This Article Full Text (PDF) References Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Geelen, P. Articles by Turgeon, J. Search for Related Content PubMed Articles by Geelen, P. Articles by Turgeon, J. Social Bookmarking                         What's this?

Concomitant Block of the Rapid (IKr) and Slow (IKs) Components of the Delayed Rectifier Potassium Current is Associated With Additional Drug Effects on Lengthening of Cardiac Repolarization

Quebec Heart Institute, Laval Hospital and Faculties of Medicine and Pharmacy, Laval University, Sainte-Foy, Quebec, Canada

Benoit Drolet

Quebec Heart Institute, Laval Hospital and Faculties of Medicine and Pharmacy, Laval University, Sainte-Foy, Quebec, Canada

Etienne Lessard

Quebec Heart Institute, Laval Hospital and Faculties of Medicine and Pharmacy, Laval University, Sainte-Foy, Quebec, Canada

Philippe Gilbert

Quebec Heart Institute, Laval Hospital and Faculties of Medicine and Pharmacy, Laval University, Sainte-Foy, Quebec, Canada

Gilles E. O'Hara

Quebec Heart Institute, Laval Hospital and Faculties of Medicine and Pharmacy, Laval University, Sainte-Foy, Quebec, Canada

Jacques Turgeon

Quebec Heart Institute, Laval Hospital and Faculties of Medicine and Pharmacy, Laval University, Sainte-Foy, Quebec, Canada

Background: The delayed rectifier potassium current, which comprises both a rapid (I _Kr) and a slow (I_Ks) component, is a major outward current involved in repolarization of cardiac myocytes. I_Kr is the target of most drugs that prolong repolarization, whereas electrophysio logical effects resulting from combined block of I_Kr and I_Ks still need to be characterized.

Methods and Results: Studies in isolated, buffer-perfused guinea pig hearts were under taken to compare lengthening of cardiac repolarization under conditions of I_Kr block alone, I _Ks block alone, or combined block of I_Kr and I_Ks. In protocol A, isolated perfusion with N-acetylprocainamide (NAPA) (I _Kr block), indapamide (I_Ks block), or combined NAPA/ indapamide was performed at a pacing cycle length of 250 msec. Increases in monophasic action potential duration measured at 90% polarization (MAPD₉₀) from baseline after per fusion with NAPA 100 µmol/L (IC₅₀ for block of I_Kr) was 19 ± 6 msec (P < .05), after indap amide 100 µmol/L (EC₅₀ for block of I_Ks) 13 ± 2 msec (P < .05), but 42 ± 5 msec after combined NAPA 100 µmol/L and indapamide 100 µmol/L (P < .05 vs. baseline and isolated administrations), suggesting the possibility of excessive lengthening of cardiac repolariza tion by blocking both I_Kr and I_Ks. As well, in protocol B where sequential perfusions with dofetilide (I_Kr blocker), dofetilide/indapamide, and indapamide in the same hearts were used, combined dofetilide/indapamide infusion showed a greater increase in MAPD₉₀ dur ing all pacing cycles studied (250 to 150 msec).

Conclusions: Combined I_Kr and I_Ks block may lead to excessive lengthening of cardiac repo larization. This may predispose patients to proarrhythmia during coadministration of drugs.

Key Words: proarrhythmia • potassium channel blockers • IKr blockers • IKs blockers.

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 4, No. 3, 143-150 (1999)
DOI: 10.1177/107424849900400303


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?