Effects of epoxyeicosatrienoic acids on the cardiac sodium channels in isolated rat ventricular myocytes

J Physiol. 1999 Aug 15;519 Pt 1(Pt 1):153-68. doi: 10.1111/j.1469-7793.1999.0153o.x.


1. Whole-cell Na+ currents (holding potential, -80 mV; test potential, -30 mV) in rat myocytes were inhibited by 8, 9-epoxyeicosatrienoic acid (8,9-EET) in a dose-dependent manner with 22+/-4% inhibition at 0.5 microM, 48+/-5% at 1 microM, and 73+/-5% at 5 microM (mean +/- S.E.M., n = 10, P<0.05 for each dose vs. control). Similar results were obtained with 5,6-, 11,12-, and 14,15-EETs, while 8,9-dihydroxyeicosatrienoic acid (DHET) was 3-fold less potent and arachidonic acid was 10- to 20-fold less potent. 2. 8,9-EET produced a dose-dependent, hyperpolarized shift in the steady-state membrane potential at half-maximum inactivation (V ), without changing the slope factor. 8,9-EET had no effect on the steady-state activation of Na+ currents. 3. Inhibition of Na+ currents by 8,9-EET was use dependent, and channel recovery was slowed. The effects of 8,9-EET were greater at depolarized potentials. 4. Single channel recordings showed 8,9-EET did not change the conductance or the number of active Na+ channels, but markedly decreased the probability of Na+ channel opening. These results were associated with a decrease in the channel open time and an increase in the channel closed times. 5. Incubation of cultured cardiac myocytes with 1 microM [3H]8,9-EET showed that 25% of the radioactivity was taken up by the cells over a 2 h period, and most of the uptake was incorporated into phospholipids, principally phosphatidylcholine. Analysis of the medium after a 2 h incubation indicated that 86% of the radioactivity remained as [3H]8,9-EET while 13% was converted into [3H]8,9-DHET. After a 30 min incubation, 1-2% of the [3H]8,9-EET uptake by cells remained as unesterified EET. 6. These results demonstrate that cardiac cells have a high capacity to take up and metabolize 8,9-EET. 8,9-EET is a potent use- and voltage-dependent inhibitor of the cardiac Na+ channels through modulation of the channel gating behaviour.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 8,11,14-Eicosatrienoic Acid / analogs & derivatives*
  • 8,11,14-Eicosatrienoic Acid / pharmacology*
  • Animals
  • Animals, Newborn
  • Arachidonic Acid / pharmacology
  • Cells, Cultured
  • Heart / drug effects
  • Heart / physiology*
  • Heart Ventricles
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Myocardium / cytology*
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Channels / drug effects
  • Sodium Channels / physiology*
  • Structure-Activity Relationship


  • Sodium Channels
  • Arachidonic Acid
  • 11,12-epoxy-5,8,14-eicosatrienoic acid
  • 5,6-epoxy-8,11,14-eicosatrienoic acid
  • 8,9-epoxyeicosatrienoic acid
  • 14,15-epoxy-5,8,11-eicosatrienoic acid
  • 8,11,14-Eicosatrienoic Acid