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.

Electrophysiological differences among M cells, epicardium, endocardium and Purkinje fibres of the canine ventricle were studied over a wide range of stimulation cycle lengths, and the pharmacological response of these cell types to the sodium channel blocker tetrodotoxin, calcium channel blocker nifedipine and ATP-sensitive potassium channel activator pinacidil was compared. The experiments were carried out by applying standard intracellular microelectrode technique in isolated dog left ventricular preparations. The results confirmed the existence of M cells in the canine ventricle, in addition, the distribution of the rate of rise of the action potential upstroke and action potential amplitude values reflecting probably the inhomogeneity of the fast sodium current in these cells was revealed. It was also demonstrated that M cells differ from Purkinje fibres in some aspects which were not expected from previous investigations: (1) The early portion of the action potential duration restitution curve in M cells is more similar to that of endocardial and epicardial cells than to Purkinje fibres. (2) The plateau phase of the action potentials in Purkinje fibres developed at a more negative potential range than that in the other cell types studied. (3) The pharmacological response to tetrodotoxin and pinacidil in M cells resembles to that in the endocardial and epicardial cells more than in the Purkinje fibres. Our results provide further evidence in support of the existence of M cells but also indicate that there are important electrophysiological as well as pharmacological differences between M cells and Purkinje fibres.

These results indicate that although basic APD has an important role in restitution, other transmembrane currents, such as I Na or I to , can also affect restitution kinetics. This raises the possibility that ion channel modifier drugs slowing restitution kinetics may have antiarrhythmic properties by altering restitution.

Even though rodents are accessible model animals, their electrophysiological properties are deeply different from that of human, making the translation of rat studies to human rather difficult. We compared the mechanisms of ventricular repolarization in various animal models to those of human by measuring cardiac ventricular action potentials from ventricular papillary muscle preparations using conventional microelectrodes, and applying selective inhibitors of various potassium transmembrane ion currents. Inhibition of the IK1 current (10 µM barium chloride) significantly prolonged rat ventricular repolarization, but only slightly prolonged it in dog, and did not affect it in human. On the contrary, IKr inhibition (50 nM dofetilide) significantly prolonged repolarization in human, rabbit, and dog, but not in rat. Inhibition of the IKur current (1 µM XEN-D0101) only prolonged rat ventricular repolarization, and had no effect in human or dog. Inhibition of the IKs (500 nM HMR-1556) and Ito currents (100 µM chromanol-293B) elicited similar effects in all investigated species. We conclude that dog ventricular preparations have the strongest, and rat ventricular preparations have the weakest translational value in cardiac electrophysiological experiments.