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Differential effects of linoleic Acid metabolites on cardiac sodium current
Maddison D Harrell1, Joseph R Stimers
1Tulane University, New Orleans, Louisiana, USA.
Abstract:
9,10-Epoxy-12-octadecenoic acid (EOA), a metabolite of linoleic acid, causes cardiac arrest in dogs. Other metabolites of linoleic acid also have toxic effects. This study investigates the mechanism of action of four of these compounds on cardiac Na(+) current (I(Na)). The whole-cell patch-clamp technique was used to investigate the effects of EOA, 9,10-dihydroxy-12-octadecenoic acid (DHOA), and their corresponding methyl esters (9,10-epoxy-12-octadecenoic methyl ester, EOM; and 9,10-dihydroxy-12-octadecenoic methyl ester, DHOM) on I(Na) in isolated adult rat ventricular myocytes. Extracellular application of each compound elicited a concentration-dependent inhibition of I(Na). The dose-response curve yielded 50% inhibition concentrations of 301 +/- 117 microM for DHOA, 41 +/- 6 microM for DHOM, 34 +/- 5 microM for EOA, and 160 +/- 41 microM for EOM. Although there was no effect on activation, 50 microM DHOM, EOA, and EOM significantly hyperpolarized the steady-state inactivation curve by approximately -6 mV. Furthermore, EOM significantly increased the slope of the steady-state inactivation curve. These compounds also seemed to stabilize the inactivated state because the time for recovery from inactivation was significantly slowed from a control value of 12.9 +/- 0.5 ms to 30.5 +/- 3.3, 31.4 +/- 1.4, and 20.5 +/- 1.0 ms by 50 microM DHOM, EOA, and EOM, respectively. These compounds have multiple actions on Na(+) channels and that despite their structural similarities their actions differ from each other. The steady-state block of I(Na) suggests that either the pore is being blocked or the channels are prevented from gating to the open state. In addition, these compounds stabilize the inactivated state and promote increased population of a slower inactivated state.
Insights
Linoleic acid metabolites like 9,10-epoxy-12-octadecenoic acid (EOA) affect cardiac sodium channels (I(Na)). These compounds inhibit I(Na), alter inactivation curves, and slow recovery, indicating complex actions on heart function.
Area of Science:
- Cardiovascular Physiology
- Molecular Pharmacology
- Biochemistry
Background:
- Linoleic acid metabolites, including 9,10-epoxy-12-octadecenoic acid (EOA), are known to induce cardiac toxicity.
- Understanding the precise mechanisms by which these compounds affect cardiac function is crucial for assessing their risk.
Purpose of the Study:
- To investigate the effects of four linoleic acid metabolites—9,10-dihydroxy-12-octadecenoic acid (DHOA), 9,10-epoxy-12-octadecenoic methyl ester (EOM), and 9,10-dihydroxy-12-octadecenoic methyl ester (DHOM), in addition to EOA—on cardiac sodium current (I(Na)).
- To elucidate the specific actions of these compounds on the gating properties of cardiac sodium channels.
Main Methods:
- Utilized the whole-cell patch-clamp technique on isolated adult rat ventricular myocytes.
- Applied varying concentrations of DHOA, DHOM, EOA, and EOM extracellularly to measure their impact on I(Na).
- Analyzed effects on I(Na) activation, steady-state inactivation, and recovery from inactivation.
Main Results:
- All four compounds demonstrated a concentration-dependent inhibition of I(Na).
- DHOM, EOA, and EOM significantly hyperpolarized the steady-state inactivation curve, with EOM also increasing its slope.
- Recovery from Na(+) channel inactivation was significantly prolonged by DHOM, EOA, and EOM, indicating stabilization of the inactivated state.
Conclusions:
- These linoleic acid metabolites exert multiple effects on cardiac sodium channels, despite structural similarities.
- Their actions include pore block or prevention of channel opening, alongside stabilization of the inactivated state.
- The observed alterations in I(Na) gating properties provide insight into the cardiotoxic mechanisms of these compounds.