title: Amiodarone-mediated increase in intracellular free Ca2+ associated with cellular injury to human pulmonary artery endothelial cells.
abstract: 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.
authors.affiliation: Department of Pharmacology, Mayo Clinic, Rochester, Minnesota 55904.
authors.forename: G
authors.initials: G
authors.lastname: Powis
authors.forename: R
authors.initials: R
authors.lastname: Olsen
authors.forename: J E
authors.initials: JE
authors.lastname: Standing
authors.forename: D
authors.initials: D
authors.lastname: Kachel
authors.forename: W J
authors.initials: WJ
authors.lastname: Martin
mesh_terms: 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*
chemical_list: D003847:Deoxyglucose; D000638:Amiodarone; D002118:Calcium