K+ current inhibition by amphiphilic fatty acid metabolites in rat ventricular myocytes

Abstract

Fatty acid metabolites accumulate in the heart under pathophysiological conditions that affect β-oxidation and can elicit marked electrophysiological changes that are arrhythmogenic. The purpose of the present study was to determine the impact of amphiphilic fatty acid metabolites on K+currents that control cardiac refractoriness and excitability. Transient outward ( I to) and inward rectifier ( I K1) K+ currents were recorded by the whole cell voltage-clamp technique in rat ventricular myocytes, and the effects of two major fatty acid metabolites were examined: palmitoylcarnitine and palmitoyl-coenzyme A (palmitoyl-CoA). Palmitoylcarnitine (0.5–10 μM) caused a concentration-dependent decrease in I todensity in myocytes internally dialyzed with the amphiphile; 10 μM reduced mean I todensity at +60 mV by 62% compared with control ( P < 0.05). In contrast, external palmitoylcarnitine at the same concentrations had no effect, nor did internal dialysis significantly alter I K1. Dialysis with palmitoyl-CoA (1–10 μM) produced a smaller decrease in I to density compared with that produced by palmitoylcarnitine; 10 μM reduced mean I to density at +60 mV by 37% compared with control ( P < 0.05). Both metabolites delayed recovery of I tofrom inactivation but did not affect voltage-dependent properties. Moreover, the effects of palmitoylcarnitine were relatively specific, as neither palmitate (10 μM) nor carnitine (10 μM) alone significantly influenced I to when added to the pipette solution. These data therefore suggest that amphiphilic fatty acid metabolites downregulate I to channels by a mechanism confined to the cytoplasmic side of the membrane. This decrease in cardiac K+ channel activity may delay repolarization under pathophysiological conditions in which amphiphile accumulation is postulated to occur, such as diabetes mellitus or myocardial infarction.