School of Human Life Sciences, University of Tasmania, Launceston, Australia.
Transpl Int. 2012 Mar;25(3):337-46. doi: 10.1111/j.1432-2277.2011.01420.x. Epub 2012 Jan 13.
Immunosuppressants have been associated with increased cardiovascular disease risk. We determined the effects of calcineurin and mammalian target of rapamycin (mTOR) inhibitor administration on endothelial dysfunction and associated inflammation and oxidative stress in adult rats. Cyclosporine A (low and high dose), sirolimus, tacrolimus, everolimus and placebo were administered to 8-week-old male Wistar rats for 10 consecutive days. Aortic vascular endothelial and smooth muscle function were assessed ex vivo in organ baths. Maximal aortic contraction to noradrenaline in sirolimus-treated rats was significantly greater than cyclosporine groups, everolimus and placebo, whereas endothelial-dependent relaxation was significantly impaired with cyclosporine and tacrolimus compared with everolimus. Endothelial-independent relaxation was impaired in tacrolimus-treated rats compared with low dose cyclosporine, everolimus and sirolimus. Sirolimus was associated with a reduction in plasma interleukin (IL)-1β and tumour necrosis factor (TNF)-α and higher levels of catalase and total antioxidant status. In nontransplanted rats, vascular dysfunction was evident following administration of cyclosporine A, sirolimus and tacrolimus, whereas everolimus did not compromise aortic endothelial or smooth muscle function. At the doses administered in this model, the immunosuppressants exerted varying effects on vascular function.
免疫抑制剂与心血管疾病风险增加有关。我们确定钙调神经磷酸酶和哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂的给药对成年大鼠内皮功能障碍以及相关炎症和氧化应激的影响。连续 10 天给 8 周龄雄性 Wistar 大鼠给予环孢素 A（低剂量和高剂量）、西罗莫司、他克莫司、依维莫司和安慰剂。在器官浴中离体评估主动脉血管内皮和平滑肌功能。西罗莫司治疗的大鼠对去甲肾上腺素的主动脉最大收缩明显大于环孢素组、依维莫司和安慰剂，而与依维莫司相比，环孢素和他克莫司显著损害内皮依赖性松弛。与低剂量环孢素、依维莫司和西罗莫司相比，他克莫司治疗的大鼠内皮非依赖性松弛受损。西罗莫司与血浆白细胞介素（IL）-1β和肿瘤坏死因子（TNF）-α减少以及过氧化氢酶和总抗氧化状态水平升高有关。在未移植大鼠中，环孢素 A、西罗莫司和他克莫司给药后出现血管功能障碍，而依维莫司不会损害主动脉内皮或平滑肌功能。在该模型中给予的剂量下，免疫抑制剂对血管功能产生不同的影响。
