Amiodarone-mediated increase in intracellular free Ca2+ associated with cellular injury to human pulmonary artery endothelial cells.
The cardiac antidysrrhythmic drug amiodarone can give rise to potentially fatal pulmonary toxicity in large numbers of patients. The effect of amiodarone on Ca2+ homeostasis and cell injury has been studied using human pulmonary artery endothelial (HPAE) cells in vitro. Amiodarone produced a concentration-dependent increase in intracellular free Ca2+ concentration ( [Ca2+]i) to micromolar levels that are similar to those seen with physiological stimuli that increase [Ca2+]i. Unlike physiological stimuli, the rise in [Ca2+]i produced by amiodarone developed slowly and was maintained over at least 30 min. Omitting Ca2+ from the external medium reversibly prevented the amiodarone-induced rise in [Ca2+]i. Amiodarone treatment increased the apparent first order rate constants for 45Ca2+ influx and efflux in intact HPAE cells. 45Ca2+ accumulation into the endoplasmic reticulum of saponin-permeabilized HPAE cells was decreased by amiodarone treatment. The release of 45Ca2+ from the endoplasmic reticulum stores by the putative intracellular second messengers inositol-1,4,5-trisphosphate, arachidonic acid, and Ca2+ was blocked by amiodarone treatment. The changes in Ca2+ homeostasis coincide with an increase in [3H]deoxyglucose release as a measure of early cell injury by amiodarone. It is concluded that amiodarone can produce an increase in [Ca2+]i by an action on the plasma membrane that allows the influx of external Ca2+. This increase in [Ca2+]i, together with other changes in Ca2+ homeostasis, may be responsible for the early cell injury associated with amiodarone toxicity.
Powis
G
G
Department of Pharmacology, Mayo Clinic, Rochester, Minnesota 55904.
Olsen
R
R
Standing
J E
JE
Kachel
D
D
Martin
W J
WJ
D000638:Amiodarone / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D003847:Deoxyglucose / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D006801:Humans; D011651:Pulmonary Artery / Q000187:drug effects*
D003847:Deoxyglucose; D000638:Amiodarone; D002118:Calcium