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

Hon Chi Lee, Tong D Lu, Neal L. Weintraub, Mike VanRollins, Arthur A. Spector, Erwin F. Shibata

Research output: Contribution to journalArticle

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Abstract

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 μM, 48 ± 5% at 1 μM, and 73 ± 5% at 5 μM (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( 1/2 )), 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 μM [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.

Original languageEnglish (US)
Pages (from-to)153-168
Number of pages16
JournalJournal of Physiology
Volume519
Issue number1
DOIs
StatePublished - Aug 15 1999
Externally publishedYes

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Sodium Channels
Muscle Cells
Acids
Radioactivity
8,9-epoxyeicosatrienoic acid
Phosphatidylcholines
Cardiac Myocytes
Arachidonic Acid
Membrane Potentials
Phospholipids

ASJC Scopus subject areas

  • Physiology

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Effects of epoxyeicosatrienoic acids on the cardiac sodium channels in isolated rat ventricular myocytes. / Lee, Hon Chi; Lu, Tong D; Weintraub, Neal L.; VanRollins, Mike; Spector, Arthur A.; Shibata, Erwin F.

In: Journal of Physiology, Vol. 519, No. 1, 15.08.1999, p. 153-168.

Research output: Contribution to journalArticle

Lee, Hon Chi ; Lu, Tong D ; Weintraub, Neal L. ; VanRollins, Mike ; Spector, Arthur A. ; Shibata, Erwin F. / Effects of epoxyeicosatrienoic acids on the cardiac sodium channels in isolated rat ventricular myocytes. In: Journal of Physiology. 1999 ; Vol. 519, No. 1. pp. 153-168.
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T1 - Effects of epoxyeicosatrienoic acids on the cardiac sodium channels in isolated rat ventricular myocytes

AU - Lee, Hon Chi

AU - Lu, Tong D

AU - Weintraub, Neal L.

AU - VanRollins, Mike

AU - Spector, Arthur A.

AU - Shibata, Erwin F.

PY - 1999/8/15

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N2 - 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 μM, 48 ± 5% at 1 μM, and 73 ± 5% at 5 μM (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( 1/2 )), 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 μM [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.

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