Evidence for Two Components of Delayed Rectifier K ⁺ Current in Human Ventricular Myocytes

Abstract

Previous voltage-clamp studies have suggested that the delayed rectifier current (IK) is small or absent in the human ventricle and, when present, consists only of the rapid component (IKr); however, molecular studies suggest the presence of functionally important IK in the human heart, specific IKr blockers are known to delay ventricular repolarization and cause the long QT syndrome in humans, and we have shown that the expression of IK is strongly influenced by cell isolation techniques. The present experiments were designed to assess the expression of IK in myocytes obtained by arterial perfusion of right ventricular tissue from explanted human hearts. Of 35 cells from three hearts, 33 (94%) showed time-dependent currents typical of IK. The envelope-of-tails test was not satisfied under control conditions but became satisfied in the presence of the benzenesulfonamide E-4031 (5 micromol/L). E-4031 suppressed a portion of IK in 32 of 33 cells, with properties of the drug-sensitive and -resistant components consistent with previous descriptions of IKr and the slow component (IKs), respectively. Action potential duration to 95% repolarization at 1 Hz was prolonged by E-4031 from 336+/-16 (mean +/- SEM) to 421 +/- 19ms (n = 5, P < .01), indicating a functional role for IK. Indapamide, a diuretic agent previously shown to inhibit IKs selectively, suppressed E-4031-resistant current. The presence of a third type of delayed rectifier, the ultrarapid delayed rectifier current (IKur), was evaluated with the use of depolarizing prepulses and low concentrations (50 micromol/L) of 4-aminopyridine. Although these techniques revealed clear IKur in five of five human atrial cells, no corresponding component was observed in any of five human ventricular myocytes. We conclude that a functionally significant IK, with components corresponding to IKr and IKs, is present in human ventricular cells, whereas IKur appears to be absent. These findings are important for understanding the molecular, physiological, and pharmacological determinants of human ventricular repolarization and arrhythmias.

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts

“…I Kr and I Ks are believed to play an important role in repolarization of cardiac APs in mammalian hearts, including dogs (22) and humans (17). The downregulation of I Kr and/or I Ks may contribute to delayed repolarization in HF.…”

Downregulation of Delayed Rectifier K + Currents in Dogs With Chronic Complete Atrioventricular Block and Acquired Torsades de Pointes

“…The importance of I Kr and I Ks for normal human cardiac repolarization has been established in cellular electrophysiological studies, 27,28 and the characteristics of both components resemble those found in the dog. Differential downregulation of RV and LV delayed rectifier K ϩ currents could possibly contribute to repolarization abnormalities and arrhythmogenesis in patients with (this or other forms of) cardiac hypertrophy or failure, which is also indicated in a recent modeling of the human ventricular action potential.…”

Density and Kinetics of I Kr and I Ks in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of I Ks Blockade at High Heart Rate in Guinea Pig and Rabbit

“…14,[25][26][27] The evidence for the relevance of its blockade by chromanol 293B is indirect and based on the similarity of action potential prolongation in guinea pig and human ventricular myocytes at high heart rate. 6 In right ventricular myocytes isolated from explanted human hearts with primarily left heart failure, Li et al 14 demonstrated the presence of I Ks with relatively slow activation kinetics ( f of 360 ms and s of 8.5 seconds at ϩ50 mV). Recently, Virág et al 27 showed I Ks in undiseased human left ventricular myocytes with slow activation ( of 903 ms at ϩ50 mV) and relatively rapid deactivation ( of 122 ms at Ϫ40 mV).…”

“…Because I Ks blocker produces APD prolongation at short cycle length in humans as in guinea pig, 6 it is suggested that I Ks is relevant in human ventricle. 14 …”