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 (I(K)) is small or absent in the human ventricle and, when present, consists only of the rapid component (I(Kr)); however, molecular studies suggest the presence of functionally important I(K) in the human heart, specific I(Kr) blockers are known to delay ventricular repolarization and cause the long QT syndrome in humans, and we have shown that the expression of I(K) is strongly influenced by cell isolation techniques. The present experiments were designed to assess the expression of I(K) 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 I(K). The envelope-of-tails test was not satisfied under control conditions but became satisfied in the presence of the benzenesulfonamide E-4031 (5 μmol/L). E-4031 suppressed a portion of I(K) in 32 of 33 cells, with properties of the drug-sensitive and -resistant components consistent with previous descriptions of I(Kr) and the slow component (I(Kr), respectively. Action potential duration to 95% repolarization at 1 Hz was prolonged by E-4031 from 336±16 (mean±SEM) to 421±19 ms (n=5, P<.01), indicating a functional role for I(K). Indapamide, a diuretic agent previously shown to inhibit I(Ks) selectively, suppressed E- 4031-resistant current. The presence of a third type of delayed rectifier, the ultrarapid delayed rectifier current (I(Kur)), was evaluated with the use of depolarizing prepulses and low concentrations (50 μmol/L) of 4- aminopyridine. Although these techniques revealed clear I(Kur) 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 I(Kr) with components corresponding to I(Kr) and I(Ks), is present in human ventricular cells, whereas I(Kur) appears to be absent. These findings are important for understanding the molecular, physiological, and pharmacological determinants of human ventricular repolarization and arrhythmias.