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(Circulation. 2005;112:1701-1710.)
© 2005 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Nontranscriptional Regulation of Cardiac Repolarization Currents by Testosterone

Chang-Xi Bai, MD, PhD; Junko Kurokawa, PhD; Masaji Tamagawa, BE; Haruaki Nakaya, MD, PhD; Tetsushi Furukawa, MD, PhD

From the Department of Bio-informational Pharmacology (C.-X.B., J.K., T.F.), Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan, and the Department of Pharmacology (M.T., H.N.), Chiba University Graduate School of Medicine, Chiba, Japan.

Correspondence to Tetsushi Furukawa, MD, PhD, Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan. E-mail t_furukawa.bip{at}mri.tmd.ac.jp

Received November 22, 2004; revision received June 27, 2005; accepted July 1, 2005.

Background— Women have longer QT_c intervals than men and are at greater risk for arrhythmias associated with long QT_c 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,L), because testosterone failed to shorten APD in the presence of an I_Ks inhibitor, chromanol 293B, and an I_Ca,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,L by testosterone is a novel regulatory mechanism of cardiac repolarization that can potentially contribute to the control of QT_c intervals by androgen.

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