RAPID ONSET OF LYSOPHOSPHATIDYLCHOLINE-INDUCED MODIFICATION OF WHOLE-CELL CARDIAC SODIUM CURRENT KINETICS

Lysophosphatidylcholine (LPC), an ischemic metabolite implicated in ar rhythmogenesis, has been shown to modulate aspects of Na+ channel gati ng, but its effects on steady-state availability (h(infinity)), recove ry from inactivation, and the timing of onset and possible reversibili ty, have not been characterized. We studied Na current (I-Na) by the w hole-cell patch clamp technique on isolated rat ventricular myocytes a t 22 degrees C with reduced Na+ (45 mM out, 5 mM in) from a holding po tential of -150 mV. Changes in the electrophysiological parameters wer e measured after LPC 10 mu M was added to the bath and compared to tim e controls (TC) taken from the time of seal formation. LPC decreased p eak current for a test potential to -30 mV by about 20%. The peak curr ent 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 di rection 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 e ffects occurred within 6 min after adding LPC to the bath and were sta tistically 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 p artially 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 als o seen in acutely ischemic myocardium, We therefore conclude that LPC action on I-Na may potentiate the arrhythmogenic substrate and that th e onset of these changes are sufficiently rapid to play a role in the electrical instability of acute ischemia. (C) 1996 Academic Press Limi ted