Restricting Excessive Cardiac Action Potential and QT Prolongation

Abstract

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 μmol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 μmol/L) produced a <12-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. In voltage-clamp experiments, L-735,821 and chromanol 293B each blocked I Ks in the presence of E-4031 to block I Kr . The E-4031–sensitive current ( I Kr ) at the end of a 150-ms-long test pulse to 30 mV was 32.9±6.7 pA (n=8); the L-735,821–sensitive current ( I Ks ) magnitude was 17.8±2.94 pA (n=10). During a longer 500-ms test pulse, I Kr was not substantially changed (33.6±6.1 pA; n=8), and I Ks was significantly increased (49.6±7.24 pA; n=10). On application of an “action potential–like” test pulse, I Kr increased as voltage became more negative, whereas I Ks remained small throughout all phases of the action potential–like test pulse. In experiments in which APD was first lengthened by 50 nmol/L dofetilide and sympathetic activation was increased by 1 μmol/L adrenaline, 1 μmol/L HMR-1556 significantly increased APD by 14.7±3.2% ( P <0.05; n=3). Conclusions— Pharmacological I Ks block in the absence of sympathetic stimulation plays little role in increasing normal human ventricular muscle APD. However, when human ventricular muscle repolarization reserve is attenuated, I Ks plays an increasingly important role in limiting action potential prolongation.