The role of the delayed rectifier component I-Ks in dog ventricular muscleand Purkinje fibre repolarization

1. The relative contributions of the rapid and slow components of the delay ed rectifier potassium current (I-Kr and I-Ks, respectively) to dog cardiac action potential configuration were compared in ventricular myocytes and i n multicellular right ventricular papillary muscle and Purkinje fibre prepa rations. Whole-cell patch-clamp techniques, conventional microelectrode and in vivo ECG measurements were made at 37 degrees C. 2. Action potential duration (APD) was minimally increased (less than 7 %) by chromanol 293B (10 mu M) and L-735,821 (100 nM), selective blockers of I -Ks, over a range of pacing cycle lengths (300-5000 ms) in both dog right v entricular papillary muscles and Purkinje fibre strands. D-Sotalol (30 mu M ) and E-4031 (1 mu M), selective blockers of I-Kr, in the same preparations markedly (20-80%) lengthened APD in a reverse frequency-dependent manner. 3. In vivo ECG; recordings in intact anaesthetized dogs indicated no signif icant 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), whi le D-sotalol(1 mg kg(-1) I.V.) significantly increased the QTc interval (32 3.9 +/- 7.3 ms before versus 346.5 +/- 6.4 ms, n = 5, after D-sotalol, P < 0.05). 4. The current density estimated during the normal ventricular muscle actio n 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 I-Kr channels than through I-Kr channels. Howe ver, if the duration of the square test pulse or the 'action potential-like ' test pulse was lengthened to 500 ms the relative contribution of I-Kr sig nificantly increased. 5. When APD was pharmacologically prolonged in papillary muscle (1 mu M E-4 031 and 1 mu g ml(-1) veratrine), 100 nM L-735,821 and 10 mu M chromanol 29 3B lengthened repolarization substantially by 14.4 +/- 3.4 and 18.0 +/- 3.4 % (n = 8), respectively. 6. We conclude that in this study I-Ks plays little role in normal dog vent ricular muscle and Purkinje fibre action potential repolarization and that I-Ks is the major source of outward current responsible for initiation of f inal action potential repolarization. Thus, when APD is abnormally increase d, the role of I-Ks in final repolarization increases to provide an importa nt safety mechanism that reduces arrhythmia risk.