Nontranscriptional regulation of cardiac repolarization currents by testosterone
Nontranscriptional regulation of cardiac repolarization currents by testosterone
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DOI：
10.1161/circulationaha.104.523217
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发表时间：
2005-09-20
期刊：
影响因子：
37.8
通讯作者：
Furukawa, T
中科院分区：
文献类型：
--
作者：
Bai, CX;Kurokawa, J;Furukawa, T
背景 - 女性的 QT(c) 间期比男性更长，并且发生与长 QTc 间期相关的心律失常的风险更大，例如药物引起的尖端扭转型室速。最近的临床和实验数据表明睾酮在心室复极的性别相关差异中发挥重要作用。然而，关于睾酮对心肌细胞离子电流影响的研究是有限的。方法和结果-我们使用膜片钳技术检查了睾酮对离体豚鼠心室肌细胞的动作电位持续时间（APD）和膜电流的影响。睾酮迅速缩短APD，EC50为2.1至8.7 nmol/L，在男性生理睾酮水平的范围内。睾酮缩短 APD 的主要原因是缓慢激活延迟整流 K+ 电流 (I-Ks) 的增强和 L 型 Ca2+ 电流 (I-Ca,I-L) 的抑制，因为在 IKs 抑制剂 chromanol 293B 和 I-Ca,I-L 抑制剂尼索地平存在下，睾酮无法缩短 APD。一氧化氮 (NO) 清除剂和 NO 合酶 3 (NOS3) 抑制剂逆转了睾酮对 APD 的影响，这表明 NOS3 释放的 NO 是睾酮电生理效应的原因。睾酮受体阻滞剂、c-Src 抑制剂、磷脂酰肌醇 3-激酶抑制剂和 Akt 抑制剂可逆转睾酮的电生理效应。免疫印迹分析显示，睾酮诱导 Akt 和 NOS3 磷酸化。结论 - 睾酮对 I-Ks 和 I-Ca、I-L 的非转录调节是心脏复极的一种新调节机制，可能有助于雄激素控制 QT(c) 间期。
Background - Women have longer QT(c) intervals than men and are at greater risk for arrhythmias associated with long QTc intervals, such as drug-induced torsade de pointes. Recent clinical and experimental data suggest an important role of testosterone in sex-related differences in ventricular repolarization. However, studies on effects of testosterone on ionic currents in cardiac myocytes are limited.Methods and Results - We examined effects of testosterone on action potential duration ( APD) and membrane currents in isolated guinea pig ventricular myocytes using patch-clamp techniques. Testosterone rapidly shortened APD, with an EC50 of 2.1 to 8.7 nmol/L, which is within the limits of physiological testosterone levels in men. APD shortening by testosterone was mainly due to enhancement of slowly activating delayed rectifier K+ currents (I-Ks) and suppression of L-type Ca2+ currents (I-Ca,I-L), because testosterone failed to shorten APD in the presence of an IKs inhibitor, chromanol 293B, and an I-Ca,I-L inhibitor, nisoldipine. A nitric oxide ( NO) scavenger and an inhibitor of NO synthase 3 (NOS3) reversed the effects of testosterone on APD, which suggests that NO released from NOS3 is responsible for the electrophysiological effects of testosterone. Electrophysiological effects of testosterone were reversed by a blocker of testosterone receptors, a c-Src inhibitor, a phosphatidylinositol 3-kinase inhibitor, and an Akt inhibitor. Immunoblot analysis revealed that testosterone induced phosphorylation of Akt and NOS3.Conclusions - The nontranscriptional regulation of I-Ks and I-Ca,I-L by testosterone is a novel regulatory mechanism of cardiac repolarization that can potentially contribute to the control of QT(c) intervals by androgen.