Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Disclaimer
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Escande, D.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Escande, D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?


Inhibition of repolarizing ionic currents by drugs

D. Escande1

INSERM U533, Hôpital Hotel Dieu, Nantes, France

1 Correspondence: Dr Denis Escande, Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires, INSERM U533, H6pital Hotel Dieu, 1 Place A. Ricordeau 44093 Nantes, France.

Abstract

Every pharmacological substance that prolongs cardiac repolarization produces a risk of serious ventricular arrhythmias leading eventually to sudden death. Numerous non-cardiovascular drugs already in the market have been associated with altered cardiac repolarization and pro-arrhythmic effects. Because this side effect is serious (albeit infrequent), every new chemical entity intended for human use should be screened during the preclinical stages of its pharmaceutical development. Various in vitro and in vivo models have been established to accomplish this screen. Standard procedures are now available to prevent that drugs non-intentionally affecting cardiac repolarization will be developed and launched in the future.

Key Words: QT interval • arrhythmias • torsades de pointe • cardiac repolarization

References

  1. Haynes RE, Hallstrom AP, Cobb LA. Repolarization abnormalities in survivors of out-of-hospital ventricular fibrillation. Circulation. 1978;57:654–658[Abstract/Free Full Text]
  2. Schwartz PL, Wolf S. QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation. 1978;57:1074–1077[Abstract/Free Full Text]
  3. Dessertenne F. La tachycardie ventriculaire á deux foyers opposes variables. Arch Mal Coeur. 1966;9:263–265
  4. Vaughan-Williams EM. A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol. 1984;24:129–147[Abstract]
  5. Selzer A, Wray HW. Quinidine syncope: paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation. 1964;30:17–26[Free Full Text]
  6. Roden DM, Woosley RL, Primm RK. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am Heart J. 1986;111:1088–1093[CrossRef][Web of Science][Medline]
  7. Hohnloser SH. Proarrhythmia with class III antiarrhythmic drugs: types, risks, and management. Am J Cardiol. 1997;80:82G–89G[CrossRef][Medline]
  8. Wooltorton IRA, Mathie A. Block of potassium currents in rat isolated sympathetic neurones by tricyclic antidepressants and structurally related compounds. Br J Pharmacol. 1993;110:1126–1132[Web of Science][Medline]
  9. Zhou Z, Vorperian VR, Gong Q, Zhang S, January CT. Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastermizole and norastemizole. J Cardiovasc Electrophysiol. 1999;10:836–843[Web of Science][Medline]
  10. Committee for Proprietary Medicinal Products (CPMP). Points to Consider: The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. The European Agency for the Evaluation of Medicinal Products. December 1997;:
  11. Escande D. Standen N.K+ channels in Cardiovascular Medicine: from basic science to clinical practice. : Springer-Verläg; 1993.
  12. Science (Washington). 1998;282:2012–2018
  13. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995;81:299–307[CrossRef][Web of Science][Medline]
  14. Chouabe C, Drici MD, Romey G, Barhanin J, Lazdunski M. HERG and KvLQTl/IsK, the cardiac K+ channels involved in long-QT syndromes, are targets for calcium-channel blockers. Mol Pharmacol. 1998;54:695–703[Abstract/Free Full Text]
  15. Walker BD, Singleton CB, Bursil JA, et al. Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states. Br J Pharmacol. 1999;128:444–450[CrossRef][Web of Science][Medline]
  16. Chen Y, Woosley RL. Ketoconazole blocks potassium currents in feline heart. Circulation. 1993;88:I–38
  17. Rampe D, Murawsky MK, Gran J, Lewis EW. The antipsychotic agent sertindole is a high-affinity antagonist of the human cardiac potassium channel HERG. J Pharmacol Exp Ther. 1998;286:788–793[Abstract/Free Full Text]
  18. Salata JJ, Jurkiewicz NK, Wallace AA, Stupienski RE, Guinosso PL, Lynch JJ. Cardiac electrophysiological actions of the histamine H1-receptor antagonists astemizole and terfenadine compared with chlorpheniramine and pyrilamine. Circ Res. 1995;76:110–119[Abstract/Free Full Text]
  19. Teschemacher AG, Seward EP, Hancox JC, Witchel HJ. Inhibition of the current of heterologously-expressed HERG potassium channels by imipramine and amitriptyline. Br J Pharmacol. 1999;128:479–485[CrossRef][Web of Science][Medline]
