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

Abstract

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.