Vol. 303, Issue 1, 347-355, October 2002

Differential Effects of Linoleic Acid Metabolites on Cardiac Sodium Current

Maddison D. Harrell and Joseph R. Stimers

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (J.R.S.); and Tulane University, New Orleans, Louisiana (M.D.H.)

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 µM for DHOA, 41 ± 6 µM for DHOM, 34 ± 5 µM for EOA, and 160 ± 41 µM for EOM. Although there was no effect on activation, 50 µM 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 µM 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.