Plasmalogen-Derived Lysolipid Induces a Depolarizing Cation Current in Rabbit Ventricular Myocytes

Abstract

Abstract —Plasmalogen rather than diacyl phospholipids are the preferred substrate for the cardiac phospholipase A 2 (PLA 2 ) 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 μmol/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, ≈ 0.12±0.06). In contrast, block of Ca 2+ channels with Cd 2+ and reducing bath Cl – failed to affect the current. The actions of LPLC were opposed by lanthanides. Gd 3+ and La 3+ 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 Gd 3+ -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 A 2 and the present results, it is suggested that LPLC accumulation may contribute to ventricular dysrhythmias during ischemia.