1 The aim of this study was to investigate the possible role of the interaction of di erent potassium channels in dog ventricular muscle, by applying the conventional microelectrode and whole cell patch-clamp techniques at 378C. 2 Complete block of I Kr by 1 mM dofetilide lengthened action potential duration (APD) by 45.6+3.6% at 0.2 Hz (n=13). Chromanol 293B applied alone at 10 mM (a concentration which selectively blocks I Ks ) did not markedly lengthen APD (57%), but when repolarization had already been prolonged by complete I Kr block with 1 mM dofetilide, inhibition of I Ks with 10 mM chromanol 293B substantially delayed repolarization by 38.5+8.2% at 0.2 Hz (n=6). 3 BaCl 2 , at a concentration of 10 mM which blocks I Kl without a ecting other currents, lengthened APD by 33.0+3.1% (n=11), but when I Kr was blocked with 1 mM dofetilide, 10 mM BaCl 2 produced a more excessive rate dependent lengthening in APD, frequently (in three out of seven preparations) initiating early afterdepolarizations. 4 These ®ndings indicate that if only one type of potassium channels is inhibited in dog ventricular muscle, excessive APD lengthening is not likely to occur. Dog ventricular myocytes seem to repolarize with a strong safety margin (`repolarization reserve'). However, when this normal repolarization reserve' is attenuated, otherwise minimal or moderate potassium current inhibition can result in excessive and potentially proarrhythmic prolongation of the ventricular APD. Therefore, application of drugs which are able to block more than one type of potassium channel is probably more hazardous than the use of a speci®c inhibitor of one given sort of potassium channel, and when simultaneous blockade of several kinds of potassium channel may be presumed, a detailed study is needed to de®ne the determinants of`repolarization reserve'.

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.

It is concluded that type 1 diabetes mellitus, although only moderately, lengthens ventricular repolarization, attenuates the repolarization reserve by decreasing I(to) and I(Ks) currents, and thereby may markedly enhance the risk of sudden cardiac death.