PERSISTENT RELEASE OF NORADRENALINE CAUSED BY ANTICANCER DRUG 4'-EPIDOXORUBICIN IN RAT TAIL ARTERY IN-VITRO

Anthracycline derivatives including 4'-epidoxorubicin are known to cau se 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 mu M gradually increased the resting tension of the arterial strips, an effect which was greatly enhanced by subsequent addition of 10 mu M co caine. This increase of the resting tension by 4'-epidoxorubicin was p revented by prazosin, suppressed in the arterial strips of reserpine-p retreated rats, and reduced by superoxide dismutase. However, tetrodot oxin and histamine receptor antagonists (diphenhydramine and cimetidin e) failed to influence it. The contractile response to electrical symp athetic stimulation was slightly attenuated by 30 mu M 4'-epidoxorubic in. 4'-Epidoxorubicin did not shift the concentration-response curve f or noradrenaline. In the superfusion experiments, the basal release of noradrenaline was increased approximately five-fold by 30 mu M 4'-epi doxorubicin, and this increase was not inhibited by 0.1 mu M prazosin, 0.5 mu M tetrodotoxin, 10 mu M cocaine or Ca2+-free medium. Noradrena line release evoked by electrical stimulation was gradually suppressed by 30 mu M 4'-epidoxorubicin treatment. These results suggest that 4' -epidoxorubicin directly acts on the sympathetic nerve to cause persis tent release of noradrenaline in rat tail artery. (C) 1998 Elsevier Sc ience B.V. All rights reserved.