8. Kirpekar M, Kirpekar SM, Prat JC (1977) Effect of 4-aminopyridine on release of noradrenaline from the perfused cat spleen by nerve stimulation. J Physiol 272:517–528

    CAS  PubMed  Google Scholar 

  9. Yanagisawa T, Satoh K, Taira N (1978) Excitation of autonomic nerves by 4-aminopyridine in the isolated, blood-perfused sino-atrial node preparation of the dog. Eur J Pharmacol 49:189–192

    Article  CAS  PubMed  Google Scholar 

  10. Isenberg G, Klockner U (1982) Calcium tolerant ventricular myocytes prepared by preincubation in a "KB medium". Pflugers Arch 395:6–18

    Article  CAS  PubMed  Google Scholar 

  11. Sanchez-Chapula J, Elizalde A (1987) Characterization of the effects of histamine on the transmembrane electrical activity of guinea-pig and rabbit SA- and AV-node cells. Naunyn Schmiedebergs Arch Pharmacol 336:218–223

    Article  CAS  PubMed  Google Scholar 

  12. Benavides-Haro DE, Navarro-Polanco RA, Sanchez-Chapula JA (2003) The cholinomimetic agent bethanechol activates IK(ACh) in feline atrial myocytes. Naunyn Schmiedebergs Arch Pharmacol 368:309–315

    Article  CAS  PubMed  Google Scholar 

  13. Verheijck EE, van Ginneken AC, Bourier J, Bouman LN (1995) Effects of delayed rectifier current blockade by E-4031 on impulse generation in single sinoatrial nodal myocytes of the rabbit. Circ Res 76:607–615

    CAS  PubMed  Google Scholar 

  14. Kodama I, Boyett MR, Nikmaram MR, Yamamoto M, Honjo H, Niwa R (1999) Regional differences in effects of E-4031 within the sinoatrial node. Am J Physiol 276:H793–H802

    CAS  PubMed  Google Scholar 

  15. Glover WE (1981) Cholinergic effect of 4-aminopyridine and adrenergic effect of 4-methyl-2-aminopyridine in cardiac muscle. Eur J Pharmacol 71:21–31

    Article  CAS  PubMed  Google Scholar 

  16. Torres-Jacome J, Tejeda-Chavez HR, Rodriguez-Menchaca AA, Sanchez-Chapula JA, Navarro-Polanco RA (2006) The D3-dopaminergic agonist 7-hydroxy-dipropylaminotetralin (7-OH-DPAT) increases cardiac action potential duration and blocks human ether-a-go-go-related gene K+ channel. J Cardiovasc Pharmacol 47:656–662

    Article  CAS  PubMed  Google Scholar 

  17. Elizalde A, Barajas H, Navarro-Polanco R, Sanchez-Chapula J (1999) Frequency-dependent effects of 4-aminopyridine and almokalant on action-potential duration of adult and neonatal rabbit ventricular muscle. J Cardiovasc Pharmacol 33:352–359

    Article  CAS  PubMed  Google Scholar 

  18. Drici MD, Diochot S, Terrenoire C, Romey G, Lazdunski M (2000) The bee venom peptide tertiapin underlines the role of I(KACh) in acetylcholine-induced atrioventricular blocks. Br J Pharmacol 131:569–577

    Article  CAS  PubMed  Google Scholar 

  19. Kitamura H, Yokoyama M, Akita H, Matsushita K, Kurachi Y, Yamada M (2000) Tertiapin potently and selectively blocks muscarinic K(+) channels in rabbit cardiac myocytes. J Pharmacol Exp Ther 293:196–205

    CAS  PubMed  Google Scholar 

  20. Jin W, Lu Z (1998) A novel high-affinity inhibitor for inward-rectifier K+ channels. Biochemistry 37:13291–13299

    Article  CAS  PubMed  Google Scholar 

  21. Kanjhan R, Coulson EJ, Adams DJ, Bellingham MC (2005) Tertiapin-Q blocks recombinant and native large conductance K+ channels in a use-dependent manner. J Pharmacol Exp Ther 314:1353–1361

    Article  CAS  PubMed  Google Scholar 

  22. Furukawa Y, Saegusa K, Chiba S (1985) The mode of action of 4-aminopyridine on the chronotropic and inotropic responses in the isolated, blood-perfused dog heart. Eur J Pharmacol 114:317–323

    Article  CAS  PubMed  Google Scholar 

  23. Cena V, Garcia AG, Gonzalez-Garcia C, Kirpekar SM (1985) Ion dependence of the release of noradrenaline by tetraethylammonium and 4-aminopyridine from cat splenic slices. Br J Pharmacol 84:299–308

    CAS  PubMed  Google Scholar 

  24. Lei M, Honjo H, Kodama I, Boyett MR (2001) Heterogeneous expression of the delayed-rectifier K+ currents i(K, r) and i(K, s) in rabbit sinoatrial node cells. J Physiol 535:703–714

    Article  CAS  PubMed  Google Scholar 

  25. Himeno Y, Sarai N, Matsuoka S, Noma A (2008) Ionic mechanisms underlying the positive chronotropy induced by beta1-adrenergic stimulation in guinea pig sinoatrial node cells: a simulation study. J Physiol Sci 58:53–65

    Article  CAS  PubMed  Google Scholar 

  26. Matsuura H, Ehara T, Ding WG, Omatsu-Kanbe M, Isono T (2002) Rapidly and slowly activating components of delayed rectifier K(+) current in guinea-pig sino-atrial node pacemaker cells. J Physiol 540:815–830

    CAS  PubMed  Google Scholar 

  27. Sridhar A, da Cunha DN, Lacombe VA, Zhou Q, Fox JJ, Hamlin RL, Carnes CA (2007) The plateau outward current in canine ventricle, sensitive to 4-aminopyridine, is a constitutive contributor to ventricular repolarization. Br J Pharmacol 152:870–879

    Article  CAS  PubMed  Google Scholar 

  28. Banyasz T, Magyar J, Szentandrassy N, Horvath B, Birinyi P, Szentmiklosi J, Nanasi PP (2007) Action potential clamp fingerprints of K+ currents in canine cardiomyocytes: their role in ventricular repolarization. Acta Physiol (Oxf) 190:189–198

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Miguel Angel Flores Virgen for technical assistance, Dr. Mike Sanguinetti (University of Utah) for critical reading of the manuscript and editorial assistance, and Dr. Leonardo C. Gutierrez Chavez for support. The work was supported by FOMIX (CONACYT-México) grant number 82948 and FRABA 2008 (Universidad de Colima).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Unidad “Carlos Méndez” del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Colima México

    Iván A. Aréchiga-Figueroa, Martin Rodríguez-Martínez, Alondra Albarado, Julián Torres-Jácome & José A. Sánchez-Chapula

  2. CUIB, Universidad de Colima, Av. 25 de Julio 965, CP 28045, Colima, Colima México

    José A. Sánchez-Chapula

Authors
  1. Iván A. Aréchiga-Figueroa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Rodríguez-Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alondra Albarado
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Julián Torres-Jácome
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. José A. Sánchez-Chapula
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José A. Sánchez-Chapula.

Additional information

Iván A. Aréchiga-Figueroa and Martin Rodríguez-Martínez contributed equally to this study

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aréchiga-Figueroa, I.A., Rodríguez-Martínez, M., Albarado, A. et al. Multiple effects of 4-aminopyridine on feline and rabbit sinoatrial node myocytes and multicellular preparations. Pflugers Arch - Eur J Physiol 459, 345–355 (2010). https://doi.org/10.1007/s00424-009-0734-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-009-0734-3

Keywords

Search

Navigation