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 I K1 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 I K1 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 I K1 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 I K1 activation.
Highlights
Aldosterone and mineralocorticoid receptor (MR) activation have an important pathophysiological role in cardiovascular events occurrence [1,2,3,4]
Clinical studies have shown that high aldosterone levels at presentation or within the first days after the onset of ST elevation myocardial infarction (STEMI) are associated with short-term occurrence of major cardiovascular events [2,3,4] and that an early aldosterone blockade in STEMI context was associated with a reduction of life-threatening ventricular arrhythmias [5,6]
During the simulated ischemia period (Table 2), aldosterone did not significantly affect Vmax and AP amplitude (APA) compared to controls
Summary
Aldosterone and mineralocorticoid receptor (MR) activation have an important pathophysiological role in cardiovascular events occurrence [1,2,3,4]. Clinical studies have shown that high aldosterone levels at presentation or within the first days after the onset of ST elevation myocardial infarction (STEMI) are associated with short-term occurrence of major cardiovascular events (death, heart failure and life-threatening ventricular arrhythmias) [2,3,4] and that an early aldosterone blockade in STEMI context was associated with a reduction of life-threatening ventricular arrhythmias [5,6] All these data strongly indicate that endogenous aldosterone can somehow promote ventricular arrhythmias and sudden cardiac death within a short timeframe; the underlying exact mechanisms remain largely unknown, whether these rapid effects are MR-mediated [7] or by the activation of distinct membrane receptors and ion channels [8]. The involvement of other hyperpolarizing currents such as IK1 could not be excluded [12,13]
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