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Research ArticleArticle

Block of Potassium Currents in Guinea Pig Ventricular Myocytes and Lengthening of Cardiac Repolarization in Man by the Histamine H1 Receptor Antagonist Diphenhydramine

Majed Khalifa, Benoit Drolet, Pascal Daleau, Christophe Lefez, Marcel Gilbert, Sylvain Plante, Gilles E. O’Hara, Onil Gleeton, Bettina A. Hamelin and Jacques Turgeon
Journal of Pharmacology and Experimental Therapeutics February 1999, 288 (2) 858-865;
Majed Khalifa
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Benoit Drolet
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Pascal Daleau
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Christophe Lefez
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Marcel Gilbert
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Sylvain Plante
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Gilles E. O’Hara
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Onil Gleeton
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Bettina A. Hamelin
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Jacques Turgeon
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Abstract

Treatment with second generation histamine H1 receptor antagonists has been associated with lengthening of the Q-T interval and proarrhythmia. Similarly, lengthening of the Q-T interval has been reported in patients after overdosing with diphenhydramine (DPH), a first generation agent. Therefore, our study was designed 1) to assess effects of DPH on cardiac repolarization and 2) to characterize effects of the drug on major voltage-dependent cardiac K+ currents. First, we noticed that oral administration of DPH at usual dosages to healthy volunteers or to patients (prior to angioplasty) was associated with prolongation of the Q-Tc interval. Although this effect was modest in most individuals, Q-Tc was increased more than 20 ms in 7 of 20 patients. Second, we noticed that exposure of isolated guinea pig hearts to DPH 10−5 M caused a lengthening of monophasic action potential duration. This effect was potentiated by the combined perfusion of other K+ channel blockers such as indapamide. Finally, experiments performed with the patch-clamp technique demonstrated unequivocal block of the rapid component of the delayed rectifier (IKr) by DPH; however, IC50 determined for block of IKr (3 · 10−5 M) is ∼40-fold greater than plasma concentrations of the drug measured at usual dosages (7 · 10−7 M). Consequently, in agreement with the long-term clinical use of the drug, prolongation of cardiac repolarization should be minimal in most patients at usual dosages but may be observed with overdosing. Nevertheless, caution remains since excessive lengthening of cardiac repolarization may occur after administration of DPH with other drugs due to 1) concomitant block of other ionic currents or 2) pharmacokinetic interactions leading to toxic concentrations of DPH.

Footnotes

  • Send reprint requests to: Dr. Jacques Turgeon, Ph.D., Centre de Recherche, Hôpital Laval, 2725 Chemin Ste-Foy, Sainte-Foy, Québec, G1V 4G5, Canada. E-mail:phajtu{at}hermes.ulaval.ca

  • ↵1 This work was supported by grant MT 11876 from the Medical Research Council of Canada, by an operating grant from the Heart and Stroke Foundation of Canada, a studentship from the Quebec Heart Institute and the Faculty of Pharmacy, Laval University (M.K.), a research studentship from the Fonds pour la Formation de Chercheurs et l’Aide à la Recherche and a Merck Frosst award (B.D.), scholarships from the Fonds de la Recherche en santé du Québec (P.D., S.P., and B.A.H.), and a scholarship from the Joseph C. Edwards Foundation (J.T.).

  • Abbreviations:
    IK
    delayed rectifier potassium current
    IKr
    rapidly activating component of IK
    IKs
    slowly activating component of IK
    MAPD90
    monophasic action potential duration at 90% repolarization
    NAPA
    N-acetylprocainamide
    DPH
    diphenhydramine
    NAPA
    N-acetylprocainamide
    PTCA
    percutaneous coronary angioplasty
    IND
    indapamide
    • Received March 17, 1998.
    • Accepted September 22, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 2
1 Feb 1999
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Research ArticleArticle

Block of Potassium Currents in Guinea Pig Ventricular Myocytes and Lengthening of Cardiac Repolarization in Man by the Histamine H1 Receptor Antagonist Diphenhydramine

Majed Khalifa, Benoit Drolet, Pascal Daleau, Christophe Lefez, Marcel Gilbert, Sylvain Plante, Gilles E. O’Hara, Onil Gleeton, Bettina A. Hamelin and Jacques Turgeon
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 858-865;

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Research ArticleArticle

Block of Potassium Currents in Guinea Pig Ventricular Myocytes and Lengthening of Cardiac Repolarization in Man by the Histamine H1 Receptor Antagonist Diphenhydramine

Majed Khalifa, Benoit Drolet, Pascal Daleau, Christophe Lefez, Marcel Gilbert, Sylvain Plante, Gilles E. O’Hara, Onil Gleeton, Bettina A. Hamelin and Jacques Turgeon
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 858-865;
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