Ilbäck N G, Stålhandske T, Lindh U
Toxicology Division, National Food Administration, Uppsala, Sweden.
Biol Trace Elem Res. 2000 Aug;76(2):133-48. doi: 10.1385/BTER:76:2:133.
The present study was undertaken in order to study the effects of the broad-acting chelating agent CaNa2-EDTA on plasma trace elements and cardiovascular function in anesthetised New Zealand White rabbits. Trace elements are important for cardiovascular and immune functions and the rabbit is a well-accepted species in cardiovascular studies. The test compound CaNa2-EDTA was administered intravenously to rabbits at single doses of 4, 20, and 100 mg/kg. In addition, at 20 mg/kg, the effects of a second dose after 3 h were also investigated. Heart rate, blood pressure and body temperature were continuously monitored during a 6-h interval after injection of CaNa2-EDTA. Immediately before administration (-1 min) and at 3 and 6 h over the period of the experiment, the plasma cytokine response (tumor necrosis factor-alpha) and trace elements (Mn, Cu, Zn, Se, Ag, Cd, Hg, Pb) were measured. Regardless of dose, blood pressure was found to decrease, but no corresponding changes in heart rate were observed. Both a repeated administration of 20 mg/kg and a single dose of 100 mg/kg were detrimental and caused severe cardiovascular effects and lethality. alpha-TNF tended to increase, though only at 100 mg/kg. The electrocardiogram and body temperature were not affected by the treatment. The most pronounced trace element change was a dose-dependent increase in Mn that was equally pronounced at all time-points after the dose. There was an initial decrease in Cd at low dose levels (4 and 20 mg/kg) that turned into an increase after 6 h at 20 mg/kg and from 2 h at 100 mg/kg. A similar pattern with pronounced decreases at low dose levels was observed for Zn. Cu decreased similarly at all dose levels. For the other trace elements, no or inconsistent effects were observed. This model allows the study of concomitant cardiovascular and trace element changes during treatment with drugs and chelating agents preceding a possible lethal end point and associated pathophysiologic changes.
本研究旨在探讨广谱螯合剂乙二胺四乙酸二钠钙（CaNa2-EDTA）对麻醉新西兰白兔血浆微量元素及心血管功能的影响。微量元素对心血管和免疫功能很重要，且兔子是心血管研究中广泛接受的实验动物。将受试化合物CaNa2-EDTA以4、20和100mg/kg的单剂量静脉注射给兔子。此外，在20mg/kg剂量下，还研究了3小时后第二次给药的效果。在注射CaNa2-EDTA后的6小时内持续监测心率、血压和体温。在给药前即刻（-1分钟）以及实验期间的3小时和6小时，测量血浆细胞因子反应（肿瘤坏死因子-α）和微量元素（锰、铜、锌、硒、银、镉、汞、铅）。无论剂量如何，均发现血压下降，但未观察到心率有相应变化。重复给予20mg/kg和单剂量100mg/kg均有害，并导致严重的心血管效应和致死率。α-肿瘤坏死因子有升高趋势，不过仅在100mg/kg时出现。心电图和体温不受该治疗影响。最明显的微量元素变化是锰呈剂量依赖性增加，且在给药后的所有时间点均同样明显。低剂量水平（4和20mg/kg）时镉最初下降，在20mg/kg时6小时后及100mg/kg时2小时后转变为升高。锌在低剂量水平时也观察到类似的明显下降模式。所有剂量水平下铜的下降情况相似。对于其他微量元素，未观察到影响或影响不一致。该模型可用于研究在可能的致死终点及相关病理生理变化之前，药物和螯合剂治疗期间心血管和微量元素的伴随变化。
