Advertisement

Pflügers Archiv

, Volume 394, Issue 3, pp 230–238 | Cite as

Effects of 4-aminopyridine on inward rectifying and pacemaker currents of cardiac purkinje fibres

  • P. P. Van Bogaert
  • D. J. Snyders
Excitable Tissues and Central Nervous Physiology

Abstract

  1. 1.

    4-Aminopyridine (4-AP), in a concentration of 1–5mM, prolongs the action potential duration, induces spontaneous activity and depolarizes sheep cardiac Purkinje strands. These effects are different from those obtained with 0.1mM and are reversible.

     
  2. 2.

    Voltage clamp experiments demonstrate that the higher drug concentrations affect membrane currents measured in the potential range between-100 and-40mV, in addition to the reduction of the transient outward current already described for small amounts of the drug (0.1–0.5mM).

     
  3. 3.

    The analysis of membrane current modifications by 4-AP in the presence of cesium and barium ions indicates that 4-AP, in the higher concentration range, reduces the inward rectifying time independent potassium currentiK1 and modifies the voltage dependence of the time and voltage dependent pacemaker current. The steady-state activation curve of the pacemaker, current is shifted towards less negative potentials and is less steeply voltage dependent. The time constant (τ) curve has an increased maximum, displaced towards less negative potentials.

     
  4. 4.

    The modifications by 4-AP of theiK1 and pacemaker currents explain the changes in resting potential, action potential duration and the induction of spontaneous activity. The latter effect is not the result of an indirect effect of 4-AP through increased release of neurotransmitters from sympathetic nerve endings. A possible action of 4-AP at the inside of the membrane, explaining the multiple actions, is discussed.

     

