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Effect of Captopril on Ca²⁺ Homeostasis and Cell Viability in Human Hepatoma Cells.

Captopril, an angiotensin-converting enzyme (ACE) inhibitor, induced different Ca²⁺ signaling responses in various cell models. However, the effect of captopril on Ca²⁺ homeostasis and cell viability in hepatoma cells is unknown. This study examined whether captopril altered Ca²⁺ homeostasis and viability in HepG2 human hepatoma cells. Intracellular Ca²⁺ concentrations in suspended cells were monitored by using the fluorescent Ca²⁺-sensitive dye fura-2. Cell viability was examined by using 4-[3-[4-lodophenyl]-2-4(4-nitrophenyl)-2H-5-tetrazolio-1,3-benzene disulfonate] water soluble tetrazolium-1 (WST-1). Captopril at concentrations of 500-3000 μM induced [Ca²⁺]i rises in a concentration-dependent manner. Ca²⁺ removal reduced the signal by approximately 15%. Mn²⁺ has been shown to enter cells through similar mechanisms as Ca²⁺ but quenches fura-2 fluorescence at all excitation wavelengths. Captopril (3000 μM)-induced Mn²⁺ influx indirectly suggested that captopril evoked Ca²⁺ entry. Captopril-induced Ca²⁺ entry was inhibited by 15% by a protein kinase C (PKC) activator (phorbol 12-myristate 13 acetate, PMA) and an inhibitor (GF109203X) and three inhibitors of store-operated Ca²⁺ channels: nifedipine, econazole and SKF96365. In Ca²⁺-free medium, treatment with the endoplasmic reticulum Ca²⁺ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) abolished captopril-evoked [Ca²⁺]i rises. Conversely, treatment with captopril abolished BHQ-evoked [Ca²⁺]i rises. Inhibition of phospholipase C (PLC) with U73122 inhibited 70% of captopril-induced [Ca²⁺]i rises. Captopril at concentrations between 150-550 μM killed cells in a concentration-dependent fashion. Chelation of cytosolic Ca²⁺ with 1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid/AM (BAPTA/AM) did not reverse captopril’s cytotoxicity. Together, in HepG2 human hepatoma cells, captopril induced [Ca²⁺]i rises and caused cell death that was not triggered by preceding [Ca²⁺]i rises.

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