Dual effects of SK&F 96365 in human leukemic HL-60 cells - Inhibition of calcium entry and activation of a novel cation influx pathway

被引:34
作者
Leung, YM [1 ]
Kwan, CY [1 ]
Loh, TT [1 ]
机构
[1] UNIV HONG KONG,FAC MED,DEPT PHYSIOL,HONG KONG,HONG KONG
关键词
SK&F 96365; thapsigargin; Ca2+ entry; La3+; Ni2+; Mn2+; HL-60; cells;
D O I
10.1016/S0006-2952(95)02181-7
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The effects of the receptor-mediated Ca2+ entry blocker, SK&F 96365 on thapsigargin (TSG)-induced Ca2+ entry in fura-2-loaded HL-60 cells were studied. After Ca2+ release induced by 30 nM TSG, readmission of Ca2+ resulted in a sustained Ca2+ entry, which could be partially inhibited by 1-3 mu M SK&F 96365. Surprisingly, SK&F 96365 at 30-100 mu M, instead of causing a stronger inhibition, actually promoted Ca2+ entry. Furthermore, at 16-100 mu M, this drug released intracellular Ca2+ on its own and induced Ca2+ entry upon readmission of Ca2+. This SK&F 96365-activated Ca2+ entry pathway was insensitive to nifedipine and, interestingly, accessible to Ni2+ and La3+. However, SK&F 96365 (30 mu M) almost completely blocked (basal) Mn2+ entry and only caused 4.4% of the cells to be stained with trypan blue, strongly suggesting that the SK&F 96365-activated cation entry was not due to damage nor to a very nonselective permeabilization of the plasma membrane. These data indicate that low concentrations of SK&F 96365 inhibited Ca2+ entry and higher concentrations activated a novel cation entry pathway. Because these 2 opposing effects overlapped at an intermediate concentration (16 mu M), which is within the range commonly used to block Ca2+ entry, cautious use of this Ca2+ antagonist appears to be warranted.
引用
收藏
页码:605 / 612
页数:8
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