title: Pharmacological block of the slow component of the outward delayed rectifier current (I(Ks)) fails to lengthen rabbit ventricular muscle QT(c) and action potential duration.
abstract: 1. The effects of I(Ks) block by chromanol 293B and L-735,821 on rabbit QT-interval, action potential duration (APD), and membrane current were compared to those of E-4031, a recognized I(Kr) blocker. Measurements were made in rabbit Langendorff-perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes. 2. Neither chromanol 293B (10 microM) nor L-735,821 (100 nM) had a significant effect on QTc interval in Langendorff-perfused hearts. E-4031 (100 nM), on the other hand, significantly increased QTc interval (35.6+/-3.9%, n=8, P<0.05). 3. Similarly both chromanol 293B (10 microM) and L-735,821 (100 nM) produced little increase in papillary muscle APD (less than 7%) while pacing at cycle lengths between 300 and 5000 ms. In contrast, E-4031 (100 nM) markedly increased (30 - 60%) APD in a reverse frequency-dependent manner. 4. In ventricular myocytes, the same concentrations of chromanol 293B (10 microM), L-735,821 (100 nM) and E-4031 (1 microM) markedly or totally blocked I(Ks) and I(Kr), respectively. 5. I(Ks) tail currents activated slowly (at +30 mV, tau=888.1+/-48.2 ms, n=21) and deactivated rapidly (at -40 mV, tau=157.1+/-4.7 ms, n=22), while I(Kr) tail currents activated rapidly (at +30 mV, tau=35.5+/-3.1 ms, n=26) and deactivated slowly (at -40 mV, tau(1)=641.5+/-29.0 ms, tau(2)=6531+/-343, n=35). I(Kr) was estimated to contribute substantially more to total current density during normal ventricular muscle action potentials (i.e., after a 150 ms square pulse to +30 mV) than does I(Ks). 6. These findings indicate that block of I(Ks) is not likely to provide antiarrhythmic benefit by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies.
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary.
authors.forename: C
authors.initials: C
authors.lastname: Lengyel
authors.forename: N
authors.initials: N
authors.lastname: Iost
authors.forename: L
authors.initials: L
authors.lastname: Virág
authors.forename: A
authors.initials: A
authors.lastname: Varró
authors.forename: D A
authors.initials: DA
authors.lastname: Lathrop
authors.forename: J G
authors.initials: JG
authors.lastname: Papp
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D002469:Cell Separation; D002839:Chromans / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D008133:Long QT Syndrome / Q000503:physiopathology; D008297:Male; D008839:Microelectrodes; D009206:Myocardium / Q000166:cytology; D010210:Papillary Muscles / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D002839:Chromans; C115921:L 735821; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; D013449:Sulfonamides; C063968:E 4031; D001569:Benzodiazepines; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D005576:Colforsin