Evidence for two components of delayed rectifier K+ current in human ventricular myocytes.

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.

[1]  L. Horowitz,et al.  Cellular electrophysiology of human myocardial infarction. 1. Abnormalities of cellular activation. , 1979, Circulation.

[2]  D. Roden,et al.  K+ currents and K+ channel mRNA in cultured atrial cardiac myocytes (AT-1 cells). , 1994, Circulation research.

[3]  W. Giles,et al.  A time- and voltage-dependent K+ current in single cardiac cells from bullfrog atrium , 1986, The Journal of general physiology.

[4]  M. Sanguinetti,et al.  Repolarizing K+ currents in nonfailing human hearts. Similarities between right septal subendocardial and left subepicardial ventricular myocytes. , 1995, Circulation.

[5]  G. Gintant,et al.  Gating of delayed rectification in acutely isolated canine cardiac Purkinje myocytes. Evidence for a single voltage-gated conductance. , 1985, Biophysical journal.

[6]  T. Shibasaki,et al.  Conductance and kinetics of delayed rectifier potassium channels in nodal cells of the rabbit heart. , 1987, The Journal of physiology.

[7]  T. Colatsky,et al.  Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias. , 1990, Circulation.

[8]  B. Fermini,et al.  Potassium channel blocking properties of propafenone in rabbit atrial myocytes. , 1993, The Journal of pharmacology and experimental therapeutics.

[9]  S. Nakanishi,et al.  Molecular cloning and sequence analysis of human genomic DNA encoding a novel membrane protein which exhibits a slowly activating potassium channel activity. , 1989, Biochemical and biophysical research communications.

[10]  D. Noble,et al.  Outward membrane currents activated in the plateau range of potentials in cardiac Purkinje fibres , 1969, The Journal of physiology.

[11]  R. Kass,et al.  Expression of a minimal K+ channel protein in mammalian cells and immunolocalization in guinea pig heart. , 1993, Circulation research.

[12]  M. Sanguinetti,et al.  Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. , 1993, Circulation research.

[13]  C. Antzelevitch,et al.  Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell. , 1995, Circulation research.

[14]  A Shrier,et al.  Repolarization currents in embryonic chick atrial heart cell aggregates. , 1986, Biophysical journal.

[15]  E. Carmeliet Electrophysiologic and voltage clamp analysis of the effects of sotalol on isolated cardiac muscle and Purkinje fibers. , 1985, The Journal of pharmacology and experimental therapeutics.

[16]  Y Rudy,et al.  Two components of the delayed rectifier K+ current in ventricular myocytes of the guinea pig type. Theoretical formulation and their role in repolarization. , 1995, Circulation research.

[17]  M. Franz,et al.  Prolongation of monophasic action potential duration and the refractory period in the human heart by tedisamil, a new potassium-blocking agent. , 1994, European heart journal.

[18]  D. Roden,et al.  Block of IKs, the slow component of the delayed rectifier K+ current, by the diuretic agent indapamide in guinea pig myocytes. , 1994, Circulation research.

[19]  E. Green,et al.  A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome , 1995, Cell.

[20]  D. Snyders,et al.  Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. , 1990, Circulation.

[21]  E. Erdmann,et al.  Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure. , 1993, Circulation research.

[22]  M. Sanguinetti,et al.  Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents , 1990, The Journal of general physiology.

[23]  T. Begenisich,et al.  Delayed rectification in the calf cardiac Purkinje fiber. Evidence for multiple state kinetics. , 1985, Biophysical journal.

[24]  J. Chant,et al.  GTPase cascades choreographing cellular behavior: Movement, morphogenesis, and more , 1995, Cell.

[25]  T. Mcdonald,et al.  THE POTASSIUM CURRENT UNDERLYING DELAYED RECTIFICATION IN CAT VENTRICULAR MUSCLE , 1978, The Journal of physiology.

[26]  B. Fermini,et al.  Identity of a novel delayed rectifier current from human heart with a cloned K+ channel current. , 1993, Circulation research.

[27]  S. Nakanishi,et al.  Cloning of a membrane protein that induces a slow voltage-gated potassium current. , 1988, Science.

[28]  B. Fermini,et al.  Rapid and slow components of delayed rectifier current in human atrial myocytes. , 1994, Cardiovascular research.

[29]  S Nattel,et al.  Sustained depolarization-induced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K+ current similar to Kv1.5 cloned channel currents. , 1993, Circulation research.

[30]  M. Rosen,et al.  Electrophysiologic Characteristics of Human Ventricular and Purkinje Fibers , 1982, Circulation.