Netticadan T, Yu L, Dhalla N S, Panagia V
Laboratory of Membrane Biology, Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
J Mol Cell Cardiol. 1999 Jul;31(7):1357-67. doi: 10.1006/jmcc.1999.0968.
Earlier studies have demonstrated that palmitoyl carnitine (PC), a long chain acyl carnitine, accumulates in the ischemic myocardium. Although perfusion of hearts with PC is known to induce contractile dysfunction which resembles ischemic contracture, the mechanisms underlying this derangement are not clear. In this study, we examined the effect of exogenous PC on the intracellular concentration of calcium (Ca(2+)) in freshly isolated cardiomyocytes from adult rat hearts. The results showed that PC elevated Ca(2+)in a dose-dependent (5-20 microm) manner; 15 microm PC evoked a marked and reversible increase in Ca(2+)without having any significant action on cell viability. The PC (15 microm)-induced increase in Ca(2+)was slightly depressed but delayed in the absence of extracellular Ca(2+). Pre-incubation of cardiomyocytes with sarcolemmal (SL) l -type Ca(2+)-channel blockers, verapamil or diltiazem, and inhibitors of SL Na(+)-Ca(2+)exchanger such as Ni(2+)or amiloride, depressed the PC-evoked increase in Ca(2+)significantly. Ouabain, a Na(+)-K(+)ATPase inhibitor, and low concentrations of extracellular Na(+)enhanced the PC-induced increase in Ca(2+). Depletion of the sarcoplasmic reticulum (SR) Ca(2+)stores by low micromolar concentrations of ryanodine (a SR Ca(2+)-release channel activator) or by thapsigargin (a SR Ca(2+)-pump ATPase inhibitor) depressed the PC-mediated increase in Ca(2+). Combined blockade of the l -type Ca(2+)channel, Na(+)-Ca(2+)exchanger and the SR Ca(2+)-pump had an additive inhibitory effect on the PC response. These observations suggest that the PC-induced increase in Ca(2+)is dependent on both Ca(2+)-influx from the extracellular space and Ca(2+)-release from the SR stores. Thus, the accumulation of PC in the myocardium may be partly responsible for the occurrence of intracellular Ca(2+)overload in ischemic heart.
早期研究表明，长链酰基肉碱棕榈酰肉碱（PC）在缺血心肌中蓄积。虽然已知用PC灌注心脏会诱发类似于缺血性挛缩的收缩功能障碍，但这种紊乱的潜在机制尚不清楚。在本研究中，我们检测了外源性PC对成年大鼠心脏新鲜分离心肌细胞内钙离子浓度（Ca(2+)）的影响。结果显示，PC以剂量依赖性（5 - 20微摩尔）方式升高Ca(2+)；15微摩尔PC引起Ca(2+)显著且可逆的升高，对细胞活力无任何显著影响。在无细胞外Ca(2+)时，PC（15微摩尔）诱导的Ca(2+)升高略有降低但延迟出现。用肌膜（SL）L型Ca(2+)通道阻滞剂维拉帕米或地尔硫䓬以及SL Na(+)-Ca(2+)交换体抑制剂如Ni(2+)或阿米洛利对心肌细胞进行预孵育，可显著抑制PC诱发的Ca(2+)升高。钠钾ATP酶抑制剂哇巴因和低浓度细胞外Na(+)增强了PC诱导的Ca(2+)升高。用低微摩尔浓度的ryanodine（一种SR Ca(2+)释放通道激活剂）或毒胡萝卜素（一种SR Ca(2+)泵ATP酶抑制剂）耗尽肌浆网（SR）Ca(2+)储存，可抑制PC介导的Ca(2+)升高。联合阻断L型Ca(2+)通道、Na(+)-Ca(2+)交换体和SR Ca(2+)泵对PC反应具有累加抑制作用。这些观察结果表明，PC诱导的Ca(2+)升高既依赖于细胞外空间的Ca(2+)内流，也依赖于SR储存的Ca(2+)释放。因此，PC在心肌中的蓄积可能部分导致了缺血性心脏细胞内Ca(2+)超载的发生。
