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

Abstract

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 Ks), 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 K, 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.