Persistent release of noradrenaline caused by anticancer drug 4'-epidoxorubicin in rat tail artery in vitro.

Anthracycline derivatives including 4'-epidoxorubicin are known to cause cardiovascular side effects. In this study we examined the effects of 4'-epidoxorubicin on sympathetic nerves of rat tail artery in vitro. Treatment with 4'-epidoxorubicin at concentrations higher than 10 microM gradually increased the resting tension of the arterial strips, an effect which was greatly enhanced by subsequent addition of 10 microM cocaine. This increase of the resting tension by 4'-epidoxorubicin was prevented by prazosin, suppressed in the arterial strips of reserpine-pretreated rats, and reduced by superoxide dismutase. However, tetrodotoxin and histamine receptor antagonists (diphenhydramine and cimetidine) failed to influence it. The contractile response to electrical sympathetic stimulation was slightly attenuated by 30 microM 4'-epidoxorubicin. 4'-epidoxorubicin did not shift the concentration-response curve for noradrenaline. In the superfusion experiments, the basal release of noradrenaline was increased approximately five-fold by 30 microM 4'-epidoxorubicin, and this increase was not inhibited by 0.1 microM prazosin, 0.5 microM tetrodotoxin, 10 microM cocaine or Ca2+-free medium. Noradrenaline release evoked by electrical stimulation was gradually suppressed by 30 microM 4'-epidoxorubicin treatment. These results suggest that 4'-epidoxorubicin directly acts on the sympathetic nerve to cause persistent release of noradrenaline in rat tail artery.