Novel effect of carvedilol on Ca2+ movement in renal tubular cells.
The effect of carvedilol on intracellular free Ca(2+) levels ([Ca(2+)](i)) has not been explored previously. This study was aimed to examine the effect of carvedilol on Ca(2+) handling in renal tubular cells. Madin-Darby canine kidney cells were used as a model for renal tubular cells and fura-2 was used as a fluorescent Ca(2+) probe. Carvedilol increased [Ca(2+)](i) in a concentration-dependent manner with an EC(50) value of 5 microM. Extracellular Ca(2+) removal partly inhibited the [Ca(2+)](i) signals. Carvedilol-induced Ca(2+) influx was verified by measuring Mn(2+)-induced quench of fura-2 fluorescence. Carvedilol-induced store Ca(2+) release was reduced by pretreatment with 1 microM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor) but not with 5 microM ryanodine or 2 microM carbonylcyanide m-chlorophenylhydrazone (a mitochondrial uncoupler). Carvedilol (30 microM)-induced Ca(2+) release was not affected by inhibiting phospholipase C with 1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-l)amino)hexyl)-1H-pyrrole-2,5-dione (U73122; 2 microM), but was potentiated by increasing cAMP levels or inhibiting protein kinase C. The carvedilol-induced Ca(2+) mobilization was not significantly sequestered by the endoplasmic reticulum or mitochondria. This study shows that carvedilol increased [Ca(2+)](i) in renal tubular cells by causing Ca(2+) release from the endoplasmic reticulum and other unknown stores in an inositol-1,4,5-trisphosphate-independent manner, and by inducing Ca(2+) influx. The Ca(2+) release was modulated by cAMP and protein kinase C.
Liu
Chun-Peng
CP
Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC.
Chiang
Hung-Ting
HT
Jan
Chung-Ren
CR
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects*; D011412:Propanolamines / Q000494:pharmacology*; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology
D002227:Carbazoles; D011412:Propanolamines; D014665:Vasodilator Agents; D000077261:Carvedilol; D002118:Calcium