Department of Pharmacology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Egypt.
Sci Rep. 2017 Feb 13;7:42457. doi: 10.1038/srep42457.
Although cardiotoxicity has been recognized as an adverse effect of cyclosporine A (CSA), no information exists regarding sex specificity of CSA cardiotoxicity. We tested the hypothesis that left ventricular (LV) and electrocardiographic (ECG) effects of CSA and related inflammatory/histopathological derangements are sex related. CSA reduced the LV slope of end-systolic pressure volume relationship and increased isovolumic relaxation constant. These effects were more pronounced in male compared to female rats, suggesting LV systolic and diastolic dysfunction. ECG recordings showed elevated ST segments and increased QTc and T peak trend intervals in CSA-treated male rats, markers of LV ischemia and arrhythmogenesis. In female rats, CSA delayed AV conduction, as reflected by prolonged PR interval. Other sex-related effects for CSA included (i) increased blood cholesterol, and reduced rates of rise and fall in LV pressure and nuclear factor kappa B and angiotensin receptors type 1 expressions in male rats, and (ii) increased LV adiponectin in females. Histopatholgically, CSA caused vascular congestion, blood extravasation, and pyknotic or even absent nuclei in both sexes. In conclusion, rats exhibit sex-independent susceptibility to negative LV and histopathological influences of CSA. These effects become more intensified in male rats, perhaps on account of aggravated ischemic and inflammatory milieus.
虽然心脏毒性已被认为是环孢素 A（CSA）的一种不良反应，但 CSA 心脏毒性的性别特异性尚无相关信息。我们验证了 CSA 及其相关炎症/组织病理学紊乱对左心室（LV）和心电图（ECG）的影响具有性别相关性的假设。CSA 降低了 LV 收缩末期压力-容积关系的斜率，并增加了等容舒张常数。这些影响在雄性大鼠中比雌性大鼠更为明显，提示 LV 收缩和舒张功能障碍。心电图记录显示 CSA 处理的雄性大鼠的 ST 段抬高和 QTc 和 T 波峰趋势间隔增加，这是 LV 缺血和心律失常发生的标志物。在雌性大鼠中，CSA 延迟了房室传导，表现为 PR 间隔延长。CSA 的其他性别相关影响包括（i）雄性大鼠的血液胆固醇增加，LV 压力和核因子 kappa B 和血管紧张素受体 1 表达的上升和下降速率降低，以及（ii）雌性大鼠的 LV 脂联素增加。组织病理学上，CSA 在两性中均引起血管充血、血液渗出和皱缩甚至细胞核缺失。总之，大鼠对 CSA 的负性 LV 和组织病理学影响具有性别独立性易感性。这些影响在雄性大鼠中更为加剧，可能是由于缺血和炎症环境加重所致。
