In vivo androgen treatment shortens the QT interval and increases the densities of inward and delayed rectifier potassium currents in orchiectomized male rabbits
In vivo androgen treatment shortens the QT interval and increases the densities of inward and delayed rectifier potassium currents in orchiectomized male rabbits
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DOI：
10.1016/s0008-6363(02)00673-9
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发表时间：
2003-01-01
影响因子：
10.8
通讯作者：
Ebert, SN
中科院分区：
文献类型：
--
作者：
Liu, XK;Katchman, A;Ebert, SN
目的：与男性相比，女性的心率校正QT间期(QTC)更长，发生危及生命的尖端扭转性室性心律失常的风险更高，尤其是在服用了阻断人类乙醚-去-去相关基因(HERG)编码的K+通道的药物后。本研究的目的是确定雄性类固醇激素双氢睾酮(DHT)是否影响去睾丸(Orch)雄兔的QT间期。方法：采用心电图和全细胞膜片钳技术，观察睾丸切除(Orch)雄性新西兰大白兔皮下注射双氢睾酮(DHT)缓释微丸和安慰剂后心脏复极和K+电流的变化。通过在治疗前和治疗后(10-14天)测定血浆DHT浓度来监测治疗方案的疗效。结果：结果表明，与安慰剂对照组相比，DHT处理组的心脏QT延长的速度和药物诱导的QT延长都有所减弱。双羟色胺对QRS无明显影响，提示双羟色胺主要通过对心室复极的影响而影响QT。此外，与安慰剂对照组相比，服用DHT的兔心脏对奎尼丁刺激的QT延长显著减少。心肌复极钾电流I-KI和I-Kr的电流密度在DHT处理的兔心室肌中显著增加。此外，与安慰剂组相比，心肌细胞I-Kr的半最大激活电压(V-1/2)显著向更负的电压方向移动(分别为21.2+/-1.2vs.30.2+/-1.4mV，n=12，P<；0.001)。Northern杂交检测未见兔乙醚-a-GO-GO相关基因(RERG)的相应变化。结论：这些结果表明雄性兔体内雄性类固醇激素的存在有助于抑制心率和药物诱导的心脏复极延迟。DHT作用导致I-KI和I-Kr的电流密度增加，I-Kr的V-1/2左移，这可能至少部分解释了观察到的男性和女性之间的QTc值差异。由于心脏RERG基因的表达变化不大，DHT在心脏中的作用可能通过转录后和/或翻译后机制影响I。(C)2002年欧洲心脏病学会。爱思唯尔科学公司出版。版权所有。
Objectives: Women have longer rate-corrected QT intervals (QTc) and are at higher risk for developing life-threatening torsades de pointes ventricular arrhythmias than men, especially after taking medications that block cardiac human ether-a-go-go-related gene (HERG)-encoded K+ channels. The purpose of the present study was to determine if the male sex steroid hormone, dihydrotestosterone, (DHT), influences QT intervals in orchiectomized (Orch) male rabbits. Methods: ECG and whole-cell patch-clamp analyses were employed to evaluate cardiac repolarization and K+ currents in hearts isolated from orchiectomized (Orch) male New Zealand White rabbits receiving subcutaneous sustained release pellets for either dihydrotestosterone (DHT) or placebo. The efficacy of the treatment paradigm was monitored by measuring plasma DHT concentrations before and after the treatment period (10-14 days). Results: The results show that rate- and drug-induced QT-lengthening is attenuated in hearts from DHT-treated rabbits relative to placebo-treated controls. No significant changes in QRS were observed in response to DHT, thereby indicating that DHT influences QT primarily through an effect on ventricular repolarization. In addition, hearts from DHT-treated rabbits displayed significantly less QT lengthening in response to quinidine challenge compared to placebo controls. Current densities for two important cardiac repolarizing K+ currents, I-KI and I-Kr were found to be significantly increased in ventricular myocardium of DHT-treated rabbits. Further, the half-maximal voltage of activation (V-1/2) for I-Kr was significantly shifted to more negative potentials in myocytes from DHT vs. placebo hearts (21.2 +/- 1.2 vs. 30.2 +/- 1.4 mV, respectively, n = 12, P < 0.001). Corresponding changes in rabbit ether-a-go-go-related gene (RERG) mRNA were not found when examined by Northern blot hybridization. Conclusions: These results suggest that the presence of male sex steroid hormones in male rabbits helps to suppress rate- and drug-induced delays in cardiac repolarization. DHT action produces increased current densities for I-KI and I-Kr and a left-shift in the V-1/2 for I-Kr that could account, at least in part, for the observed QTc differences between males and females. Since little change was seen in ventricular RERG gene expression, DHT action in the heart may influence I, via post-transcriptional and/or post-translational mechanisms. (C) 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.