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

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 Ca²⁺ transients, longer action potential (AP) duration, and higher incidence of unsynchronized Ca²⁺ oscillations. Moreover, it also gave rise to increases in both cell membrane capacitance (C_m, 30 %) and activity of L-type Ca²⁺ channels (LTCCs, 100 %). Concerning K⁺ currents, a twofold increase was also observed, but only in a delayed rectifier component (I_Ksus). Interestingly, the maximal conductance (G_max) 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_Na-max. With regard to the effects on both C_m and LTCCs, they involved activation of mineralocorticoid receptors (MRs), were dose-dependent (EC₅₀ ∼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_m, 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.