Nontranscriptional regulation of cardiac repolarization currents by testosterone.
BACKGROUND
Women have longer QTc 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.


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 (IKs) and suppression of L-type Ca2+ currents (I(Ca,L)), because testosterone failed to shorten APD in the presence of an IKs 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 IKs and I(Ca,L) by testosterone is a novel regulatory mechanism of cardiac repolarization that can potentially contribute to the control of QTc intervals by androgen.
Bai
Chang-Xi
CX
Department of Bio-Informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Tokyo 101-0062, Japan.
Kurokawa
Junko
J
Tamagawa
Masaji
M
Nakaya
Haruaki
H
Furukawa
Tetsushi
T
D000200:Action Potentials / Q000187:drug effects*; D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D004594:Electrophysiology / Q000379:methods; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects; D048289:Imidazolidines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D023421:Models, Animal; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D013739:Testosterone / Q000494:pharmacology*; D016276:Ventricular Function
D000726:Androgen Antagonists; D048289:Imidazolidines; D013739:Testosterone; C021277:nilutamide