Hydrocarbon Chain Length-dependent Antagonism of Acylcarnitines to the Depressant Effect of Lysophosphatidylcholine on Cardiac Sodium Current

Amphiphilic lipid metabolites, including lysophosphatidylcholine (lysoPC) and long-chain acylcarnitine, accumulate in an ischemic myocardium and exert deleterious effects on membrane function. The effects of short-chain (3-carbon-chain, C3), medium-chain (C6and C8), long-chain (C16) acylcarnitines, and lysoPC on the sodium current (INa) of isolated guinea-pig ventricular cells and on membrane fluidity and [14C]lysoPC uptake in cultured mouse embryo ventricular cells were examined. Guinea-pig ventricular cells were superfused with low-Na+(60 m ) Tyrode solution at a temperature of 32–33°C. Ca2+and K+currents were blocked by external Co2+(3 m ) and internal Cs+(140 m ), respectively. Neither propionylcarnitine (PpC, C3) nor hexanoylcarnitine (HxoC, C6) at concentrations of 50, 100, 500μ affected the amplitude of peak LNa, evoked by depolarizing pulses (0.5 Hz) to −20 mV from a holding potential of −100 mV. Octanoylcarnitine (OcoC, C8) (50 and 100μ ) did not alter the amplitude of peak INawhile the highest concentration (500μ ) did inhibit it by 7.7±3.0% (mean± ,n=6) significantly. Palmitoylcarnitine (PamC, C16) (1, 5, and 50μ ) decreased the amplitude of peak INaby 16.6±5.2% (n=5), 36.1±4.3% (n=11), and 52.7±8.8% (n=4), respectively. LysoPC (50μ ) irreversibly depressed INawithin 30±4 seconds (n=4), and cell contracture occurred. If short- and medium-chain acylcarnitines would prevent the depressant effects of lysoPC on INawas then investigated. In the presence of PpC (100μ ) or HxoC (100μ ), the effects of lysoPC (either depression of INaor development of cell contracture) were not observed, while OcoC (100μ ) did not prevent any of these effects of lysoPC. In contrast, PpC and HxoC failed to prevent the reduction of INacaused by PamC. From these findings and membrane fluidity and [14C]lysoPC uptake studies, it was concluded that PpC exerts the protective effect by preventing the incorporation of lysoPC into phospholipid bilayers, and that short-chain acylcarnitine has a potent anti-amphiphilic effect against the amphipathic insults caused by lysoPC, whereas long-chain acylcarnitine had a potent amphiphilic effect; medium-chain acylcarnitine appeared to share both characteristics.