1 Introduction c Torsade de Pointes [1–4] + I Kr I Kr c [2,4,5] I Kr [6,7] + [5,8–10] c [11–13] [14] [15] [16] [17] [14] [18–20] c [19] [20] c [21–23] I HERG I HERG 2 Methods 2.1 Maintenance of mammalian cell lines stably expressing wild-type and mutant HERG channels [24] Fig. 8 + 2.2 [25] [26] [27] [25] −1 −1 −1 2.2 Experimental solutions I HERG 2 2 [28,29] [8,25] I HERG 2 [28,29] 2.3 Experiments on rabbit isolated ventricular myocytes I Kr Fig. 2 [30,31] I Kr I HERG 2.4 Electrophysiological recording and analysis P The following equations were used for numerical analysis and graphical fits to data: I HERG (1) Fractional block = 1 − I HERG – DOXEPIN I HERG – CONTROL I HERG I HERG–DOXEPIN I HERG–CONTROL (2) Fractional block = 1 1 + ( I C 50 / DOXEPIN ) h 50 I HERG h I HERG I HERG I V (3) I = I max 1 + exp V 0.5 − V m k I I HERG V m I max I HERG V 0.5 I HERG k I HERG V 0.5 k V 0.5 k Fig. 3 I HERG (4) Inactivation parameter = 1 − 1 1 + exp ( V 0.5 − V m ) / k V m V 0.5 I HERG k 3 Results 3.1 I HERG I HERG Fig. 1 I HERG [28,29,32] I HERG I HERG I HERG I HERG Fig. 1 I HERG I HERG Fig. 1 Fig. 1 I HERG 50 I HERG I HERG I HERG τ fast n p τ slow p τ fast I HERG [33] I HERG [32,34] Fig. 2 [32] Fig. 2 I HERG n I HERG Fig. 1 n p I Kr [32] Fig. 2 I Kr n I Kr Fig. 2 I Kr Fig. 2 (2) 50 I Kr I HERG 3.2 I HERG I HERG [32] Fig. 3 Fig. 3 I HERG I HERG (1) I HERG Fig. 3 Fig. 3 I HERG 2 V 0.5 k V 0.5 V 0.5 p k k p I HERG Fig. 3 I HERG p I HERG I HERG [32,35] Fig. 3 [35] Fig. 3 (4) 2 V 0.5 k I HERG I HERG p 3.3 I HERG I HERG HERG Fig. 4 I HERG Fig. 4 I HERG Fig. 4 I HERG n I HERG K −1 K Fig. 4 I HERG I HERG [29,32] [29] I HERG [29] Fig. 5 Fig. 5 Fig. 5 I HERG Fig. 5 I HERG p [25,29,36] 3.4 I HERG I HERG I HERG [26] [27] I HERG [35,37] I HERG I HERG Fig. 1 Fig. 6 Fig. 6 I HERG Fig. 6 I HERG [26,35,37] p p n Fig. 6 (2) I HERG 50 p I HERG 3.5 I HERG [5,9,38] I HERG I HERG [29,32,39–41] Fig. 7 I HERG Fig. 7 I HERG Fig. 1 Fig. 6 I HERG I HERG Fig. 7 I HERG Fig. 7 I HERG Fig. 7 I HERG p I HERG Fig. 7 (2) 50 I HERG p 50 I HERG I HERG Fig. 8 [25,28,29] Fig. 1 I HERG + e I HERG Fig. 8 I HERG [28] I HERG + e 2 + e Fig. 1 p Fig. 8 I HERG I HERG I HERG p I HERG I HERG p I HERG I HERG 4 Discussion [42] [18–20] + I HERG [21–23] I HERG 4.1 I HERG I HERG 50 [23] 50 [21] Xenopus 50 + e [22] I HERG 50 I HERG I HERG [22] [23] [21–23] [43] [44] I HERG I HERG I HERG I HERG I HERG Fig. 3 I HERG [10,45–48] I HERG [23] [25,49] [24,49,50] I HERG I HERG [5,9,38,51] 50 [8] 50 I HERG (2) I HERG I HERG [25,28] I HERG [43,44] 50 50 [43] I HERG I HERG I HERG + e I HERG + e + e I HERG + e [28,52] [53] [54] I HERG 4.2 I HERG c [42] I HERG [18–20] [15] I HERG I HERG 4.1 Fig. 5 Fig. 2 I HERG I HERG β I Kr [55] [51] I Kr [56] I HERG I Kr 50 I HERG I Kr [57] [58] I HERG I Kr [59] I HERG I Kr I HERG I HERG I HERG [27,60] I Kr [27,61] I Kr [62,63] I [27,62,63] I [63] I HERG I HERG