Rapid onset of lysophosphatidylcholine-induced modification of whole cell cardiac sodium current kinetics

Lysophosphatidylcholine (LPC), an ischemic metabolite implicated in arrhythmogenesis, has been shown to modulate aspects of Na+ channel gating, but its effects on steady-state availability (h(infinity)), recovery from inactivation, and the timing of onset and possible reversibility, have not been characterized. We studied Na current (I-Na) by the whole-cell patch clamp technique on isolated rat ventricular myocytes at 22 degrees C with reduced Na+ (45 mM out, 5 mM in) from a holding potential of -150 mV. Changes in the electrophysiological parameters were measured after LPC 10 mu M was added to the bath and compared to time controls (TC) taken from the time of seal formation. LPC decreased peak current for a test potential to -30 mV by about 20%. The peak current voltage relationship shifted in a positive direction by about 5 mV after LPC as compared to a small 2 mV negative shift in TC cells. LPC shifted the steady-state availability curve in the hyperpolarizing direction by about 6 mV. LPC perfusion caused a slowing of the decay of I-Na, and also a slowing of recovery from inactivation. Onset of the effects occurred within 6 min after adding LPC to the bath and were statistically significant with respect to TC cells between 12 and 16 min. In three cells, some of the effects on I-Na were either arrested or partially reversed by washout and cell survival was less than 20 min if LPC was not removed from the bath. These LPC induced changes in I-Na would tend to slow conduction and increase refractoriness, effects also seen in acutely ischemic myocardium, We therefore conclude that LPC action on I-Na may potentiate the arrhythmogenic substrate and that the onset of these changes are sufficiently rapid to play a role in the electrical instability of acute ischemia. (C) 1996 Academic Press Limited