Chronic atrial ionic remodeling by aldosterone: potentiation of L-type Ca2+ channels and its arrhythmogenic significance

Abstract

It is widely accepted that aldosterone induces atrial fibrillation (AF) by promoting structural changes, but its effects on the function of primary atrial myocytes remain unknown. We have investigated this point in adult rat atrial myocytes, chronically exposed to the hormone. This treatment produced larger amplitude of Ca transients, longer action potential (AP) duration, and higher incidence of unsynchronized Ca oscillations. Moreover, it also gave rise to increases in both cell membrane capacitance (C, 30 %) and activity of L-type Ca channels (LTCCs, 100 %). Concerning K currents, a twofold increase was also observed, but only in a delayed rectifier component (I). Interestingly, the maximal conductance (G) of Na channels was also enhanced, but it occurred in the face of a negative shift in the voltage dependence of inactivation. Thus, at physiological potentials, a decreased fraction of available channels neutralized the effect on G. With regard to the effects on both C and LTCCs, they involved activation of mineralocorticoid receptors (MRs), were dose-dependent (EC ∼20-130 nM), and developed and recovered in days. Neither gating currents nor protein levels of LTCCs were altered. Instead, the effect on LTCCs was mimicked by cAMP, reverted by a PKA inhibitor, and attenuated by a nitric oxide donor (short-term exposures). Both EGTA and the antioxidant NAC prevented the increase in C, without significantly interfering with the upregulation of LTCCs. Overall, these results show that chronic exposures to aldosterone result in dire functional changes at the single myocyte level, which may explain the link between aldosteronism and AF.

Interaction of MDIMP with the Voltage-Gated Calcium Channels

“…Indeed, a previous study showed that MDIMP preferentially acts on LVA calcium currents of atrial myocytes, suggesting that Ca V 3 channels exhibit the highest affinity for this compound (Santamaria-Herrera et al, 2016). In these cells, the LVA calcium current is thought to reflect the activity not only of Ca V 3 channels (i.e., Ca V 3.1 and Ca V 3.2) but also Ca V 1.3 and Ca V 2.3 (Piedras-Rentería et al, 1997;Larsen et al, 2002;Zhang et al, 2005;Ríos-Pérez et al, 2016). Thus, the present study represents the first unequivocal demonstration that MDIMP preferentially binds to Ca V 3 channels.…”

“…Independently of its potential to be used clinically, MDIMP may also be helpful to dissect the activity of non-T-type calcium channels in native expression systems, specifically in conditions in which HVA channels exhibit characteristics typically associated with LVA channels, for example, in rat atrial myocytes in which the LVA calcium current is thought to reflect the activity of not only Ca V 3.1 and Ca V 3.2 but also Ca V 1.3 and Ca V 2.3 (Piedras-Rentería et al, 1997;Larsen et al, 2002;Zhang et al, 2005;Ríos-Pérez et al, 2016).…”

“…The case of VGCCs of atrial and ventricular myocytes is typical. In adult rats, for example, the former expresses both HVA (Ca V 1.2, Ca V 1.3, and Ca V 2.3) and LVA (Ca V 3.1 and Ca V 3.2) channels, whereas the latter primordially expresses Ca V 1.2 (Piedras-Rentería et al, 1997;Larsen et al, 2002;Perez-Reyes, 2003;Zhang et al, 2005;Zamponi et al, 2015;Ríos-Pérez et al, 2016).…”

Long-Term Regulation of Excitation–Contraction Coupling and Oxidative Stress in Cardiac Myocytes by Pirfenidone

“…Production of ROS and NO was estimated using fluorescence sensors for these molecules (CM-H 2 DCF DA and DAF-FM DA; Ríos-Pérez et al, 2016). Either atrial or ventricular myocytes were incubated (15 min at room temperature) with Tyrode’s solution supplemented with a 1:1 mixture of Fura-2 AM and the appropriated sensor (3 μM each).…”