Effects of linoleic acid metabolites on electrical activity in adult rat ventricular myocytes

Leukotoxin (Lx), an epoxide derivative of linoleic acid, has been suggested to be a toxic mediator of multiple organ failure in burn patients and of a cute respiratory distress syndrome. Lx production was recently shown during myocardial ischemia/ reperfusion. However, a recent study suggested that t o be toxic Lx must be metabolized to Lx-diol. In the present study, isolate d adult rat ventricular myocytes were studied with the whole-cell patch-cla mp technique to determine the effects of these compounds on cardiac electri cal activity. Measurements of action potentials showed that neither linolei c acid nor Lx (100 mu M) caused any significant changes in action potential properties. However, Lx-diol in the range of 10-100 mu M produced a dose d ependent increase in duration and a decrease in overshoot of the action pot ential. Subsequent voltage clamp experiments isolating Na current (I-Na) an d transient outward K current (I-to) revealed that Lx-diol inhibited I-Na a nd I-to by about 80% at 100 mu M, while linoleic acid and Lx had no effect on these currents at the same concentration. While Lx-diol produced the sam e inhibition of I-Na and I-to at 100 mu M, its effects were more potent on I-to with significant inhibition at 10 mu M. Lx-diol also hastened the acti vation kinetics of I-to but not I-Na. The action of Lx-diol was rapid (reac hing steady state in 3-5 min) and was reversible in 5-10 min following wash out. Thus, Lx-diol could favor arrhythmias or cardiac arrest in intact hear t and may be responsible for the cardiac problems seen in systemic inflamma tory response syndrome. These results further support the suggestion that L x is not toxic in the heart but rather must be metabolized to Lx-diol to pr oduce toxic effects on cardiac muscle. (C) 1999 Elsevier Science B.V. All r ights reserved.