Sex and strain differences in adult mouse cardiac repolarization: importance of androgens

Objective: Gender differences in mouse cardiac repolarization have been reported to be due to the stimulatory action of androgens on the ultrarapid delayed rectifier K+ current (I-Kur) and its underlying Kv1.5 channel. To confirm the regulation of ventricular repolarization by androgens, the present study compared two strains of mice (CD-1 and C57BL/6) that present different androgen levels. Methods and results: Measurement of testosterone levels in different strains of mice (CD-1, C57BL/6, C3H and FVB) revealed that male C57BL/6 mice had very low levels of testosterone, whereas males of the other strains displayed normal testosterone levels. Furthermore, whole-cell voltage clamp recordings in isolated ventricular myocytes showed that the current density of I-Kur in male C5713L/6 mice was similar to that in female mice but smaller with respect to male CD-1 mice. Androgen replacement in male C5713L/6 mice as well as in castrated male CD-1 mice shortened ventricular repolarization, increased I-Kur current density, and increased expression of Kv1.5 channels. Conclusion: Strain and gender differences observed in mouse cardiac repolarization can be explained by different androgen levels. As a consequence, androgens are major regulatory factors in cardiac repolarization and special attention should be paid to the hormonal status of the animal when studying hormonal regulation of cardiac repolarization. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.