Key words

Purkinje strands Ionic currents 4-AP Cs Ba 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Attwell D, Cohen I, Eisner D, Ohba M, Ojeda C (1979) The steady state TTX-sensitive (“window”) sodium current in cardiac Purkinje fibres. Pflügers Arch 379:137–142Google Scholar
  2. 2.
    Attwell D, Eisner D, Cohen I (1979) Voltage clamp and tracer flux data: effects of a restricted extracellular space. Q Rev Biophys 12:213–261Google Scholar
  3. 3.
    Baumgarten CM, Isenberg G (1977) Depletion and accumulation of potassium in the extracellular clefts of cardiac Purkinje fibres during voltage clamp hyperpolarization and depolarization. Pflügers Arch 369:19–31Google Scholar
  4. 4.
    Brown RH Jr, Noble D (1978) Displacement of activation thresholds in cardiac muscle by protons and calcium ions. J Physiol (Lond) 282:333–343Google Scholar
  5. 5.
    Brown HF, Clark A, Noble SJ (1976a) Identification of the pacemaker current in frog atrium. J Physiol (Lond) 258:521–545Google Scholar
  6. 6.
    Brown HF, Clark A, Noble SJ (1976b) Analysis of pacemaker and repolarization currents in frog atrial muscle. J Physiol (Lond) 258:547–577Google Scholar
  7. 7.
    Brown HF, Di Francesco D, Noble D, Noble SJ (1980) The contribution of potassium accumulation to outward currents in frog atrium. J Physiol (Lond) 306:127–149Google Scholar
  8. 8.
    Carmeliet EE (1961) Chloride and potassium permeability in cardiac Purkinje fibres. Presses Académiques Européennes, S. C. BruxellesGoogle Scholar
  9. 9.
    Carmeliet EE (1980) Decrease of K efflux and influx by external Cs ions in cardiac Purkinje and muscle cells. Pflügers Arch 383:143–150Google Scholar
  10. 10.
    Carmeliet EE, Vereecke J (1979) Electrogenesis of the action potential and automaticity. In: Berne RM (ed) Handbook of physiology. The cardiovascular system. I. American Physiological Society. Baltimore, pp 269–334Google Scholar
  11. 11.
    Cohen I, Noble D, Ohba M, Ojeda C (1979) Action of salicylate ions on the electrical properties of sheep cardiac Purkinje fibres. J Physiol (Lond) 297:163–185Google Scholar
  12. 12.
    Deitmer JW, Ellis D (1980) The intracellular sodium activity of sheep heart Purkinje fibres: effects of local anaesthetics and tetrodotoxin. J Physiol (Lond) 300:269–282Google Scholar
  13. 13.
    Di Francesco D (1981a) A new interpretation of the pacemaker current in calf Purkinje fibres. J Physiol (Lond) 314:359–376Google Scholar
  14. 14.
    Di Francesco D (1981b) A study of the ionic nature of the pacemaker current in calf Purkinje fibres. J Physiol (Lond) 314:377–393Google Scholar
  15. 15.
    Di Francesco D, McNaughton PA (1979) The effects of calcium on outward membrane currents in the cardiac Purkinje fibre. J Physiol (Lond) 289:347–373Google Scholar
  16. 16.
    Dudel J, Peper K, Rudel R, Trautwein W (1967) The potassium component of membrane current in Purkinje fibres. Pflügers Arch 296:308–327Google Scholar
  17. 17.
    Eisner DA, Lederer WJ (1979) The role of the sodium pump in the effects of potassium-depleted solution on mammalian cardiac muscle. J Physiol (Lond) 294:279–301Google Scholar
  18. 18.
    Fink R, Wettwer E (1978) Modified K-channel gating by exhaustion and the block by internally applied TEA and 4-AP in muscle. Pflügers Arch 374:289–292Google Scholar
  19. 19.
    Freeman SE (1979) Cholinergic mechanisms in the heart: interactions with 4-AP. J Pharmacol Exp Ther 210:7–14Google Scholar
  20. 20.
    Gillespie JE (1977) Voltage dependent blockage, of the delayed potassium current in skeletal muscle by 4-AP. J Physiol (Lond) 273:64–65PGoogle Scholar
  21. 21.
    Gillespie JI, Hutter OF (1975) The actions of 4-AP on the delayed potassium current in skeletal muscle fibres. J Physiol (Lond) 252:70–71PGoogle Scholar
  22. 22.
    Guerrero S, Novakovic L (1980) Effects of 4-aminopyridine on pacemaker activity of frog sinus venousus. Eur J Pharmacol 62:335–340Google Scholar
  23. 23.
    Hall AE, Hutter OF, Noble D (1963) Current-voltage relations of Purkinje fibres in sodium-deficient solutions. J Physiol (Lond) 166:225–240Google Scholar
  24. 24.
    Hart G, Noble D, Shimoni Y (1980) Adrenaline shifts the voltage dependence of the Na and K components of the if in sheep Purkinje fibres. J Physiol (Lond) 308:34PGoogle Scholar
  25. 25.
    Hauswirth O, Noble D, Tsien RW (1968) Adrenaline. Mechanism of action on the pacemaker potential in cardiac Purkinje fibres. Science 162:916–917Google Scholar
  26. 26.
    Isenberg G (1976) Cardiac Purkinje fibres. Cesium as a tool to block inward rectivying potassium currents. Plfügers Arch 365:99–106Google Scholar
  27. 27.
    Isenberg G (1978) The positive dynamic current of the cardiac Purkinje fibre is not a chloride but a potassium current. Pflügers Arch 377 (Suppl)R5Google Scholar
  28. 28.
    Isenberg G (1979) Risk and advantages of using strongly bevelled microelectrodes for electrophysiological studies in cardiac Purkinje fibres. Pflügers Arch 380:91–98Google Scholar
