PT  - JOURNAL ARTICLE
AU  - Harrell, Maddison D.
AU  - Stimers, Joseph R.
TI  - Differential Effects of Linoleic Acid Metabolites on Cardiac Sodium Current
AID  - 10.1124/jpet.102.038166
DP  - 2002 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 347--355
VI  - 303
IP  - 1
4099  - http://jpet.aspetjournals.org/content/303/1/347.short
4100  - http://jpet.aspetjournals.org/content/303/1/347.full
SO  - J Pharmacol Exp Ther2002 Oct 01; 303
AB  - 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 (INa). 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) onINa in isolated adult rat ventricular myocytes. Extracellular application of each compound elicited a concentration-dependent inhibition of INa. 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 INa 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. The American Society for Pharmacology and Experimental Therapeutics