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(Circulation. 2007;116:2913-2922.)
© 2007 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Progesterone Regulates Cardiac Repolarization Through a Nongenomic Pathway

An In Vitro Patch-Clamp and Computational Modeling Study

Hiroaki Nakamura, MD; Junko Kurokawa, PhD; Chang-Xi Bai, MD, PhD; Ken Asada, MS; Jun Xu, PhD; Ronit V. Oren, MS; Zheng I. Zhu, PhD; Colleen E. Clancy, PhD; Mitsuaki Isobe, MD, PhD; Tetsushi Furukawa, MD, PhD

From the Department of Bio-Informational Pharmacology, Medical Research Institute (H.N., J.K., C.-X.B., K.A., T.F.) and Department of Cardiovascular Medicine, Graduate School of Medicine (H.N., M.I.), Tokyo Medical Research Institute, Tokyo, Japan, and Department of Physiology and Biophysics (J.X., R.V.O., Z.I.Z., C.E.C.), Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY.

Correspondence to Tetsushi Furukawa, MD, PhD, 2–3–10 Kandasurugadai, Chiyoda-ku, Tokyo 101–0062, Japan. E-mail t_furukawa.bip{at}mri.tmd.ac.jp

Received March 12, 2007; accepted October 12, 2007.

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.

Methods and 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_V1.2 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.

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