Leung Y M, Kwan C Y, Loh T T
Department of Physiology, Faculty of Medicine, University of Hong Kong.
Biochem Pharmacol. 1996 Mar 8;51(5):605-12. doi: 10.1016/s0006-2952(95)02181-7.
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 microM SK&F 96365. Surprisingly, SK&F 96365 at 30-100 microM, instead of causing a stronger inhibition, actually promoted Ca2+ entry. Furthermore, at 16-100 microM, 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 microM) 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 microM), which is within the range commonly used to block Ca2+ entry, cautious use of this Ca2+ antagonist appears to be warranted.
研究了受体介导的钙离子内流阻滞剂SK&F 96365对毒胡萝卜素（TSG）诱导的、负载fura-2的HL-60细胞中钙离子内流的影响。在用30 nM TSG诱导钙离子释放后，重新引入钙离子会导致持续的钙离子内流，1-3 microM的SK&F 96365可部分抑制这种内流。令人惊讶的是，30-100 microM的SK&F 96365非但没有产生更强的抑制作用，反而实际上促进了钙离子内流。此外，在16-100 microM时，这种药物自身可释放细胞内钙离子，并在重新引入钙离子时诱导钙离子内流。这种由SK&F 96365激活的钙离子内流途径对硝苯地平不敏感，有趣的是，可被Ni2+和La3+阻断。然而，30 microM的SK&F 96365几乎完全阻断了（基础）锰离子内流，并且仅使4.4%的细胞被台盼蓝染色，这强烈表明SK&F 96365激活的阳离子内流并非由于细胞膜损伤或非常非选择性的通透化。这些数据表明，低浓度的SK&F 96365抑制钙离子内流，而高浓度则激活一种新的阳离子内流途径。由于这两种相反的作用在中间浓度（16 microM）时重叠，该浓度处于通常用于阻断钙离子内流的范围内，因此似乎有必要谨慎使用这种钙离子拮抗剂。
