Pharmacological block of the slow component of the outward delayed rectifier current (IKs) fails to lengthen rabbit ventricular muscle QTc and action potential duration

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Abstract

1. The effects of IKs 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 IKr blocker. Measurements were made in rabbit Langendorff-perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes. 2. Neither chromanol 293B (10 μm) 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 μM) 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 μM), L-735,821 (100 nm) and E-4031 (1 μm) markedly or totally blocked IKs and IKr, respectively. 5. IKs tail currents activated slowly (at + 30 mV, τ= 888.1 ± 48.2 ms, n = 21) and deactivated rapidly (at -40 mV, τ=157.1±4.7 ms, n=22), while IKr tail currents activated rapidly (at + 30 mV, τ=35.5±3.1 ms, n=26) and deactivated slowly (at -40 mV, τ1=641.5±29.0 ms, τ2=6531±343, n=35). IKr 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 IKs. 6. These findings indicate that block of IKs is not likely to provide antiarrhythmic benefit by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies.

Original languageEnglish
Pages (from-to)101-110
Number of pages10
JournalBritish journal of pharmacology
Volume132
Issue number1
DOIs
Publication statusPublished - Jan 1 2001

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Keywords

  • Arrhythmia
  • Chromanol 293B
  • L-735,821
  • Rabbit heart

ASJC Scopus subject areas

  • Pharmacology

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