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 acute respiratory distress syndrome. Lx production was recently shown during myocardial ischemia/ reperfusion. However, a recent study suggested that to be toxic Lx must be metabolized to Lx-diol. In the present study, isolated adult rat ventricular myocytes were studied with the whole-cell patch-clamp technique to determine the effects of these compounds on cardiac electrical activity. Measurements of action potentials showed that neither linoleic 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 dependent increase in duration and a decrease in overshoot of the action potential. Subsequent voltage clamp experiments isolating Na current (I-Na) and transient outward K current (I-to) revealed that Lx-diol inhibited I-Na and 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 same 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 activation kinetics of I-to but not I-Na. The action of Lx-diol was rapid (reaching steady state in 3-5 min) and was reversible in 5-10 min following washout. Thus, Lx-diol could favor arrhythmias or cardiac arrest in intact heart and may be responsible for the cardiac problems seen in systemic inflammatory response syndrome. These results further support the suggestion that Lx is not toxic in the heart but rather must be metabolized to Lx-diol to produce toxic effects on cardiac muscle. (C) 1999 Elsevier Science B.V. All rights reserved.