Nontranscriptional regulation of cardiac repolarization currents by testosterone

Article

关键词: RECTIFIER K+ CURRENT;    NITRIC-OXIDE SYNTHASE;    LONG-QT SYNDROME;    ANDROGEN RECEPTOR;    GONADAL-STEROIDS;    SEX-DIFFERENCES;    GINSENOSIDE RE;    DE-POINTES;    INTERVAL;    HORMONES;   

DOI  :  10.1161/CIRCULATIONAHA.104.523217

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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