Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Effects of (+)- and (±)-sotalol on repolarizing outward currents and pacemaker current in sheep cardiac Purkinje fibres

  • 16 Accesses

  • 34 Citations

Summary

This study was aimed to differentiate the action of (+)- and (±)-sotalol (10–1000 μmol/l) on membrane currents which are active during the repolarization of cardiac action potentials Effects where studied in shortened sheep cardiac Purkinje fibres with the two-microelectrode voltage-clamp technique Action potentials were activated at a frequency of 0.25 Hz and membrane currents at 0.03 Hz or 0.05 Hz in most experiments.

Out of the currents investigated the transient outward current (ito) reacted most sensitively to (+)- and (±)-sotalol. Ito-amplitude was decreased on the average to 77% of reference at 10 μmol/l and to 53% at 1000 μmol/l (+)- or (±)-sotalol. The maximally available ito-current was decreased but the voltage-dependent control of inactivation was left nearly unchanged. The initial inwardly rectifying current (iKi), which propels the last repolarization phase of the action potential and controls resting potential to a large extent was reduced on the average to 93% of reference at 10 μmol/l and to 62% at 1000 μmol/l (+)- or (±)-sotalol. Time-dependent (delayed) outward current (iK) was on the average not affected by (+)- or (±)-sotalol up to 100 μmol/l and was decreased to 84% of reference current under the influence of 1000 μmol/l. An initial outward current, which is activated at positive membrane potentials (iinst) was not clearly affected by (+)- or (±)-sotalol at concentrations up to 1000 μmol/l Pacemaker current (if) was not influenced by the drugs up to 100 μmol/l. Only at 1000 μmol/l was the amount of available if-current decreased to 79% of reference. (The potential-dependent control of activation was not affected) Time constants of time-dependent currents ito, iK and if did not change in concentrations up to 1000 μmol/l of the drug.

Action potential duration increased at (+)- or (±)-sotalol concentrations ≥ 10 μmol/l and maximal prolongation was achieved at concentrations of 100–300 μmol/l Resting potential remained nearly unchanged at these concentrations, but the membranes depolarized at 1000 μmol/l. According to our data action potential prolongation in sheep Purkinje fibres under the influence of (+)- and (±)-sotalol correlates to the drug-induced block to ito-current and inwardly rectifying iK1-current.

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

References

  1. Aronson RS, Gelles JM, Hoffman BF (1973) A new method for producing short cardiac Purkinje fibers suitable for voltage clamp. J Appl Physiol 34:527–530

  2. 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 368:19–31

  3. Biermans G, Vereecke J, Carmeliet E (1987) The mechanism of the inactivation of the inward-rectifying K current during hyperpolarizing steps in guinea-pig ventricular myocytes. Pflügers Arch 410:604–613

  4. Borchard U, Hafner D, Henning B, Scherlitz A (1985) Effects of (±)-sotalol and its optical isomers on cardiac action potential. Naunyn-Schmiedeberg's Arch Pharmacol (Suppl) 329:R54

  5. Borchard U, Berger F, Hafner D (1988) Concentration dependent effects of sotalol on action potentials, repolarizing outward currents and pacemaker current in cardiac tissues. Naunyn-Schmiedeberg's Arch Pharmacol (Suppl) 338:R41

  6. Borchard U, Berger F, Hafner D, Kammer T (1989) Pharmacological inhibition of transient outward current correlates with action potential prolongation in sheep cardiac Purkinje fibres. Naunyn-Schmiedeberg's Arch Pharmacol (Suppl) 339:R59

  7. Boyett MR, Coray A, McGuigan JAS (1980) Cow ventricular muscle. I. The effect of the extracellular potassium concentration on the current-voltage relationship. II. Evidence for a time-dependent outward current. Pflügers Arch 389:37–44

  8. Callewaert G, Carmeliet E, Vereecke J (1984) Single cardiac Purkinje cells: general electrophysiology and voltage-clamp analysis of the pace-maker current. J Physiol (Lond) 349:643–661

  9. Campbell TJ, Gavaghan TP, Morgan JJ (1985) Intravenous sotalol for the treatment of atrial fibrillation and flutter after cardiopulmonary bypass. Comparison with disopyramide and digoxin in a randomised trial. Br Heart J 54:86–90

  10. Carmeliet E (1985) Electrophysiologic and voltage clamp analysis of the effects of sotalol on isolated cardiac muscle and Purkinje fibers. J Pharmacol Exp Ther 232:817–825

  11. Coraboeuf E, Carmeliet E (1982) Existence of two transient outward currents in sheep cardiac Purkinje fibers. Pflügers Arch 392:352–359

  12. Deck KA, Kern R, Trautwein W (1964) Voltage clamp technique in mammalian cardiac fibres. Pflügers Arch 280:50–62

  13. DiFrancesco D (1981) A new interpretation of the pace-maker current in calf Purkinje fibres. J Physiol (Lond) 314:359–376

  14. DiFrancesco D, Noble D (1985) A model of cardiac electrical activity incorporating ionic pumps and concentration changes. Philos Trans R Soc Lond (Biol) 307:353–398

  15. DiFrancesco D, Ferroni A, Visentin S (1984) Barium-induced blockade of the inward rectifier in calf Purkinje fibres. Pflügers Arch 402:446–453

  16. DiFrancesco D, Ferroni A, Mazzanti M, Tromba C (1986) Properties of the hyperpolarizing-activated current (if) in cells isolated from the rabbit sino-atrial node. J Physiol (Lond) 377:61–88

  17. Echt DS, Bette LE, Clusin WT, Samuelsson RG, Harrison DC, Mason JW (1982) Prolongation of the human cardiac monophasic action potential by sotalol. Am J Cardiol 50:1082–1086

