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Rapid and MR-Independent IK1 Activation by Aldosterone during Ischemia-Reperfusion.

Alexandre J, Hof T, Puddu PE, Rouet R, Guinamard R, Manrique A, Beygui F, Sallé L, Milliez P - PLoS ONE (2015)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

A: Single channel NPo under aldosterone superfusion (10 nmol/L), RU 28318 (1μmol/L) and aldosterone (10 nmol/L) with RU 28318 (1μmol/L) relative to the NPo in control B: Representative experiment showing the single channel NPo in function of the time under control followed by RU 28318 superfusion (1 μmol/L) and aldosterone (10 nmol/L) with RU 28318 (1 μmol/L) in the same patch membrane C: Single channel NPo under Potassium Canrenoate superfusion (100 nmol/L) and aldosterone (10 nmol/L) with Potassium Canrenoate (100 nmol/L) relative to the NPo in control. Numbers in bars are the numbers of experiments.*P<0.05; ns: non-significant.
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pone.0132592.g006: A: Single channel NPo under aldosterone superfusion (10 nmol/L), RU 28318 (1μmol/L) and aldosterone (10 nmol/L) with RU 28318 (1μmol/L) relative to the NPo in control B: Representative experiment showing the single channel NPo in function of the time under control followed by RU 28318 superfusion (1 μmol/L) and aldosterone (10 nmol/L) with RU 28318 (1 μmol/L) in the same patch membrane C: Single channel NPo under Potassium Canrenoate superfusion (100 nmol/L) and aldosterone (10 nmol/L) with Potassium Canrenoate (100 nmol/L) relative to the NPo in control. Numbers in bars are the numbers of experiments.*P<0.05; ns: non-significant.

Mentions: Aldosterone 10 nmol/L was superfused during cell-attached recordings (holding potential = -40 mV). It produced in all patches a significant increase in channel NPo within 6.2±0.4 min until the end of the superfusion (1.9±0.4 in control vs 3.0±0.4 with aldosterone; P<0.05, n = 10) (Fig 5A and 5B) without affecting its single channel conductance (29.8±0.5 n = 6 in control vs 29.4±1.3 pS n = 5 under aldosterone superfusion) (Fig 5A). Increase in channel NPo persisted in presence of RU 28318 (NPo relative to the control = 1.4±0.05 under aldosterone alone, n = 9 vs 1.2±0.1 under aldosterone with RU 28318, n = 7, P<0.05) (Fig 6A and 6B). Superfusion of RU 28318 alone had no effect on NPo (NPo relative to the control = 1.0±0.1 under RU 28318 alone, n = 9) (Fig 6A and 6B). Potassium canrenoate superfusion with aldosterone prevented the aldosterone-induced increase in the NPo. 10 different rabbits were used to assess the aldosterone sensitivity. In our experimental conditions, no other aldosterone-activated channel type was observed.


Rapid and MR-Independent IK1 Activation by Aldosterone during Ischemia-Reperfusion.

Alexandre J, Hof T, Puddu PE, Rouet R, Guinamard R, Manrique A, Beygui F, Sallé L, Milliez P - PLoS ONE (2015)

A: Single channel NPo under aldosterone superfusion (10 nmol/L), RU 28318 (1μmol/L) and aldosterone (10 nmol/L) with RU 28318 (1μmol/L) relative to the NPo in control B: Representative experiment showing the single channel NPo in function of the time under control followed by RU 28318 superfusion (1 μmol/L) and aldosterone (10 nmol/L) with RU 28318 (1 μmol/L) in the same patch membrane C: Single channel NPo under Potassium Canrenoate superfusion (100 nmol/L) and aldosterone (10 nmol/L) with Potassium Canrenoate (100 nmol/L) relative to the NPo in control. Numbers in bars are the numbers of experiments.*P<0.05; ns: non-significant.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519293&req=5

pone.0132592.g006: A: Single channel NPo under aldosterone superfusion (10 nmol/L), RU 28318 (1μmol/L) and aldosterone (10 nmol/L) with RU 28318 (1μmol/L) relative to the NPo in control B: Representative experiment showing the single channel NPo in function of the time under control followed by RU 28318 superfusion (1 μmol/L) and aldosterone (10 nmol/L) with RU 28318 (1 μmol/L) in the same patch membrane C: Single channel NPo under Potassium Canrenoate superfusion (100 nmol/L) and aldosterone (10 nmol/L) with Potassium Canrenoate (100 nmol/L) relative to the NPo in control. Numbers in bars are the numbers of experiments.*P<0.05; ns: non-significant.
Mentions: Aldosterone 10 nmol/L was superfused during cell-attached recordings (holding potential = -40 mV). It produced in all patches a significant increase in channel NPo within 6.2±0.4 min until the end of the superfusion (1.9±0.4 in control vs 3.0±0.4 with aldosterone; P<0.05, n = 10) (Fig 5A and 5B) without affecting its single channel conductance (29.8±0.5 n = 6 in control vs 29.4±1.3 pS n = 5 under aldosterone superfusion) (Fig 5A). Increase in channel NPo persisted in presence of RU 28318 (NPo relative to the control = 1.4±0.05 under aldosterone alone, n = 9 vs 1.2±0.1 under aldosterone with RU 28318, n = 7, P<0.05) (Fig 6A and 6B). Superfusion of RU 28318 alone had no effect on NPo (NPo relative to the control = 1.0±0.1 under RU 28318 alone, n = 9) (Fig 6A and 6B). Potassium canrenoate superfusion with aldosterone prevented the aldosterone-induced increase in the NPo. 10 different rabbits were used to assess the aldosterone sensitivity. In our experimental conditions, no other aldosterone-activated channel type was observed.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus