title: Rapid and MR-Independent IK1 Activation by Aldosterone during Ischemia-Reperfusion.
abstract: In ST elevation myocardial infarction (STEMI) context, clinical studies have shown the deleterious effect of high aldosterone levels on ventricular arrhythmia occurrence and cardiac mortality. Previous in vitro reports showed that during ischemia-reperfusion, aldosterone modulates K+ currents involved in the holding of the resting membrane potential (RMP). The aim of this study was to assess the electrophysiological impact of aldosterone on IK1 current during myocardial ischemia-reperfusion. We used an in vitro model of "border zone" using right rabbit ventricle and standard microelectrode technique followed by cell-attached recordings from freshly isolated rabbit ventricular cardiomyocytes. In microelectrode experiments, aldosterone (10 and 100 nmol/L, n=7 respectively) increased the action potential duration (APD) dispersion at 90% between ischemic and normoxic zones (from 95±4 ms to 116±6 ms and 127±5 ms respectively, P<0.05) and reperfusion-induced sustained premature ventricular contractions occurrence (from 2/12 to 5/7 preparations, P<0.05). Conversely, potassium canrenoate 100 nmol/L and RU 28318 1 μmol/l alone did not affect AP parameters and premature ventricular contractions occurrence (except Vmax which was decreased by potassium canrenoate during simulated-ischemia). Furthermore, aldosterone induced a RMP hyperpolarization, evoking an implication of a K+ current involved in the holding of the RMP. Cell-attached recordings showed that aldosterone 10 nmol/L quickly activated (within 6.2±0.4 min) a 30 pS K+-selective current, inward rectifier, with pharmacological and biophysical properties consistent with the IK1 current (NPo =1.9±0.4 in control vs NPo=3.0±0.4, n=10, P<0.05). These deleterious effects persisted in presence of RU 28318, a specific MR antagonist, and were successfully prevented by potassium canrenoate, a non specific MR antagonist, in both microelectrode and patch-clamp recordings, thus indicating a MR-independent IK1 activation. In this ischemia-reperfusion context, aldosterone induced rapid and MR-independent deleterious effects including an arrhythmia substrate (increased APD90 dispersion) and triggered activities (increased premature ventricular contractions occurrence on reperfusion) possibly related to direct IK1 activation.
authors.affiliation: CHU de Caen, Department of Cardiology, Caen, France; Université de Caen Basse-Normandie, EA 4650 Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, Caen, France.
authors.forename: Joachim
authors.initials: J
authors.lastname: Alexandre
authors.affiliation: Université de Caen Basse-Normandie, EA 4650 Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, Caen, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hof
authors.affiliation: Department of Cardiovascular Sciences, Sapienza University, Rome, Italy.
authors.forename: Paolo Emilio
authors.initials: PE
authors.lastname: Puddu
authors.affiliation: Université de Caen Basse-Normandie, EA 4650 Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, Caen, France; Université de Caen Basse-Normandie, Medical School, Caen, F-14000, France.
authors.forename: René
authors.initials: R
authors.lastname: Rouet
authors.affiliation: Université de Caen Basse-Normandie, EA 4650 Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, Caen, France; Université de Caen Basse-Normandie, Medical School, Caen, F-14000, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Guinamard
authors.affiliation: Université de Caen Basse-Normandie, EA 4650 Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, Caen, France; Université de Caen Basse-Normandie, Medical School, Caen, F-14000, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Manrique
authors.affiliation: CHU de Caen, Department of Cardiology, Caen, France; Université de Caen Basse-Normandie, Medical School, Caen, F-14000, France.
authors.forename: Farzin
authors.initials: F
authors.lastname: Beygui
authors.affiliation: Université de Caen Basse-Normandie, EA 4650 Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, Caen, France; Université de Caen Basse-Normandie, Medical School, Caen, F-14000, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Sallé
authors.affiliation: CHU de Caen, Department of Cardiology, Caen, France; Université de Caen Basse-Normandie, EA 4650 Signalisation, électrophysiologie et imagerie des lésions d'ischémie-reperfusion myocardique, Caen, France; Université de Caen Basse-Normandie, Medical School, Caen, F-14000, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Milliez
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D005260:Female; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011817:Rabbits
chemical_list: D000450:Aldosterone