K+ current inhibition by amphiphilic fatty acid metabolites in rat ventricular myocytes.
Fatty acid metabolites accumulate in the heart under pathophysiological conditions that affect beta-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 (Ito) and inward rectifier (IK1) 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 microM) caused a concentration-dependent decrease in Ito density in myocytes internally dialyzed with the amphiphile; 10 microM reduced mean Ito density 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 IK1. Dialysis with palmitoyl-CoA (1-10 microM) produced a smaller decrease in Ito density compared with that produced by palmitoylcarnitine; 10 microM reduced mean Ito density at +60 mV by 37% compared with control (P < 0.05). Both metabolites delayed recovery of Ito from inactivation but did not affect voltage-dependent properties. Moreover, the effects of palmitoylcarnitine were relatively specific, as neither palmitate (10 microM) nor carnitine (10 microM) alone significantly influenced Ito when added to the pipette solution. These data therefore suggest that amphiphilic fatty acid metabolites downregulate Ito 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.
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Department of Physiology and Biophysics, University of Nebraska Medical Center, Omaha, Nebraska, 68198-4575, USA.
Rozanski
G J
GJ
D000818:Animals; D002331:Carnitine / Q000494:pharmacology; D004553:Electric Conductivity; D005110:Extracellular Space / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D006352:Heart Ventricles; D007425:Intracellular Membranes / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology; D010171:Palmitoyl Coenzyme A / Q000494:pharmacology*; D010172:Palmitoylcarnitine / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D005227:Fatty Acids; D010168:Palmitates; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D010171:Palmitoyl Coenzyme A; D010172:Palmitoylcarnitine; D002331:Carnitine