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

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Abstract
Background: The delayed rectifier potassium current, which comprises both a rapid (I Kr) and a slow (IKs) component, is a major outward current involved in repolarization of cardiac myocytes. IKr is the target of most drugs that prolong repolarization, whereas electrophysio logical effects resulting from combined block of IKr and IKs 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 IKr block alone, I Ks block alone, or combined block of IKr and IKs. In protocol A, isolated perfusion with N-acetylprocainamide (NAPA) (I Kr block), indapamide (IKs 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 IKr) was 19 ± 6 msec (P < .05), after indap amide 100 μmol/L (EC50 for block of IKs) 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 IKr and IKs. As well, in protocol B where sequential perfusions with dofetilide (IKr 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 IKr and IKs block may lead to excessive lengthening of cardiac repo larization. This may predispose patients to proarrhythmia during coadministration of drugs.