  20. Escande D, Drici MD, Barhanin J. Molecular Basis of Inherited Long QT Syndromes and Cardiac Arrhythmias. Sperelakis N, Kurachi Y, Terzic A, Cohen M. Heart Physiology and Pathophysiology. 4th edn. San Diego: Academic Press; 2000. p. 1097–1105
  21. Loussouarn G, Charpentier F, Mohammad-Panah R, Kunzelmann K, Baro I, Escande D. KvLQTl but not IsK is the Molecular Target for Chromanol 293B. Mol Pharmacol. 1997;52:1131–1136[Abstract/Free Full Text]
  22. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol. 1990;96:195–215[Abstract/Free Full Text]
  23. Salata JJ, Jurkiewicz N, Jow B, et al. IK of rabbit ventricle is composed of two currents: evidence for IKs. Am J Physiol. 1996;271:H2477–H2489
  24. Antzelevitch C, Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations. Role of M cells in the generation of U waves, triggered activity and torsade de pointes. J Am Coll Cardiol. 1994;23:259–277[Abstract]
  25. Shimizu W, Antzelevitch C. Cellular basis for the ECG features of the LQTI form of the Long-QT syndrome. Effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and Torsade de Pointes. Circulation. 1998;98:2314–2322[Abstract/Free Full Text]
  26. Antzelevitch C, Shimizu W, Yan GX, et al. The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol. 1999;10:1124–1152[Web of Science][Medline]
  27. Adamantidis MM, Kerram P, Caron IF, Dupuis BA. Droperidol exerts dual effects on repolarization and induces early afterdepolarizations and triggered activity in rabbit Purkinje fibers. J Pharmacol Exp Ther. 1993;266:884–893[Abstract/Free Full Text]
  28. Pinney SP, Koller BS, Franz MR, Woosley RL. Terfenadine increases the QT interval in isolated guinea pig heart. J Cardiovasc Pharmacol. 1995;25:30–34[Web of Science][Medline]
  29. Echardt L, Haverkamp W, Mertens H, et al. Drug related torsade de pointes in the isolated rabbit heart: comparison of clofilium, d,l-sotalol and erythromycin. J Cardiovasc Pharmacol. 1998;32:425–434[CrossRef][Web of Science][Medline]
  30. Carlsson L, Almgren O, Duker G. QTU-prolongation and torsades de pointes induced by putative class III antiarrhythmic agents in the rabbit: etiology and interventions. J Cardiovasc Pharmacol. 1990;16:276–285[Web of Science][Medline]
  31. Chezalviel-Guilbert F, Davy JM, Poirier JM, Weissenburger J. Mexiletine antagonizes effects of sotalol on QT interval duration and its proarrythmic effects in a canine model of torsade de pointes. J Am Coll Cardiol. 1995;26:787–792[Abstract]
  32. Weissenburger J, Davy JM, Chezalviel F, Ertzbischoff O, Poirier JM, Engel F, Lainee P, Penin E, Motte G, Cheymol G. Arrhythmogenic activities of antiarrhythmic drugs in conscious hypokalemic dogs with atrioventricular block: Comparison between quinidine, lidocaine, flecainide, propranolol and sotalol. J Pharmacol Exp Ther. 1991;259:871–883[Abstract/Free Full Text]
  33. Vos MA, Verduyn SC, Gorgels AP, Lipcsei GC, Wellens HL. Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by d-sotalol and pacing in dogs with chronic atrioventricular block. Circulation. 1995;91:864–872[Abstract/Free Full Text]
  34. Duff HL, Feng ZP, Sheldon RS. High- and low-affinity sites for [3H]dofetilide binding to guinea pig myocytes. Circ Res. 1995;77:718–725[Abstract/Free Full Text]
  35. Lande G, Funck-Brentano C, Ghadanfar M, Escande D. Steady-state versus non-steady-state QT-RR relationships in 24-hour Holier recordings. Pacing Clin Electrophysiol. 2000;23:293–302[CrossRef][Medline]
  36. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation. 1999;99:529–533[Abstract/Free Full Text]
  37. Lande G, Kyndt F, Baro I, et al. Genetically uniform type of long QTl syndrome: from molecular to QT analysis. Eur Heart J. 2001;22:410–422[Abstract/Free Full Text]
  38. Mishra A, Friedman HS, Sinha AK. The effects of erythromycin on the electrocardiogram. Chest. 1999;115:983–986[Abstract/Free Full Text]
  39. Bohets H, Lavrijsen K, Hendrickx J, et al. Identification of the cytochrome P450 enzymes involved in the metabolism of cisapride: in vitro studies of potential co-medication interactions. Br J Pharmacol. 2000;129:1655–1667[CrossRef][Web of Science][Medline]
  40. Benardeau A, Weissenburger J, Hondeghem L, Ertel EA. Effects of the T-type Ca2+ channel blocker mibefradil on repolarization of guinea pig, rabbit, dog, monkey, and human cardiac tissue. J Pharmacol Exp Ther. 2000;292:561–575[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Disclaimer
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Escande, D.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Escande, D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?