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Effect of Carvedilol on Ca 2+ Movement and Cytotoxicity in Human MG63 Osteosarcoma Cells
Author(s) -
Liu Chun Peng,
Jan ChungRen
Publication year - 2004
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2004.950203.x
Subject(s) - carvedilol , thapsigargin , extracellular , chemistry , intracellular , phospholipase c , endocrinology , endoplasmic reticulum , forskolin , medicine , pharmacology , phorbol , biochemistry , protein kinase c , biology , kinase , in vitro , receptor , heart failure
Carvedilol is a useful cardiovascular drug for treating heart failure, however, the in vitro effect on many cell types is unclear. In human MG63 osteosarcoma cells, the effect of carvedilol on intracellular Ca 2+ concentrations ([Ca 2+ ] i ) and cytotoxicity was explored by using fura‐2 and tetrazolium, respectively. Carvedilol at concentrations greater than 1 μM caused a rapid rise in [Ca 2+ ] i in a concentration‐dependent manner (EC 50 =15 μM). Carvedilol‐induced [Ca 2+ ] i rise was reduced by 60% by removal of extracellular Ca 2+ . Carvedilol‐induced Mn 2+ ‐associated quench of intracellular fura‐2 fluorescence also suggests that carvedilol induced extracellular Ca 2+ influx. In Ca 2+ ‐free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca 2+ ‐ATPase, caused a monophasic [Ca 2+ ] i rise, after which the increasing effect of carvedilol on [Ca 2+ ] i was inhibited by 50%. Conversely, pretreatment with carvedilol to deplete intracellular Ca 2+ stores totally prevented thapsigargin from releasing more Ca 2+ . U73122, an inhibitor of phospholipase C, abolished histamine (an inositol 1,4,5‐trisphosphate‐dependent Ca 2+ mobilizer)‐induced, but not carvedilol‐induced, [Ca 2+ ] i rise. Pretreatment with phorbol 12‐myristate 13‐acetate and forskolin to activate protein kinase C and adenylate cyclase, respectively, did not alter carvedilol‐induced [Ca 2+ ] i rise. Separately, overnight treatment with 0.1–30 μM carvedilol inhibited cell proliferation in a concentration‐dependent manner. These findings suggest that in human MG63 osteosarcoma cells, carvedilol increases [Ca 2+ ] i by stimulating extracellular Ca 2+ influx and also by causing intracellular Ca 2+ release from the endoplasmic reticulum and other stores via a phospholipase C‐independent manner. Carvedilol may be cytotoxic to osteoblasts.