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 (INa) 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 microM 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 INa, 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 INa 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 INa would tend to slow conduction and increase refractoriness, effects also seen in acutely ischemic myocardium. We therefore conclude that LPC action on INa 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.
Shander
G S
GS
Department of Medicine, University of Chicago, USA.
Undrovinas
A I
AI
Makielski
J C
JC
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism; D002478:Cells, Cultured; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D017202:Myocardial Ischemia / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D015222:Sodium Channels / Q000378:metabolism* / Q000502:physiology*
D008244:Lysophosphatidylcholines; D015222:Sodium Channels