  29. 29.
    Isenberg G, Trautwein W (1974) The effects of dihydro-ouabaine and lithium ions on the outward current in cardiac Purkinje fibres. Pflügers Arch 350:41–54Google Scholar
  30. 30.
    Jaeger DM, Gibbons WR (1981) The effects of 4-AP on the late outward plateau currents in cardiac Purkinje fibres. Biophys J 33:72aGoogle Scholar
  31. 31.
    Kanaya S, Katzung BG (1980) Effects of 4-AP on depolarization induced automaticity in ventricular, myocardium. Proc West Pharmacol Soc 23:263–267Google Scholar
  32. 32.
    Kenyon JL, Gibbons WR (1979) 4-AP and the early outward current of sheep cardiac Purkinje fibres. J Gen Physiol 73:139–157Google Scholar
  33. 33.
    Lemeignan M, Auclair MC, Rodallec A, Lechat P (1975) Analyse electrophysiologique des effets de l'amino-4-pyridine sur le lambeau ventriculaire isolé du cœur de cobaye,. Arch Int Pharmacol 216:165–176Google Scholar
  34. 34.
    McAllister RE, Noble D, Tsien RW (1975) Reconstruction of the electrical activity of cardiac Purkinje fibres. J Physiol (Lond) 251:1–59Google Scholar
  35. 35.
    Meves H, Pichon Y (1977) The effect of internal and external 4-AP on the potassium currents in intracellularly perfused squid giant axons. J Physiol (Lond) 268:511–532Google Scholar
  36. 36.
    Molgo J (1978) Voltage-clamp analysis of the sodium and potassium currents in skeletal muscle fibres treated with 4-aminopyridine. Experientia 34:1275–1277Google Scholar
  37. 37.
    Noble D (1965) Electrical properties of cardiac muscle attributable to inward going (anomalous) rectification. J Cell Comp Physiol 66:127–136Google Scholar
  38. 38.
    Noble D (1975) The initiation of the heartbeat. Clarendon Press, OxfordGoogle Scholar
  39. 39.
    Noble SJ (1976) Potassium accumulation and depletion in frog atrial muscle. J Physiol (Lond) 258:579–613Google Scholar
  40. 40.
    Noble D, Tsien RW (1968) The kinetics and rectifier properties of the slow potassium current in cardiac Purkinje fibres. J Physiol (Lond) 195:185–214Google Scholar
  41. 41.
    Pelhate H, Pichon Y (1974) Selective inhibition of potassium current in the giant axon of the cockroach. J Physiol (Lond) 242:90–91Google Scholar
  42. 42.
    Schauf SC, Colton JS, Davis FA (1976) Aminopyridines and sparteine as inhibitors of membrane potassium conductance. Effects on myxicola giant axons and the lobster neuromuscular junction. J Pharmacol Exp Ther 197:414–425Google Scholar
  43. 43.
    Snyders DJ, van Bogaert PP (1978) Modification, of cardiac pacemaker current by 4-aminopyridine. Arch Int Physiol Biochem 86:190–191Google Scholar
  44. 44.
    Thompson SH (1977) Three pharmacologically distinct potassium channels in molluscan neurones. J Physiol (Lond) 265:465–488Google Scholar
  45. 45.
    Tsien RW (1974a) Effects of epinephrine, on the pacemaker potassium current of cardiac Purkinje fibres. J Gen Physiol 64:293–319Google Scholar
  46. 46.
    Tsien RW (1974b) Mode of action of chronotropic agents in cardiac Purkinje fibres. J Gen Physiol 64:320–342Google Scholar
  47. 47.
    Ulbricht W, Wagner HH (1976) Block of potassium channels of the nodal membrane by 4-aminopyridine and its partial removal on depolarization. Pflügers Arch 367:77–87Google Scholar
  48. 48.
    Van Bogaert, PP (1981) Shifts in pacemaker current voltage dependence during intracellular pH transients. Arch Int Physiol Biochem 89:24–25Google Scholar
  49. 49.
    Van Bogaert PP, Snyders DJ (1978) Dose-dependent effects of 4-AP on the electrical activity of cardiac Purkinje fibres. Pflügers Arch 373 (Suppl):R13Google Scholar
  50. 50.
    Van Bogaert PP, Vereecke JS, Carmeliet EE (1978) The effect of raised pH on pacemaker activity and ionic currents in cardiac Purkinje fibres. Pflügers Arch 375:45–52Google Scholar
  51. 51.
    Vassalle M (1965) Cardiac pacemaker potentials at different extra and intracellular K concentrations. Am J Physiol 208:770–775Google Scholar
  52. 52.
    Vereecke JS, Isenberg G, Carmeliet EE (1980) K-efflux through inward rectifying K channels in voltage clamped Purkinje fibres. Pflügers Arch 384:207–217Google Scholar
  53. 53.
    Woods TW, Urthaler F, James TN (1978) Chronotropic effects of tetraethylammonium and 4-aminopyridine in canine sinus node pacemaker cells. Circulation 57 and 58 (Suppl II):46Google Scholar
  54. 54.
    Yanagisawa I, Taira N (1979) Positive inotropic effect of 4-aminopyridine on dog ventricular muscle. Naunyn-Schmiedeberg's Arch Pharmacol 307:207–212Google Scholar
  55. 55.
    Yeh JZ, Oxford GS, Wu CH, Narahashi T (1976) Dynamics of aminopyridine block of potassium channels in squid axon membranes. J Gen Physiol 68:519–535Google Scholar

Copyright information

© Springer-Verlag 1982

Authors and Affiliations

  • P. P. Van Bogaert
    • 1
  • D. J. Snyders
    • 1
  1. 1.Laboratory of PhysiologyUniversity of Antwerp, (RUCA)AntwerpenBelgium

Personalised recommendations