Acta Pharmacologica Sinica (2009) 30: 1488–1495; doi: 10.1038/aps.2009.145; published online 12 October 2009

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 µmol/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 µmol/L doxorubicin enhanced RC amplitude, but 1 mmol/L doxorubicin abolished RC, with an increase in maximal tension. Caffeine at 100 µmol/L increased the frequency of the RC only. In the presence of 100 µmol/L caffeine, however, 100 µmol/L doxorubicin abolished the RC and decreased its maximal tension. Treatment with 10 µmol/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.

Keywords: doxorubicin; rhythmic contraction; sarcoplasmic reticulum; vascular smooth muscle