title: Restricting excessive cardiac action potential and QT prolongation: a vital role for IKs in human ventricular muscle.
abstract: BACKGROUND
  Although pharmacological block of the slow, delayed rectifier potassium current (IKs) by chromanol 293B, L-735,821, or HMR-1556 produces little effect on action potential duration (APD) in isolated rabbit and dog ventricular myocytes, the effect of IKs block on normal human ventricular muscle APD is not known. Therefore, studies were conducted to elucidate the role of IKs in normal human ventricular muscle and in preparations in which both repolarization reserve was attenuated and sympathetic activation was increased by exogenous dofetilide and adrenaline.
  
  
  RESULTS
  Preparations were obtained from undiseased organ donors. Action potentials were measured in ventricular trabeculae and papillary muscles using conventional microelectrode techniques; membrane currents were measured in ventricular myocytes using voltage-clamp techniques. Chromanol 293B (10 micromol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 micromol/L) produced a <12-ms change in APD while pacing at cycle lengths ranging from 300 to 5000 ms, whereas the IKr blockers sotalol and E-4031 markedly lengthened APD. In voltage-clamp experiments, L-735,821 and chromanol 293B each blocked IKs in the presence of E-4031 to block IKr. The E-4031-sensitive current (IKr) at the end of a 150-ms-long test pulse to 30 mV was 32.9+/-6.7 pA (n=8); the L-735,821-sensitive current (IKs) magnitude was 17.8+/-2.94 pA (n=10). During a longer 500-ms test pulse, IKr was not substantially changed (33.6+/-6.1 pA; n=8), and IKs was significantly increased (49.6+/-7.24 pA; n=10). On application of an "action potential-like" test pulse, IKr increased as voltage became more negative, whereas IKs remained small throughout all phases of the action potential-like test pulse. In experiments in which APD was first lengthened by 50 nmol/L dofetilide and sympathetic activation was increased by 1 micromol/L adrenaline, 1 micromol/L HMR-1556 significantly increased APD by 14.7+/-3.2% (P<0.05; n=3).
  
  
  CONCLUSIONS
  Pharmacological IKs block in the absence of sympathetic stimulation plays little role in increasing normal human ventricular muscle APD. However, when human ventricular muscle repolarization reserve is attenuated, IKs plays an increasingly important role in limiting action potential prolongation.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Szeged, H-6720 Szeged, Hungary.
authors.forename: Norbert
authors.initials: N
authors.lastname: Jost
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.forename: Miklós
authors.initials: M
authors.lastname: Bitay
authors.forename: János
authors.initials: J
authors.lastname: Takács
authors.forename: Csaba
authors.initials: C
authors.lastname: Lengyel
authors.forename: Péter
authors.initials: P
authors.lastname: Biliczki
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Nagy
authors.forename: Gábor
authors.initials: G
authors.lastname: Bogáts
authors.forename: David A
authors.initials: DA
authors.lastname: Lathrop
authors.forename: Julius G
authors.initials: JG
authors.lastname: Papp
authors.forename: András
authors.initials: A
authors.lastname: Varró
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D005260:Female; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D049528:Insulin, Long-Acting; D008133:Long QT Syndrome / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010210:Papillary Muscles / Q000166:cytology / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology*; D013015:Sotalol / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000502:physiology
chemical_list: D000889:Anti-Arrhythmia Agents; D049528:Insulin, Long-Acting; D015221:Potassium Channels; D013015:Sotalol