Ryan S V, Carrithers S L, Parkinson S J, Skurk C, Nuss C, Pooler P M, Owen C S, Lefer A M, Waldman S A
Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
J Clin Pharmacol. 1996 Apr;36(4):365-73. doi: 10.1002/j.1552-4604.1996.tb04214.x.
Amifostine, a chemo- and radioprotective agent developed as adjunctive therapy for malignancies, induces hypotension after approximately 20% of patient administrations. This study examines the molecular mechanisms underlying hypotension induced by amifostine. Amifostine and its metabolite, WR-1065, induced dose-dependent hypotension in anesthetized rats that was not blocked by N(G)-methyl L arginine (L-NAME), an NO synthase inhibitor. WR-1065 but not amifostine induced concentration-dependent relaxation of isolated rat aortic rings in an endothelium-independent fashion. Relaxation was not associated with increases in cGMP or cAMP and could not be blocked by L-NAME or indomethacin. Similarly, neither amifostine or WR-1065 activated adenylyl, particulate guanylyl, or soluble guanylyl cyclases. WR-1065 relaxed rat aortic rings precontracted with norepinepherine, suggesting alpha-adrenergic blocking activity. However, neither amifostine nor WR-1065 altered the ability of prazosin or phentolamine to bind to alpha-adrenergic receptors. Further, WR-1065 had no effect on receptor-mediated increases in intracellular calcium in BAL 17 murine B lymphocytes in vitro. Thus, hypotension after administration of amifostine is mediated by WR-1065 and appears to result from direct relaxation of vascular smooth muscle. Smooth muscle relaxation induced by WR-1065 is not related to production of nitric oxide, prostaglandins, or cyclic nucleotides; alpha-adrenergic receptor antagonism; or interference with receptor-dependent increases in intracellular calcium. Administration of ephedrine, an efficacious adrenergic agonist, attenuated hypotension induced by amifostine in anesthetized rats and may be useful in alleviating hypotension associated with amifostine administration in patients.
氨磷汀是一种作为恶性肿瘤辅助治疗药物开发的化疗和放疗保护剂，约20%的患者用药后会出现低血压。本研究探讨了氨磷汀诱导低血压的分子机制。氨磷汀及其代谢产物WR-1065在麻醉大鼠中诱导剂量依赖性低血压，而一氧化氮合酶抑制剂N(G)-甲基-L-精氨酸（L-NAME）不能阻断这种低血压。WR-1065而非氨磷汀以不依赖内皮的方式诱导离体大鼠主动脉环浓度依赖性舒张。舒张与cGMP或cAMP增加无关，且不能被L-NAME或吲哚美辛阻断。同样，氨磷汀和WR-1065均未激活腺苷酸环化酶、颗粒型鸟苷酸环化酶或可溶性鸟苷酸环化酶。WR-1065使预先用去甲肾上腺素收缩的大鼠主动脉环舒张，提示其具有α-肾上腺素能阻断活性。然而，氨磷汀和WR-1065均未改变哌唑嗪或酚妥拉明与α-肾上腺素能受体结合的能力。此外，WR-1065对体外BAL 17小鼠B淋巴细胞中受体介导的细胞内钙增加没有影响。因此，氨磷汀给药后的低血压由WR-1065介导，似乎是血管平滑肌直接舒张的结果。WR-1065诱导的平滑肌舒张与一氧化氮、前列腺素或环核苷酸的产生、α-肾上腺素能受体拮抗作用或对受体依赖性细胞内钙增加的干扰无关。麻黄碱是一种有效的肾上腺素能激动剂，可减轻麻醉大鼠中氨磷汀诱导的低血压，可能有助于缓解患者中与氨磷汀给药相关的低血压。
