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Extracellular acidosis modulates drug block of Kv4.3 currents by flecainide and quinidine

Suresh Singarayar1, Jane Bursill, Ken Wyse

  • 1Department of Medicine, The University of New South Wales, Victor Chang Cardiac Research Institute, Sydney Australia.

Journal of Cardiovascular Electrophysiology
|July 24, 2003
PubMed
Abstract

Insights

Extracellular acidosis reduces the effectiveness of flecainide and quinidine in blocking Kv4.3 potassium channels. This finding offers a molecular explanation for how ischemia-related acidosis may alter drug efficacy and contribute to cardiac arrhythmias.

Area of Science:

  • Cardiovascular Pharmacology
  • Molecular Physiology
  • Ion Channel Function

Background:

  • Investigating the impact of ischemia on drug interactions with cardiac ion channels.
  • Understanding the role of acidosis in modulating drug block of potassium currents.

Purpose of the Study:

  • To determine the effect of extracellular acidosis on the blocking properties of flecainide and quinidine on Kv4.3 currents.
  • To elucidate the molecular mechanisms underlying acidosis-induced changes in drug-channel interactions.

Main Methods:

  • Stable expression of Kv4.3 channels in Chinese hamster ovary cells.
  • Whole-cell voltage clamp techniques to measure drug block at different pH levels (7.4 and 6.0).
  • Analysis of IC50 values and effects on channel inactivation and recovery.

Main Results:

  • Extracellular acidosis significantly attenuated the block of Kv4.3 channels by both flecainide and quinidine.
  • IC50 values for flecainide and quinidine increased substantially at pH 6.0 compared to pH 7.4.
  • Acidosis reduced the impact of these drugs on channel inactivation time course and frequency-dependent block.

Conclusions:

  • Extracellular acidosis decreases the potency of flecainide and quinidine blockade of Kv4.3 channels.
  • Potential mechanisms include allosteric channel changes, altered drug ionization, or modified binding kinetics.
  • Findings contrast with effects on sodium channels, providing a molecular basis for ischemia-associated proarrhythmia.

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