Gassó S, Sanfeliu C, Suñol C, Rodríguez-Farré E, Cristòfol R M
Department of Pharmacology and Toxicology, Institut d'Investigacions Biomèdiques de Barcelona, CSIC, IDIBAPS, Spain.
Toxicol Appl Pharmacol. 2000 Feb 1;162(3):189-96. doi: 10.1006/taap.1999.8845.
The environmental contaminants trimethyltin (TMT) and triethyltin (TET) stimulated the spontaneous release of [(3)H]noradrenaline ([(3)H]NA) from hippocampal slices in a time- and concentration-dependent manner. TMT was the most potent compound, exhibiting an EC50 value 10-fold lower (3.8 microM) than that of TET (39.5 microM). Metal-evoked [(3)H]NA release did not increase in the absence of desipramine and was completely blocked by reserpine preincubation, indicating a vesicular origin of [(3)H]NA release but not a mechanism involving reversal of the transmitter transporter. The voltage-gated Na(+) channel blocker tetrodotoxin (TTX) did not affect metal-evoked [(3)H]NA release. [(3)H]NA release elicited by TMT was partially extracellular Ca(2+)-dependent, since it was significantly decreased in a Ca(2+)-free EGTA-containing medium, whereas TET induced an extracellular Ca(2+)-independent release of [(3)H]NA. Neither inhibitors of Ca(2+)-entry through Na(+)/Ca(2+)exchanger and voltage-gated calcium channels, nor agents that interfere with Ca(2+)-mobilization from intracellular stores affected [(3)H]NA release induced by TMT. TET-evoked [(3)H]NA release was reduced by ruthenium red, which depletes mitochondrial Ca(2+)stores, but was not modified by caffeine and thapsigargin, which interfere with Ca(2+)mobilization from endoplasmic reticulum. The fact that TET effect was also attenuated by DIDS, an inhibitor of anion exchange, indicates that the effect of TET on spontaneous [(3)H]NA release may be mediated by intracellular mobilization of Ca(2+) from mitochondrial stores through a Cl(-) dependent mechanism.
环境污染物三甲基锡（TMT）和三乙基锡（TET）以时间和浓度依赖的方式刺激海马切片中[³H]去甲肾上腺素（[³H]NA）的自发释放。TMT是最有效的化合物，其半数有效浓度（EC50）值比TET（39.5 microM）低10倍（3.8 microM）。在没有地昔帕明的情况下，金属诱发的[³H]NA释放没有增加，并且通过利血平预孵育被完全阻断，这表明[³H]NA释放起源于囊泡，但不是涉及递质转运体逆转的机制。电压门控钠通道阻滞剂河豚毒素（TTX）不影响金属诱发的[³H]NA释放。TMT引发的[³H]NA释放部分依赖细胞外钙，因为在不含钙的含乙二醇双四乙酸（EGTA）的培养基中其显著降低，而TET诱导[³H]NA的细胞外钙非依赖性释放。通过钠/钙交换体和电压门控钙通道进入钙的抑制剂，以及干扰细胞内钙库中钙动员的试剂，均不影响TMT诱导的[³H]NA释放。TET诱发的[³H]NA释放被钌红降低，钌红可耗尽线粒体钙库，但不受咖啡因和毒胡萝卜素的影响，咖啡因和毒胡萝卜素干扰内质网中的钙动员。阴离子交换抑制剂二异丙基氟磷酸（DIDS）也减弱了TET的作用，这一事实表明TET对自发[³H]NA释放的作用可能通过氯离子依赖机制由线粒体钙库中钙的细胞内动员介导。