  18. Edvardsson N, Hirsch I, Emanuelsson H, Ponten J, Olssen SB (1980) Sotalol-induced delayed ventricular repolarization in man. Eur Heart J 1:335–343

  19. Escande D, Coulombe A, Faivre J-F, Deroubaix E, Coraboeuf E (1987) Two types of transient outward currents in adult human atrial cells. Am J Physiol 252:H 142-H 148

  20. Fedida D, Boyett MR (1985) Activity-dependent changes in the electrical behaviour of sheep cardiac Purkinje fibres. Proc R Soc Lond (Biol) 225:457–479

  21. Fozzard HA, Hiraoka M (1973) The positive dynamic current and its inactivation properties in cardiac Purkinje fibres. J Physiol (Lond) 234:569–586

  22. Hafner D, Berger F, Borchard U, Kullmann A, Scherlitz A (1988) Electrophysiological characterization of the class III activity of sotalol and its enantiomers. New interpretation of use-dependent effects. Arzneimittelforschung 38:231–236

  23. Hayward RP, Taggart P (1986) Effect of sotalol on human atrial action potential duration and refractoriness: cycle length dependency of class III activity. Cardiovasc Res 20:100–107

  24. Isenberg G (1976) Cardiac Purkinje fibers: Cesium as a tool to block inward rectifying potassium currents. Pflügers Arch 365:99–106

  25. Isenberg G, Vereecke J, van der Heyden G, Carmeliet E (1983) The shortening of the action potential by DNP in guinea-pig ventricular myocytes is mediated by an increase of a time-independent K conductance. Pflügers Arch 397:251–259

  26. Kaumann AJ, Olson CB (1968) Temporal relation between long-lasting after contractions and action potentials in cat papillary muscle. Science 161:293–295

  27. Kenyon JL, Gibbons WR (1979) 4-Aminopyridine and the early outward current of sheep cardiac Purkinje fibers. J Gen Physiol 73:139–157

  28. Kern R, Müller H, Schumacher T (1983) Effects of a β-blocking agent, sotalol, on membrane currents and contraction in frog atrial fibres. Naunyn-Schmiedeberg's Arch Pharmacol (Suppl) 322:R29

  29. Lidell C, Rehnqvist N, Sjögren A, Yli-Uotila RJ, Rønnevik PK (1985) Comparative efficacy of oral sotalol and procainamide in patients with chronic ventricular arrhythmias: A multicenter study. Am Heart J 109:970–975

  30. McComb JM, McGovern B, McGowan JB, Ruskin JN, Garan H (1987) Electrophysiologic effects of d-sotalol in humans. J Am Coll Cardiol 10:211–217

  31. McDonald TF, Trautwein W (1978) The potassium current underlying delayed rectification in cat ventricular muscle. J Physiol (Lond) 274:217–246

  32. Nademanee K, Feld G, Hendrickson J, Singh PN, Singh BN (1985) Electrophysiologic and antiarrhythmic effects of sotalol in patients with life-threatening ventricular tachyarrhythmias. Circulation 72:555–564

  33. Neuvonen PJ, Elonen E, Tanskanen A, Tuomilehto J (1981) Sotalol and prolonged Q-Tc interval (letter). Lancet 2:426

  34. Noble D, Tsien RW (1969) Outward membrane currents activated in the plateau range of potentials in cardiac Purkinje fibres. J Physiol (Lond) 200:205–231

  35. Patil PN (1968) Steric aspects of adrenergic drugs. VIII. Optical isomers of beta adrenergic receptor antagonists. J Pharmacol Exp Ther 160:308–314

  36. Rizos I, Senges J, Jauernig R, Lengfelder W, Czygan E, Brachmann J, Kübler W (1984) Differential effects of Sotalol and Metoprolol on induction of paroxysmal supraventricular tachycardia. Am J Cardiol 53:1022–1027

  37. Sakmann B, Trube G (1984) Voltage-dependent inactivation of inward-rectifying single-channel currents in the guinea-pig heart cell membrane. J Physiol (Lond) 347:659–683

  38. Schwartz J, Crocker K, Wynn J, Somberg JC (1987) The antiarrhythmic effects of d-Sotalol. Am Heart J 114:539–544

  39. Senges J, Lengfelder W, Jauernig R, Czygan E, Brachmann J, Rizos I, Cobbe S, Kübler W (1984) Electrophysiological testing in assessment of therapy with sotalol for sustained ventricular tachycardia. Circulation 69:577–584

  40. Singh BN, Vaughan Williams EM (1970) A third class of antiarrhythmic action. Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ 1999 and AH 3474. Br J Pharmacol 39:675–687

  41. Somani P, Watson DL (1968) Antiarrhythmic activity of the dextro- and levorotatory isomers of 4-(2-isopropylamino-l-hydroxy-ethyl) methanesulfonanilide (MJ 1999). J Pharmacol Exp Ther 164:317–325

  42. Strauss HC, Bigger JT, Hoffmann BF (1970) Electrophysiological and beta-receptor blocking effects of MJ 1999 on dog and rabbit cardiac tissue. Cir Res 26:661–678

Download references

Author information

Additional information

Supported by the Deutsche Forschungsgemeinschaft SFB 242, C 1

Send offprint requests to U. Borchard at the above address

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Berger, F., Borchard, U. & Hafner, D. Effects of (+)- and (±)-sotalol on repolarizing outward currents and pacemaker current in sheep cardiac Purkinje fibres. Naunyn-Schmiedeberg's Arch. Pharmacol. 340, 696–704 (1989). https://doi.org/10.1007/BF00717747

Download citation

Key words

  • Sheep Purkinje fibre
  • Outward currents
  • Pacemaker current
  • (+)-Sotalol
  • (±)-Sotalol