Journal
ACTA PHARMACOLOGICA SINICA
Volume 30, Issue 11, Pages 1488-1495Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/aps.2009.145
Keywords
doxorubicin; rhythmic contraction; sarcoplasmic reticulum; vascular smooth muscle
Funding
- National Natural Science Foundation of China [30070873]
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Aim: To explore the action of doxorubicin on vascular smooth muscle cells. Methods: Isometric tension of denuded or intact thoracic aortic vessels was recorded and [Ca2+](I) in isolated aortic smooth muscle cells was measured by using Fluo-3. Results: Doxorubicin induced phasic and tonic contractions in denuded vessels and increased levels of [Ca2+](I) in single muscle cells. Treatment with 10 mu mol/L ryanodine had no effect on basal tension, but it did abolish doxorubicin-induced phasic contraction. Treatment with 10 mmol/L caffeine induced a transient phasic contraction only, and the effect was not significantly altered by ryanodine, the omission of extracellular Ca2+ or both. Phenylephrine induced rhythmic contraction (RC) in intact vessels. Treatment with 100 mu mol/L doxorubicin enhanced RC amplitude, but 1 mmol/L doxorubicin abolished RC, with an increase in maximal tension. Caffeine at 100 mu mol/L increased the frequency of the RC only. In the presence of 100 mu mol/L caffeine, however, 100 mu mol/L doxorubicin abolished the RC and decreased its maximal tension. Treatment with 10 mu mol/L ryanodine abolished the RC, with an increase in the maximal tension. In Ca2+-free solution, doxorubicin induced a transient [Ca2+](I) increase that could be abolished by ryanodine pretreatment in single muscle cells. The doxorubicin-induced increase in [Ca2+](I) was suppressed by nifedipine and potentiated by ryanodine and charybdotoxin. Conclusion: Doxorubicin not only releases Ca2+ from the sarcoplasmic reticulum but also promotes the entry of extracellular Ca2+ into vascular smooth muscle cells.
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