Griffiths N, Lamb J F, Ogden P
Br J Pharmacol. 1983 Aug;79(4):877-90. doi: 10.1111/j.1476-5381.1983.tb10532.x.
We have studied the effects of the weak bases chloroquine, NH4Cl and amantadine on the handling of certain cardiac glycosides by HeLa cells. When these weak bases are applied acutely to HeLa cells they have only minor effects on the binding of cardiac glycosides to the sodium pumps and on the recovery of pump function following block. When cells are grown in these weak bases there is a variable (10-30%) reduction in pump numbers. This effect is additive to that of chronic treatment with cardiac glycosides. If all sodium pumps are blocked with ouabain, digoxin or digitoxin then recovery of function recovers with a T1/2 of about 7 h (10% h-1); digoxin and digitoxin molecules are excreted at a similar rate but ouabain excretion occurs at a much slower rate (3% h-1). These weak bases greatly slow (x 3) the rate of excretion of digoxin and digitoxin but do not alter that of ouabain. The process affected by chloroquine was estimated to have a T1/2 of 8 h. Cells grown in the presence of cardiac glycosides accumulate large numbers of glycoside molecules; chloroquine, NH4Cl and amantadine increase the accumulation of digoxin and digitoxin and may decrease that of ouabain. Quantitatively these results fit a model whereby cardiac glycosides are accumulated by HeLa cells bound to the sodium pumps, are processed by the lysosomes and then excreted. The results are consistent with a process of internalisation and renewal of sodium pumps by HeLa cells.
我们研究了弱碱氯喹、氯化铵和金刚烷胺对HeLa细胞处理某些强心苷的影响。当将这些弱碱急性应用于HeLa细胞时，它们对强心苷与钠泵的结合以及阻断后泵功能的恢复仅有轻微影响。当细胞在这些弱碱中生长时，泵数量会有可变的（10% - 30%）减少。这种效应与长期用强心苷治疗的效应相加。如果所有钠泵都被哇巴因、地高辛或洋地黄毒苷阻断，那么功能恢复的半衰期约为7小时（10% h⁻¹）；地高辛和洋地黄毒苷分子以相似的速率排泄，但哇巴因的排泄速率要慢得多（3% h⁻¹）。这些弱碱极大地减慢（3倍）了地高辛和洋地黄毒苷的排泄速率，但不改变哇巴因的排泄速率。受氯喹影响的过程估计半衰期为8小时。在强心苷存在下生长的细胞会积累大量的苷分子；氯喹、氯化铵和金刚烷胺增加了地高辛和洋地黄毒苷的积累，可能减少了哇巴因的积累。从数量上看，这些结果符合一个模型，即强心苷被与钠泵结合的HeLa细胞积累，由溶酶体处理，然后排泄。这些结果与HeLa细胞对钠泵的内化和更新过程一致。
