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Effects of Tetrandrine on Calcium Mobilization in Non-excitable Cells

Contact Person: Haruo Takemura (takemura@sapmed.ac.jp)


Tetrandrine (TET) is a bis-benzyl-isoquinoline alkaloid extracted from the Chinese medicinal herb Stephania tetrandra and has various pharmacological actions. TET is traditionally used for the treatment of hypertension and angina pectoris, which is thought to be due to the antagonistic action of Ca2+ (1;2). For example, TET has been proposed to be a voltage-operated Ca2+ channel (VOC) blocker in a radioligand binding study using cardiac muscle sarcolemma (3). TET blocks L-type VOC currents in GH3 anterior pituitary cells (3) and vascular smooth muscle cells (4) and inhibits T-type VOC currents in neuroblastoma cells (5) and bovine adrenal glomerulosa cells (6). Furthermore, TET inhibits both T- and L-type VOC currents in ventricular cells (7) and N- and L-type VOC currents in bovine chromaffin cells (8). However, recent reports showed that inhibitory effects of TET are more complex than simple action as a VOC blocker. First, TET act as receptor-operated Ca2+ channel (ROC) blockers in vascular smooth muscle cells (4;9), leukemia HL-60 cells (10) and vascular endothelial cells (11). Second, Leung et al. (1994) observed that TET inhibit intracellular Ca2+ release although they increase [Ca2+]i by themselves. Third, we have recently reported that Ca2+ antagonistic actions of TET are dependent on cell type (12). However, the mechanism of the complex actions of TET on Ca2+ mobilization is unknown.

Other pharmacological effects of TET are anti-inflammation (13) and immunosuppression (14). In addition, TET has been used in China as a treatment for fibrotic lung diseases such as silicosis. These properties were confirmed by experiments that showed inhibitory effects on biological functions of various cells such as lymphocytes (14;15), neutrophils (16), monocytes (15), natural killer cells (14), mast cells (17) and alveolar type II cells (18). These actions therefore inhibit the production and release of inflammatory mediators and cytokines (2). The mechanisms of such inhibitory effects of TET on various cells are less known. It is, thus, of importance to precisely examine the effects of TET on Ca2+ mobilization because the production and release of inflammatory mediators and cytokines involve an increase in [Ca2+]i. In fact, it has been reported that the immunosuppressive properties of TET are in part mediated by the capacity of TET to interfere with Ca2+ mobilization (15).

In non-excitable cells, the analysis of Ca2+ movement is not complicated because VOC is lacking (19). The mobilization of cellular Ca2+ by neurotransmitters and hormones is typically a biphasic process, involving the release of Ca2+ to the cytosol from intracellular stores, as well as activation of Ca2+ entry across the plasma membrane (20). Generally, this alteration corresponds to a transient increase in [Ca2+]i followed by a sustained phase. Ca2+ signaling in non-excitable cells is regulated in more direct way by the inositol phosphate system; especially, the role of inositol 1,4,5-trisphosphate (IP3) in the initial Ca2+ release phase of the response is well established (20;21). We have reported that rat glioma C6 cells do not possess VOC and this cell line is a good model for investigating signal transduction via ROC (22). In this report, we examined the inhibitory effects of TET on Ca2+ mobilization induced by bombesin, an IP3-generating agent, and TG, a microsomal Ca2+-ATPase inhibitor, in rat glioma C6 cells.

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Takemura, H.; (1998). Effects of Tetrandrine on Calcium Mobilization in Non-excitable Cells. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/kwan/takemura0224/index.html
© 1998 Author(s) Hold Copyright