Effect of carvedilol on Ca2+ movement and cytotoxicity in human MG63 osteosarcoma cells.

Publisher: Blackwell Country of Publication: England NLM ID: 101208422 Publication Model: Print Cited Medium: Print ISSN: 1742-7835 (Print) Linking ISSN: 17427835 NLM ISO Abbreviation: Basic Clin Pharmacol Toxicol Subsets: MEDLINE

Publication: <2005-> : Oxford : Blackwell
Original Publication: Copenhagen, Denmark : Oxford, UK : Nordic Pharmacological Society Distributed by Blackwell Munksgaard, 2004-

Cell Line, Tumor*; Calcium/*metabolism ; Carbazoles/*pharmacology ; Cell Survival/*drug effects ; Osteosarcoma/*pathology ; Propanolamines/*pharmacology; Adenylyl Cyclases/metabolism ; Calcium Channels/drug effects ; Calcium Channels/physiology ; Calcium Signaling/drug effects ; Calcium Signaling/physiology ; Carbazoles/antagonists & inhibitors ; Carbazoles/metabolism ; Carvedilol ; Cell Compartmentation/drug effects ; Cell Proliferation/drug effects ; Colforsin/pharmacology ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum/drug effects ; Estrenes/pharmacology ; Fluorescence ; Fura-2/pharmacology ; Histamine/pharmacology ; Histamine Antagonists/pharmacology ; Humans ; Inositol 1,4,5-Trisphosphate/physiology ; Manganese/metabolism ; Manganese/pharmacology ; Phorbol Esters/pharmacology ; Propanolamines/antagonists & inhibitors ; Propanolamines/metabolism ; Protein Kinase C/metabolism ; Pyrrolidinones/pharmacology ; Tetrazolium Salts/pharmacology ; Thapsigargin/antagonists & inhibitors ; Thapsigargin/pharmacology ; Time Factors ; Type C Phospholipases/antagonists & inhibitors ; Type C Phospholipases/physiology

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 Ca2+ concentrations ([Ca2+]i) and cytotoxicity was explored by using fura-2 and tetrazolium, respectively. Carvedilol at concentrations greater than 1 microM caused a rapid rise in [Ca2+]i in a concentration-dependent manner (EC50=15 microM). Carvedilol-induced [Ca2+]i rise was reduced by 60% by removal of extracellular Ca2+. Carvedilol-induced Mn2+-associated quench of intracellular fura-2 fluorescence also suggests that carvedilol induced extracellular Ca2+ influx. In Ca2+-free medium, thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, caused a monophasic [Ca2+]i rise, after which the increasing effect of carvedilol on [Ca2+]i was inhibited by 50%. Conversely, pretreatment with carvedilol to deplete intracellular Ca2+ stores totally prevented thapsigargin from releasing more Ca2+. U73122, an inhibitor of phospholipase C, abolished histamine (an inositol 1,4,5-trisphosphate-dependent Ca2+ mobilizer)-induced, but not carvedilol-induced, [Ca2+]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 [Ca2+]i rise. Separately, overnight treatment with 0.1-30 microM carvedilol inhibited cell proliferation in a concentration-dependent manner. These findings suggest that in human MG63 osteosarcoma cells, carvedilol increases [Ca2+]i by stimulating extracellular Ca2+ influx and also by causing intracellular Ca2+ release from the endoplasmic reticulum and other stores via a phospholipase C-independent manner. Carvedilol may be cytotoxic to osteoblasts.
(Copyright 2004 Basic & Clinical Pharmacology & Toxicology)

0 (Calcium Channels)
0 (Carbazoles)
0 (Estrenes)
0 (Histamine Antagonists)
0 (Phorbol Esters)
0 (Propanolamines)
0 (Pyrrolidinones)
0 (Tetrazolium Salts)
0K47UL67F2 (Carvedilol)
112648-68-7 (1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione)
1F7A44V6OU (Colforsin)
20839-06-9 (phorbol-12-myristate)
42Z2K6ZL8P (Manganese)
67526-95-8 (Thapsigargin)
820484N8I3 (Histamine)
85166-31-0 (Inositol 1,4,5-Trisphosphate)
EC 2.7.11.13 (Protein Kinase C)
EC 3.1.4.- (Type C Phospholipases)
EC 4.6.1.1 (Adenylyl Cyclases)
SY7Q814VUP (Calcium)
TSN3DL106G (Fura-2)

Date Created: 20040924 Date Completed: 20050614 Latest Revision: 20181130

20240829

10.1111/j.1742-7843.2004.950203.x

15379781