Background-Although pharmacological block of the slow, delayed rectifier potassium current (I Ks ) by chromanol 293B, L-735,821, or HMR-1556 produces little effect on action potential duration (APD) in isolated rabbit and dog ventricular myocytes, the effect of I Ks block on normal human ventricular muscle APD is not known. Therefore, studies were conducted to elucidate the role of I Ks in normal human ventricular muscle and in preparations in which both repolarization reserve was attenuated and sympathetic activation was increased by exogenous dofetilide and adrenaline. Methods and Results-Preparations were obtained from undiseased organ donors. Action potentials were measured in ventricular trabeculae and papillary muscles using conventional microelectrode techniques; membrane currents were measured in ventricular myocytes using voltage-clamp techniques. Chromanol 293B (10 mol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 mol/L) produced a Ͻ12-ms change in APD while pacing at cycle lengths ranging from 300 to 5000 ms, whereas the I Kr blockers sotalol and E-4031 markedly lengthened APD.

The relative contributions of the rapid and slow components of the delayed rectifier potassium current (IKr and IKs, respectively) to dog cardiac action potential configuration were compared in ventricular myocytes and in multicellular right ventricular papillary muscle and Purkinje fibre preparations. Whole‐cell patch‐clamp techniques, conventional microelectrode and in vivo ECG measurements were made at 37°C. Action potential duration (APD) was minimally increased (less than 7%) by chromanol 293B (10 μM) and L‐735,821 (100 nM), selective blockers of IKs, over a range of pacing cycle lengths (300–5000 ms) in both dog right ventricular papillary muscles and Purkinje fibre strands. D‐Sotalol (30 μM) and E‐4031 (1 μM), selective blockers of IKr, in the same preparations markedly (20–80%) lengthened APD in a reverse frequency‐dependent manner. In vivo ECG recordings in intact anaesthetized dogs indicated no significant chromanol 293B (1 mg kg−1 i.v.) effect on the QTc interval (332.9 ± 16.1 ms before versus 330.5 ± 11.2 ms, n= 6, after chromanol 293B), while D‐sotalol (1 mg kg−1 i.v.) significantly increased the QTc interval (323.9 ± 7.3 ms before versus 346.5 ± 6.4 ms, n= 5, after D‐sotalol, P < 0.05). The current density estimated during the normal ventricular muscle action potential (i.e. after a 200 ms square pulse to +30 mV or during a 250 ms long ‘action potential‐like’ test pulse) indicates that substantially more current is conducted through IKr channels than through IKs channels. However, if the duration of the square test pulse or the ‘action potential‐like’ test pulse was lengthened to 500 ms the relative contribution of IKs significantly increased. When APD was pharmacologically prolonged in papillary muscle (1 μM E‐4031 and 1 μg ml−1 veratrine), 100 nM L‐735,821 and 10 μM chromanol 293B lengthened repolarization substantially by 14.4 ± 3.4 and 18.0 ± 3.4% (n= 8), respectively. We conclude that in this study IKs plays little role in normal dog ventricular muscle and Purkinje fibre action potential repolarization and that IKr is the major source of outward current responsible for initiation of final action potential repolarization. Thus, when APD is abnormally increased, the role of IKs in final repolarization increases to provide an important safety mechanism that reduces arrhythmia risk.

1 The electrophysiological e ects of dronedarone, a new nonionidated analogue of amiodarone were studied after chronic and acute administration in dog Purkinje ®bres, papillary muscle and isolated ventricular myocytes, and compared with those of amiodarone by applying conventional microelectrode and patch-clamp techniques. 2 Chronic treatment with dronedarone (2625 mg 71 kg 71 day p.o. for 4 weeks), unlike chronic administration of amiodarone (50 mg 71 kg 71 day p.o. for 4 weeks), did not lengthen signi®cantly the QTc interval of the electrocardiogram or the action potential duration (APD) in papillary muscle. After chronic oral treatment with dronedarone a small, but signi®cant use-dependent V max block was noticed, while after chronic amiodarone administration a strong use-dependent V max depression was observed. 3 Acute superfusion of dronedarone (10 mM), similar to that of amiodarone (10 mM), moderately lengthened APD in papillary muscle (at 1 Hz from 239.6+5.3 to 248.6+5.3 ms, n=13, P50.05), but shortened it in Purkinje ®bres (at 1 Hz from 309.6+11.8 to 287.1+10.8 ms, n=7, P50.05). 4 Both dronedarone (10 mM) and amiodarone (10 mM) superfusion reduced the incidence of early and delayed afterdepolarizations evoked by 1 mM dofetilide and 0.2 mM strophantidine in Purkinje ®bres. 5 In patch-clamp experiments 10 mM dronedarone markedly reduced the L-type calcium current (76.5+0.7 %, n=6, P50.05) and the rapid component of the delayed recti®er potassium current (97+1.2 %, n=5, P50.05) in ventricular myocytes. 6 It is concluded that after acute administration dronedarone exhibits e ects on cardiac electrical activity similar to those of amiodarone, but it lacks the`amiodarone like' chronic electrophysiological characteristics.