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

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

Research output: Contribution to journalArticle

75 Citations (Scopus)

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

Fingerprint

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

ASJC Scopus subject areas

  • Physiology

Cite this

Effects of epoxyeicosatrienoic acids on the cardiac sodium channels in isolated rat ventricular myocytes. / Lee, Hon Chi; Lu, Tong; 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 ; 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.
@article{83ec46fed57a44bb8225314fbfe3dfa9,
title = "Effects of epoxyeicosatrienoic acids on the cardiac sodium channels in isolated rat ventricular myocytes",
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.",
author = "Lee, {Hon Chi} and Tong Lu and Weintraub, {Neal L.} and Mike VanRollins and Spector, {Arthur A.} and Shibata, {Erwin F.}",
year = "1999",
month = "8",
day = "15",
doi = "10.1111/j.1469-7793.1999.0153o.x",
language = "English (US)",
volume = "519",
pages = "153--168",
journal = "Journal of Physiology",
issn = "0022-3751",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Effects of epoxyeicosatrienoic acids on the cardiac sodium channels in isolated rat ventricular myocytes

AU - Lee, Hon Chi

AU - Lu, Tong

AU - Weintraub, Neal L.

AU - VanRollins, Mike

AU - Spector, Arthur A.

AU - Shibata, Erwin F.

PY - 1999/8/15

Y1 - 1999/8/15

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0033567249&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033567249&partnerID=8YFLogxK

U2 - 10.1111/j.1469-7793.1999.0153o.x

DO - 10.1111/j.1469-7793.1999.0153o.x

M3 - Article

C2 - 10432346

AN - SCOPUS:0033567249

VL - 519

SP - 153

EP - 168

JO - Journal of Physiology

JF - Journal of Physiology

SN - 0022-3751

IS - 1

ER -