| Concomitant Block of the Rapid (I(Kr)) and Slow (I(Ks)) Components of the Delayed Rectifier Potassium Current is Associated With Additional Drug Effects on Lengthening of Cardiac Repolarization. | |
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MedLine Citation:
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PMID: 10684535 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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BACKGROUND: The delayed rectifier potassium current, which comprises both a rapid (I(Kr)) and as 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 electrophysiological 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 undertaken 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 (MAPD(90)) from baseline after perfusion with NAPA 100 µmol/L (IC(50) for block of I(Kr)) was 19 +/- 6 msed (P <.05), after indapamide 100 µmol/L (EC(50) 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 repolarization 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 MAPD(90) during all pacing cycles studied (250 to 150 msec). CONCLUSIONS: Combined I(Kr) and I(Ks) block may lead to excessive lengthening of cardiac repolarization. This may predispose patients to proarrhythmia during coadministration of drugs. |
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Authors:
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Geelen; Drolet; Lessard; Gilbert; O'Hara; Turgeon |
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Publication Detail:
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Type: JOURNAL ARTICLE |
Journal Detail:
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Title: Journal of cardiovascular pharmacology and therapeutics Volume: 4 ISSN: 1940-4034 ISO Abbreviation: J. Cardiovasc. Pharmacol. Ther. Publication Date: 1999 Jul |
Date Detail:
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Created Date: 2000-02-22 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9602617 Medline TA: J Cardiovasc Pharmacol Ther Country: - |
Other Details:
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Languages: ENG Pagination: 143-150 Citation Subset: - |
Affiliation:
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Quebec Heart Institute, Sainte-Foy, Quebec, Canada |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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