Pharmacological block of the slow component of the outward delayed rectifier current (IKs) fails to lengthen rabbit ventricular muscle QTc and action potential duration

1 The effects of I-Ks block by chromanol 293B and L-735,821 on rabbit QT-interval, action potential duration (APD), and membrane current were compared to those of E-4031, a recognized I-Kr blocker. Measurements were made in rabbit Langendorff-perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes. 2 Neither chromanol 293B (10 muM) nor L-735,821 (100 nM) had a significant effect on QTc interval in Langendorff-perfused hearts. E-4031 (100 nM), on the other hand, significantly increased QTc interval (35.6 +/- 3.9%, n = 8, P < 0.05). 3 Similarly both chromanol 293B (10 <mu>M) and L-735,821 (100 nM) produced little increase in papillary muscle APD (less than 7%) while pacing at cycle lengths between 300 and 5000 ms. In contrast, E-4031 (100 nM) markedly increased (30-60%) APD in a reverse frequency-dependent manner. 4 In ventricular myocytes, the same concentrations of chromanol 293B (10 muM), L-735,821 (100 nM) and E-4031 (1 muM) markedly or totally blocked I-Ks and I-Kr, respectively. 5 I-Ks tail currents activated slowly (at + 30 mV, tau = 885.1 +/- 48.2 ms, n = 21) and deactivated rapidly (at -40 mV, tau = 157.1+/-4.7 ms, n = 22), while IKr tail currents activated rapidly (at +30 mV, tau = 35.5 +/- 3.1 ms, n = 26) and deactivated slowly (at -40 mV, tau (1) = 641.5 +/- 29.0 ms, tau (2) = 6531 +/- 343, n = 35). I-Kr, was estimated to contribute substantially more to total current density during normal ventricular muscle action potentials (i.e., after a 150 ms square pulse to + 30 mV) than does I-Ks 6 These findings indicate that block of I-Ks is not likely to provide antiarrhythmic benefit by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies.