Plasmalogen-derived lysolipid induces a depolarizing cation current in rabbit ventricular myocytes.
Plasmalogen rather than diacyl phospholipids are the preferred substrate for the cardiac phospholipase A2 (PLA2) isoform activated during ischemia. The diacyl metabolite, lysophosphatidylcholine, is arrhythmogenic, but the effects of the plasmalogen metabolite, lysoplasmenylcholine (LPLC), are essentially unknown. We found that 2.5 and 5 micromol/L LPLC induced spontaneous contractions of intact isolated rabbit ventricular myocytes (median times, 27.4 and 16.4 minutes, respectively) significantly faster than lysophosphatidylcholine (>60 and 37.8 minutes, respectively). Whole-cell recordings revealed that LPLC depolarized the resting membrane potential from -83.5+/-0.2 to -21.5+/-1.0 mV. Depolarization was due to a guanidinium toxin-insensitive Na+ influx. The LPLC-induced current reversed at -18.5+/-0.9 mV and was shifted 26.7+/-4.2 mV negative by a 10-fold reduction of bath Na+ (Na+/K+ permeability ratio, approximately 0.12+/-0.06). In contrast, block of Ca2+ channels with Cd2+ and reducing bath Cl failed to affect the current. The actions of LPLC were opposed by lanthanides. Gd3+ and La3+ were equally effective inhibitors of the LPLC-induced current and equally delayed the onset of spontaneous contractions. However, the characteristics of lanthanide block imply that Gd3+-sensitive, poorly selective, stretch-activated channels were not involved. Instead, the data are consistent with the view that lanthanides increase phospholipid ordering and may thereby oppose membrane perturbations caused by LPLC. Plasmalogens constitute a significant fraction of cardiac sarcolemmal choline phospholipids. In light of their subclass-specific catabolism by phospholipase A2 and the present results, it is suggested that LPLC accumulation may contribute to ventricular dysrhythmias during ischemia.
Caldwell
R A
RA
Department of Physiology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0551, USA.
Baumgarten
C M
CM
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D005682:Gadolinium / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects*; D007811:Lanthanum / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D011817:Rabbits
D007473:Ion Channels; D008246:Lysophospholipids; C021215:lysoplasmalogens; D007811:Lanthanum; D005682:Gadolinium