Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.
Cell Calcium. 2017 Nov;67:22-30. doi: 10.1016/j.ceca.2017.08.003. Epub 2017 Aug 10.
Testosterone deficiency in elderly men increases the risk of cardiovascular disease. In bilateral orchiectomized (ORX) animals, impaired cardiac Ca regulation was observed, and this impairment could be improved by testosterone replacement, indicating the important role of testosterone in cardiac Ca regulation. However, the temporal changes of Ca dyshomeostasis in testosterone-deprived conditions are unclear. Moreover, the effects of early vs. late testosterone replacement are unknown. We hypothesized that the longer the deprivation of testosterone, the greater the impairment of cardiac Ca homeostasis, and that early testosterone replacement can effectively reduce this adverse effect.
Male Wistar rats were randomly divided into twelve groups, four sets of three. The first set were ORX for 2, 4 and 8 weeks, the second set were sham-operated groups of the same periods, the third set were ORX for 8 weeks coupled with a subcutaneous injection of vehicle (control), testosterone during weeks 1-8 (early replacement) or testosterone during weeks 5-8 (late replacement), and finally the 12-week sham-operated, ORX and ORX treated with testosterone groups. Cardiac Ca transients (n=4-5/group), L-type calcium current (I) (n=4/group), Ca regulatory proteins (n=6/group) and cardiac function (n=5/group) were determined.
In the ORX rats, impaired cardiac Ca transients and reduced I were observed initially 4 weeks after ORX as shown by decreased Ca transient amplitude, rising rate and maximum and average decay rates. No alteration of Ca regulatory proteins such as the L-type Ca channels, ryanodine receptor type 2, Na-Ca exchangers and SERCA2a were observed. Early testosterone replacement markedly improved cardiac Ca transients, whereas late testosterone replacement did not. The cardiac contractility was also improved after early testosterone replacement.
Impaired cardiac Ca homeostasis is time-dependent after testosterone deprivation. Early testosterone replacement improves cardiac Ca transient regulation and contractility, suggesting the necessity of early intervention in conditions of testosterone-deprivation.
老年男性睾丸酮缺乏会增加心血管疾病的风险。在双侧去势（ORX）动物中，观察到心脏 Ca 调节受损，而这种损伤可以通过睾丸酮替代来改善，这表明睾丸酮在心脏 Ca 调节中起着重要作用。然而，在缺乏睾丸酮的情况下，Ca 稳态失调的时间变化尚不清楚。此外，早期和晚期睾丸酮替代的效果尚不清楚。我们假设，睾丸酮缺乏的时间越长，心脏 Ca 动态平衡的损伤越大，早期睾丸酮替代可以有效地降低这种不良影响。
雄性 Wistar 大鼠随机分为十二组，每组三组。第一组 ORX 2、4 和 8 周，第二组为相同时间的假手术组，第三组为 8 周 ORX 合并皮下注射载体（对照）、1-8 周睾丸酮（早期替代）或 5-8 周睾丸酮（晚期替代），最后一组为 12 周假手术、ORX 和 ORX 用睾丸酮处理组。测定心脏 Ca 瞬变（n=4-5/组）、L 型钙电流（I）（n=4/组）、Ca 调节蛋白（n=6/组）和心脏功能（n=5/组）。
在 ORX 大鼠中，4 周后 ORX 后最初观察到心脏 Ca 瞬变受损和 I 降低，表现为 Ca 瞬变幅度、上升率和最大和平均衰减率降低。L 型钙通道、兰尼碱受体 2、Na-Ca 交换体和 SERCA2a 等 Ca 调节蛋白无改变。早期睾丸酮替代显著改善了心脏 Ca 瞬变，而晚期睾丸酮替代则没有。早期睾丸酮替代也改善了心脏收缩力。
睾丸酮缺乏后，心脏 Ca 稳态失调是时间依赖性的。早期睾丸酮替代可改善心脏 Ca 瞬变调节和收缩力，提示在睾丸酮缺乏的情况下需要早期干预。
