Long-chain acylcarnitine induces Ca2+ efflux from the sarcoplasmic reticulum.
Long-chain acylcarnitines increase intracellular Ca2+ (Ca2+i) and induce electrophysiologic alterations that likely contribute to the genesis of malignant ventricular arrhythmias induced during myocardial ischemia. The mechanisms by which long-chain acylcarnitines increase Ca2+i are not known, although it occurs in the presence of Ca2+ channel blockade and inhibition of Na+/Ca2+ exchange. Long-chain acylcarnitines activate Ca2+ release channels from skeletal muscle sarcoplasmic reticulum (SR), but their effect on cardiac SR is unclear. To test the hypothesis that long-chain acylcarnitines increase Ca2+i from the SR, SR-enriched membrane fractions were prepared from rabbit left ventricular myocardium using sucrose density-gradient centrifugation and characterized by marker enzyme analysis. 45Ca2+ efflux was assessed in the presence or absence of long-chain acylcarnitines. Palmitoylcarnitine and stearoylcarnitine produced concentration-dependent efflux of 45Ca2+, whereas shorter chain acylcarnitines, palmitate, and palmitoyl-coenzyme A did not. Pretreatment of cardiac SR vesicles with ryanodine did not prevent palmitoylcarnitine-induced Ca2+ release. In addition, palmitoylcarnitine did not influence specific [3H]ryanodine binding, suggesting a mechanism independent of alterations in ryanodine receptor/Ca2+ release channel binding. In summary, long-chain acylcarnitines enhance Ca2+ release from cardiac SR vesicles and may thereby mobilize Ca2+i to induce electrophysiologic derangements under conditions, such as ischemia, in which these amphiphiles accumulate.
Yamada
K A
KA
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Kanter
E M
EM
Newatia
A
A
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism; D002331:Carnitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D010172:Palmitoylcarnitine / Q000494:pharmacology; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism
D015220:Calcium Channels; D019837:Ryanodine Receptor Calcium Release Channel; C116917:acylcarnitine; D010172:Palmitoylcarnitine; D000252:Calcium-Transporting ATPases; D002331:Carnitine; D002118:Calcium