Sakai T, Inagaki R, Taniguchi T, Shinozuka K, Kunitomo M, Hayashi N, Ishii Y, Muramatsu I
Department of Radiology, School of Medicine, Fukui Medical University, Japan.
Eur J Pharmacol. 1998 Aug 28;356(1):25-30. doi: 10.1016/s0014-2999(98)00505-6.
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.
包括4'-表阿霉素在内的蒽环类衍生物已知会引起心血管副作用。在本研究中，我们在体外研究了4'-表阿霉素对大鼠尾动脉交感神经的影响。用浓度高于10 microM的4'-表阿霉素处理会逐渐增加动脉条的静息张力，随后添加10 microM可卡因可大大增强这种作用。哌唑嗪可阻止4'-表阿霉素引起的静息张力增加，在利血平预处理大鼠的动脉条中这种增加受到抑制，超氧化物歧化酶可使其降低。然而，河豚毒素和组胺受体拮抗剂（苯海拉明和西咪替丁）未能对其产生影响。30 microM的4'-表阿霉素会使对交感神经电刺激的收缩反应略有减弱。4'-表阿霉素不会使去甲肾上腺素的浓度-反应曲线发生偏移。在灌流实验中，30 microM的4'-表阿霉素可使去甲肾上腺素的基础释放量增加约五倍，且这种增加不受0.1 microM哌唑嗪、0.5 microM河豚毒素、10 microM可卡因或无钙培养基的抑制。30 microM的4'-表阿霉素处理会逐渐抑制电刺激引起的去甲肾上腺素释放。这些结果表明，4'-表阿霉素直接作用于交感神经，导致大鼠尾动脉中去甲肾上腺素持续释放。
