Mineralocorticoid receptor antagonism prevents the electrical remodeling that precedes cellular hypertrophy after myocardial infarction.
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.


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 alpha1C subunit (Ca(v)1.2) increased, and that of the K+ channel K(v)4.2 subunit decreased. Three weeks after MI, AP prolongation endured, whereas cellular hypertrophy developed. I(Ca) density, Ca(v)1.2, and K(v)4.2 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.
INSERM U637-EA3759, IFR3, Montpellier, France.
Emeline
E
Perrier
Benoît-Gilles
BG
Kerfant
Nathalie
N
Lalevee
Patrice
P
Bideaux
Michel F
MF
Rossier
Sylvain
S
Richard
Ana María
AM
Gómez
Jean-Pierre
JP
Benitah
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001012:Aorta, Abdominal; D001024:Aortic Valve Stenosis / Q000150:complications / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D006329:Heart Conduction System / Q000503:physiopathology*; D006727:Hormone Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D017136:Ion Transport; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018161:Receptors, Mineralocorticoid / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051672:Shal Potassium Channels; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*
D020746:Calcium Channels, L-Type; D006727:Hormone Antagonists; C419385:L-type calcium channel alpha(1C); D000451:Mineralocorticoid Receptor Antagonists; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D051672:Shal Potassium Channels; D013148:Spironolactone; C041006:RU 28318; D011188:Potassium; D002118:Calcium