Skip to main content
SpringerLink
Log in

Comparison of acute electrophysiological effects of amiodarone and its metabolite desethylamiodarone in Langendorff perfused guinea pig hearts

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

Summary

During long-term treatment with amiodarone, slowing of conduction through the atrioventricular node, a prolongation of the QT-interval, and a prolongation of the atrial and ventricular myocardial refractoriness always developed. During short-term treatment, these effects were not found, except for depression of the AV-nodal conduction. This led to the suggestion that the electrophysiological effects of amiodarone during long-term treatment might be partly the result of the accumulation of its metabolite desethylamiodarone. Therefore, we examined the electrophysiological effects of amiodarone and desethylamiodarone on conduction and refractoriness in isolated spontaneously beating guinea pig hearts perfused by the method of Langendorff. Within 1 h of perfusion, desethyl-amiodarone caused a more pronounced prolongation of the AV-nodal, His-bundle, and intraventricular conduction intervals than did amiodarone. Desethylamiodarone, but not amiodarone led to a prolongation of the QT-interval. The refractoriness of sinoatrial-, AV-nodal conduction, and of the atrial myocardium were significantly more prolonged by amiodarone than by desethylamiodarone. Both compounds showed a comparable strong rate-dependent effect on AV-nodal refractoriness. The ventricular refractoriness was similarily prolonged by either compound. These results show that for the class-III effects (i.e., prolongation of repolarization period) observed under chronic treatment of amiodarone the metabolite desethylamiodarone may be responsible. Desethylamiodarone also exerts more pronounced effects on the fast-channel-dependent parts of the conduction system than does amiodarone, a fact indicated by a higher prolongation of His-bundle and intraventricular conduction.

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

Similar content being viewed by others

References

  1. Cramer M, Siegal M, Bigger JT jr, Hoffman BE (1977) Characteristics of extracellular potentials recorded from the sinoatrial pacemaker of the rabbit. Circ Res 41/3:292–300

    PubMed  Google Scholar 

  2. Debbas NMG, du Cailar C, Bexton RS, Demaille JG, Caram AJ, Puech P (1984) The QT interval: a predictor of the plasma and myocardial concentrations of amiodarone. Br Heart J 51:316–322

    PubMed  Google Scholar 

  3. Escoubet B, Coumel P, Poirier JM, Mason-Blanche P, Jaillon P, Leclerque JF, Menasche P, Cheymol G, Piwnica A, Lagier G, Slama R (1985) Suppression of arrhythmias within hours after a single oral dose of amiodarone and relation to plasma and myocardial concentrations. Am J Cardiol 55:696–702

    Article  PubMed  Google Scholar 

  4. Fogoros RN, Anderson KP, Winkle RA, Swerdlow CD, Mason JW (1983) Amiodarone. Clinical efficacy and toxicity in 96 patients with recurrent, drug-refractory arrhythmias. Circulation 68:88–94

    PubMed  Google Scholar 

  5. Gloor HO, Urthaler F, James TN (1983) Acute effects of amiodarone upon the canine sinus node and atrioventricular junctional region. J Clin Invest 71/5:1457–1466

    PubMed  Google Scholar 

  6. Heger JJ, Prystowsky EN, Jackman WM, Nacarelli GV, Warfel KA, Reichenberger RL, Zipes DP (1981) Amiodarone: Clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia of ventricular fibrillation. N Engl J Med 305:539–545

    PubMed  Google Scholar 

  7. Heger JJ, Prystowsky EN, Zipes DP (1983) Clinical efficacy of amiodarone dosage in treatment of recurrent ventricular tachycardia and ventricular fibrillation. Am Heart J 106:887–893

    Article  PubMed  Google Scholar 

  8. Hofer E, Stark U, Stark G, Tritthart HA (1990) Detection and continuous monitoring of intracardiac low-level potentials from the surface of the Langendorff-perfused heart. Basic Res Cardiol 85:198–208

    Article  PubMed  Google Scholar 

  9. Horowitz LN, Greenspan AM, Spielman SR (1985) Usefulness of electrophysiologic testing in evaluation of amiodarone therapy for sustained ventricular tachyarrhythmias associated with coronary heart disease. Am J Cardiol 55:367–371

    Article  PubMed  Google Scholar 

  10. Ikeda N, Nademanee K, Kaman R, Singh BN (1984) Electrophysiologic effects of amiodarone: experimental and clinical observation relative to serum and tissue drug concentrations. Am Heart J 108:890–898

    Article  PubMed  Google Scholar 

  11. Kadoya M, Konishi T, Tamamura T, Ikeguchi S, Hashimoto S (1985) Electrophysiological effects of amiodarone on isolated rabbit heart muscles. J Cardiovasc Pharmacol 7:643–648

    PubMed  Google Scholar 

  12. Lambert C, Vermeulen M, Cardinal R, Nadeau R (1986) Effect of the induction of amiodarone biotransformation on ventricular refractory periods in rats. J Pharmacol Exp Ther 238:307–312

    PubMed  Google Scholar 

  13. Latini R, Bizzi A, Cini M, Veneroni E, Marchi S, Riva E (1987) Amiodarone and desethylamiodarone tissue uptake in rats chronically treated with amiodarone is non-linear with the dose. J Pharm Pharmacol 39:426–431

    PubMed  Google Scholar 

  14. Mason JW, Hondeghem LM, Katzung BG (1984) Block of inactivated sodium channels and of depolarization-induced automaticity in guinea pig papillary muscle by amiodarone. Circ Res 55:277–285

