Premium
The cardiotoxic antibiotic doxorubicin inhibits the Na + /Ca 2+ exchange of dog heart sarcolemmal vesicles
Author(s) -
Caroni Pico,
Villani Fabrizio,
Carafoli Ernesto
Publication year - 1981
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(81)81115-5
Subject(s) - citation , library science , chemistry , medicine , computer science
The antitumoral anthracycline antibiotic doxorubicin (adriamycin) has cardiotoxic side effects that have been related to disturbances in the intracellular metabolism of Ca’+. A number of authors have reported alterations in mitochondrial Ca2+ transport in heart, ranging from inhibition of uptake by mitochondria upon exposure to doxorubicin in vitro [ 1,2] to stimulation of uptake in rabbits chronically intoxicated with the antibiotic [3]. Substantial inhibitory effects on mitochondrial Ca2+ uptake were seen at concentrations of doxorubicin in excess of 100 PM, and were not seen, or seen only at extremely high concentrations of the antibiotic, when the process was energized by ATP. The other Ca’+ transporting intracellular organelle in heart, the sarcoplasmic reticulum, was not affected by doxorubicin [I]. In heart cells, Ca2+ fluxes are controlled also by two plasma membrane (sarcolemma) pumping systems, a specific ATPase [4], and a Na+/Ca’+ exchange system [5,6]. The Ca’+ disturbances induced by doxorubicin could thus conceivably be mediated (also) by the impairment of either one ofthese two pumping functions, or of both. The involvement of sarcolemma is indicated by the finding [7] of reduced exchangeability of Ca2+ in doxorubicin-treated isolated guinea pig atria. In the present article, we wish to report on the inhibition of the Na+/Ca2+ exchange in isolated dog heart sarcolemma1 vesicles by low concentrations of doxorubicin. The finding may have important pharmacological implications, and opens new possibilities in the study of the Na+/Ca’+ exchanger. Doxorubicin is the first known specific inhibitor of this exchange system.