Progesterone regulates cardiac repolarization through a nongenomic pathway: an in vitro patch-clamp and computational modeling study.
BACKGROUND
Female sex is an independent risk factor for torsade de pointes in long-QT syndrome. In women, QT interval and torsade de pointes risk fluctuate dynamically during the menstrual cycle and pregnancy. Accumulating clinical evidence suggests a role for progesterone; however, the effect of progesterone on cardiac repolarization remains undetermined.


RESULTS
We investigated the effects of progesterone on action potential duration and membrane currents in isolated guinea pig ventricular myocytes. Progesterone rapidly shortened action potential duration, which was attributable mainly to enhancement of the slow delayed rectifier K+ current (I(Ks)) under basal conditions and inhibition of L-type Ca2+ currents (I(Ca,L)) under cAMP-stimulated conditions. The effects of progesterone were mediated by nitric oxide released via nongenomic activation of endothelial nitric oxide synthase; this signal transduction likely takes place in the caveolae because sucrose density gradient fractionation experiments showed colocalization of the progesterone receptor c-Src, phosphoinositide 3-kinase, Akt, and endothelial nitric oxide synthase with KCNQ1, KCNE1, and Ca(V)1.2 in the caveolae fraction. We used computational single-cell and coupled-tissue action potential models incorporating the effects of progesterone on I(Ks) and I(Ca,L); the model reproduces the fluctuations of cardiac repolarization during the menstrual cycle observed in women and predicts the protective effects of progesterone against rhythm disturbances in congenital and drug-induced long-QT syndrome.


CONCLUSIONS
Our data show that progesterone modulates cardiac repolarization by nitric oxide produced via a nongenomic pathway. A combination of experimental and computational analyses of progesterone effects provides a framework to understand complex fluctuations of QT interval and torsade de pointes risks in various hormonal states in women.
Department of Bio-Informational Pharmacology, Medical Research Institute, Tokyo, Japan.
Hiroaki
H
Nakamura
Junko
J
Kurokawa
Chang-Xi
CX
Bai
Ken
K
Asada
Jun
J
Xu
Ronit V
RV
Oren
Zheng I
ZI
Zhu
Colleen E
CE
Clancy
Mitsuaki
M
Isobe
Tetsushi
T
Furukawa
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D019295:Computational Biology; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000378:metabolism / Q000503:physiopathology*; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000502:physiology; D011374:Progesterone / Q000494:pharmacology / Q000502:physiology*; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016171:Torsades de Pointes / Q000378:metabolism / Q000503:physiopathology*
D015221:Potassium Channels; D009569:Nitric Oxide; D011374:Progesterone; D000242:Cyclic AMP