PMID- 26222262 OWN - NLM STAT- MEDLINE DCOM- 20160428 LR - 20181113 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 7 DP - 2015 TI - Rapid and MR-Independent IK1 Activation by Aldosterone during Ischemia-Reperfusion. PG - e0132592 LID - 10.1371/journal.pone.0132592 [doi] LID - e0132592 AB - 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 mumol/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. FAU - Alexandre, Joachim AU - Alexandre J AD - CHU de Caen, Department of Cardiology, Caen, France; Universite de Caen Basse-Normandie, EA 4650 Signalisation, electrophysiologie et imagerie des lesions d'ischemie-reperfusion myocardique, Caen, France. FAU - Hof, Thomas AU - Hof T AD - Universite de Caen Basse-Normandie, EA 4650 Signalisation, electrophysiologie et imagerie des lesions d'ischemie-reperfusion myocardique, Caen, France. FAU - Puddu, Paolo Emilio AU - Puddu PE AD - Department of Cardiovascular Sciences, Sapienza University, Rome, Italy. FAU - Rouet, Rene AU - Rouet R AD - Universite de Caen Basse-Normandie, EA 4650 Signalisation, electrophysiologie et imagerie des lesions d'ischemie-reperfusion myocardique, Caen, France; Universite de Caen Basse-Normandie, Medical School, Caen, F-14000, France. FAU - Guinamard, Romain AU - Guinamard R AD - Universite de Caen Basse-Normandie, EA 4650 Signalisation, electrophysiologie et imagerie des lesions d'ischemie-reperfusion myocardique, Caen, France; Universite de Caen Basse-Normandie, Medical School, Caen, F-14000, France. FAU - Manrique, Alain AU - Manrique A AD - Universite de Caen Basse-Normandie, EA 4650 Signalisation, electrophysiologie et imagerie des lesions d'ischemie-reperfusion myocardique, Caen, France; Universite de Caen Basse-Normandie, Medical School, Caen, F-14000, France. FAU - Beygui, Farzin AU - Beygui F AD - CHU de Caen, Department of Cardiology, Caen, France; Universite de Caen Basse-Normandie, Medical School, Caen, F-14000, France. FAU - Salle, Laurent AU - Salle L AD - Universite de Caen Basse-Normandie, EA 4650 Signalisation, electrophysiologie et imagerie des lesions d'ischemie-reperfusion myocardique, Caen, France; Universite de Caen Basse-Normandie, Medical School, Caen, F-14000, France. FAU - Milliez, Paul AU - Milliez P AD - CHU de Caen, Department of Cardiology, Caen, France; Universite de Caen Basse-Normandie, EA 4650 Signalisation, electrophysiologie et imagerie des lesions d'ischemie-reperfusion myocardique, Caen, France; Universite de Caen Basse-Normandie, Medical School, Caen, F-14000, France. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150729 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 4964P6T9RB (Aldosterone) SB - IM MH - Aldosterone/*pharmacology MH - Animals MH - Female MH - Heart Ventricles/*metabolism/pathology MH - Male MH - Membrane Potentials/*drug effects MH - Myocardial Contraction/*drug effects MH - Myocardial Infarction/metabolism/pathology MH - Myocardial Reperfusion Injury/*metabolism/pathology MH - Myocytes, Cardiac/*metabolism/pathology MH - Rabbits PMC - PMC4519293 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2015/07/30 06:00 MHDA- 2016/04/29 06:00 PMCR- 2015/07/29 CRDT- 2015/07/30 06:00 PHST- 2014/09/21 00:00 [received] PHST- 2015/06/16 00:00 [accepted] PHST- 2015/07/30 06:00 [entrez] PHST- 2015/07/30 06:00 [pubmed] PHST- 2016/04/29 06:00 [medline] PHST- 2015/07/29 00:00 [pmc-release] AID - PONE-D-14-40793 [pii] AID - 10.1371/journal.pone.0132592 [doi] PST - epublish SO - PLoS One. 2015 Jul 29;10(7):e0132592. doi: 10.1371/journal.pone.0132592. eCollection 2015.