    Google Scholar 

  15. McComb JM, Logan KR, Khan MM, Geddes JS, Adgey AA (1980) Amiodarone induced ventricular fibrillation. Eur J Cardiol 11:381–385

    PubMed  Google Scholar 

  16. McGovern B, Garan H, Malacoff RE (1984) Long-term clinical outcome of ventricular tachycardia or fibrillation treated with amiodarone. Am J Cardiol 53:1558–1563

    Article  PubMed  Google Scholar 

  17. Morady F, Di Carlo LA Jr, Krol RB, Baerman JM, de Buitleir M (1986) Acute and chronic effects of amiodarone on ventricular refractoriness, intraventricular conduction and ventricular tachycardia induction. J Am Coll Cardiol 71:48–157

    Google Scholar 

  18. Nadamee K, Hendrickson JA, Cannon DS, Goldreyer BN, Singh BN (1981) Control of refractory cardiac arrhythmias with amiodarone. Am Heart J 101:759–768

    Article  PubMed  Google Scholar 

  19. Nattel S, Talajic M, Quantz M, De Roode M (1987) Frequency-dependent effects of amiodarone on atrioventricular nodal function and slow-channel action potentials: Evidence for calcium channel blocking activity. Circulation 76/2:442–449

    PubMed  Google Scholar 

  20. Northover BJ, Leicester UK (1984) Alterations to the electrical activity of atrial muscle isolated from the rat heart, produced by exposure in vitro to amiodarone. Br J Pharmacol 82:191–197

    PubMed  Google Scholar 

  21. Singh BN, Vaughan Williams EM (1970) The effect of amiodarone, a new anti-anginal drug, on cardiac muscle. Br J Pharmacol 39:657–667

    PubMed  Google Scholar 

  22. Stark G, Huber U, Hofer E, Tritthart HA (1987) Continuous ECG measurements of intracardiac activity from the surface of Langendorff-perfused guinea pig hearts. Basic Res Cardiol 82:437–444

    Article  PubMed  Google Scholar 

  23. Stark U, Stark G, Tritthart HA (1987) Acute effects of amiodarone on the pacemaker and conduction system of the Langendorff perfused guinea pig heart. Z Kardiol 76 (Suppl 2):71

    PubMed  Google Scholar 

  24. Stark G, Stark U, Tritthart HA (1988) The modulation of cardiac impulse generation and conduction by nifedipine and verapamil analyzed by a refined surface ECG technique in Langendorff perfused guinea pig hearts. Basic Res Cardiol 83:202–212

    Article  PubMed  Google Scholar 

  25. Stark G, Stark U, Tritthart HA (1989) Assessment of the conduction of the cardiac impulse by a new epicardiac surface and stimulation technique (SST-ECG) in Langendorff perfused mammalian hearts. J Pharmacol Meth 21:195–209

    Article  Google Scholar 

  26. Stark G, Windisch M, Stark U, Bertuch H, Pilger E, Hönigl K, Tritthart HA (1989) Electrophysiological effects of amiodarone in correlation to tissue concentrations in isolated Langendorff perfused guinea pig hearts. Eur Heart J 10 (Suppl):2199

    Google Scholar 

  27. Talajic M, De Roode MR, Nattel S (1987) Comparative electrophysiologic effects of intravenous amiodarone and desethylamiodarone in dogs: evidence for clinically relevant activity of the metabolite. Circulation 75:265–271

    PubMed  Google Scholar 

  28. Torres V, Tepper D, Flowers D, Wynn J, Lam S, Keefe D, Miura DS, Somuerg JC (1986) QT prolongation and the antiarrhythmic efficacy of amiodarone. J Am Coll Cardiol 7:142–147

    PubMed  Google Scholar 

  29. Varro A, Nakaya Y, Surawicz B (1985) Use-dependent effects of amiodarone on Vmax in cardiac Purkinje and ventricular muscle fibers. Eur J Pharmacol 112:419–422

    Article  PubMed  Google Scholar 

  30. Vaughan Williams EM (1970) Classification of antiarrhythmic drugs. In: Sandoe E, FlenstedJensen E, Olesen K (eds) Cardiac Arrhythmias. Sodertalje, Sweden: Ad Astra 449–473

    Google Scholar 

  31. Wellens HJJ, Brugada H, Abdollah H, Dassen WR (1984) A comparison of the electrophysiologic effects of intravenous and oral amiodarone in the same patient. Circulation 69:120–124

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Medical Physics and Biophysics, Karl-Franzens-University, Graz, Austria

    U. Stark, S. Nagl & H. A. Tritthart

  2. Medical Physics and Biophysics and Zoology, Karl-Franzens-University, Graz, Austria

    M. Windisch, U. Eggenreich & K. Kral

  3. Department of Internal Medicine, Karl-Franzens-University, Graz, Austria

    G. Stark M.D., M. Vicenzi & E. Pilger

Authors
  1. G. Stark M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. U. Stark
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Windisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Vicenzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. U. Eggenreich
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Nagl
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K. Kral
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E. Pilger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H. A. Tritthart
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported by the Austrian Research Foundation, grant P 7141 and by the Austrian Development Fund, grant 5/545 and grant Z13/7098/513

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stark, G., Stark, U., Windisch, M. et al. Comparison of acute electrophysiological effects of amiodarone and its metabolite desethylamiodarone in Langendorff perfused guinea pig hearts. Basic Res Cardiol 86, 136–147 (1991). https://doi.org/10.1007/BF02190546

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02190546

Key words

Search

Navigation