Published Online
on August 2, 2004

A more recent version of this article appeared on August 17, 2004

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Submitted on October 28, 2003
Revised on April 15, 2004
Accepted on April 16, 2004

Mineralocorticoid Receptor Antagonism Prevents the Electrical Remodeling That Precedes Cellular Hypertrophy After Myocardial Infarction

Emeline Perrier PhD, Benoît-Gilles Kerfant PhD, Nathalie Lalevee PhD, Patrice Bideaux , Michel F. Rossier PhD, Sylvain Richard PhD, Ana María Gómez PhD, and Jean-Pierre Benitah PhD^*

From INSERM U637-EA3759 (E.P., B.-G.K., P.B., S.R., A.M.G., J.-P.B.), IFR3, Montpellier, France, and the Division of Endocrinology and Diabetology and Laboratory of Clinical Chemistry (N.L., M.F.R.), University Hospital, Geneva, Switzerland.

^* To whom correspondence should be addressed. E-mail: benitah{at}montp.inserm.fr..

Background--Cardiac hypertrophy underlies arrhythmias and sudden death, for which mineralocorticoid receptor (MR) activity has recently been implicated. We sought to establish the sequence of ionic events that link the initiating insult and MR to hypertrophy development.

Methods and Results--Using whole-cell, patch-clamp and quantitative reverse transcription-polymerase chain reaction techniques on right ventricular myocytes of a myocardial infarction (MI) rat model, we examined the cellular response over time. One week after MI, no sign of cellular hypertrophy was found, but action potential duration (APD) was lengthened. Both an increase in Ca²⁺ current (I_Ca) and a decrease in K⁺ transient outward current (I_to) underlay this effect. Consistently, the relative expression of mRNA coding for the Ca²⁺ channel 1C subunit (Ca_v1.2) increased, and that of the K⁺ channel K_v4.2 subunit decreased. Three weeks after MI, AP prolongation endured, whereas cellular hypertrophy developed. I_Ca density, Ca_v1.2, and K_v4.2 mRNA levels regained control levels, but I_to density remained reduced. Long-term treatment with RU28318, an MR antagonist, prevented this electrical remodeling. In a different etiologic model of abdominal aortic constriction, we confirmed that APD prolongation and modifications of ionic currents precede cellular hypertrophy.

Conclusions--Electrical remodeling, which is triggered at least in part by MR activation, is an initial, early cellular response to hypertrophic insults.

Key words: hypertrophy • action potentials • ion channels • remodeling • hormones

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