© 1996 American Heart Association, Inc.
Articles |
Evidence for Two Components of Delayed Rectifier K+ Current in Human Ventricular Myocytes
From the Department of Medicine, Montreal Heart Institute (G.-R.L., J.F., S.N.) and University of Montreal (G.-R.L., S.N.), the Department of Surgery, Montreal Heart Institute and University of Montreal (M.C.), and the Department of Pharmacology and Therapeutics, McGill University (L.Y., S.N.), Montreal, Canada.
Correspondence to Dr Stanley Nattel, Research Center, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec, Canada H1T 1C8.
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 µmol/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±19 ms (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 µmol/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.
Key Words: repolarization • cardiac arrhythmias • ion channels • antiarrhythmic agents • class III drugs
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|
|
|
|
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|
|
|
|
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|
|
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|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
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|
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