Hypercalcemia impairs sino-atrial automaticity through excessive Cav1.2-mediated Ca2+ influx - 25/09/20
Résumé |
Introduction |
We investigated whether abnormal activity of the L-type Ca2+ channels (LTCCs), Cav1.2 and Cav1.3, under extracellular hypercalcemia, impaired heart pacemaker activity. Membrane currents and intracellular Ca2+ ([Ca2+]i) dynamics of the sino-atrial node (SAN) generate the heart pacemaker activity. Impairments of SAN activity, also called SAN dysfunction (SND), harms heart automaticity. Recent studies have associated abnormal [Ca2+]i dynamics with SNDs. Cav1.2 and Cav1.3 carry the main Ca2+ influx of SAN cells to sustain their [Ca2+]i dynamics. Modified extracellular Ca2+ ([Ca2+]o) could alter Ca2+ influx through these channels. For example, cancer and hyperparathyroidism can raise [Ca2+]o, causing an extracellular hypercalcemia that could alter [Ca2+]i dynamics and impair SAN activity and heart automaticity.
Methods and results |
To test this hypothesis, we measured contractions, [Ca2+]i release and L-type Ca2+ current (ICa,L) in spontaneous cells of the murine SAN. Then, we recorded rate and propagation of the spontaneous action potentials (APs) generated by the SAN tissue ex-vivo. In spontaneous SAN cells, we observed that the modification of [Ca2+]o modulates [Ca2+]i and cells contraction through changes of ICa,L. In particular, the increase of [Ca2+]o dysregulated pacemaker activity, likely through excessive Ca2+ influx mediated by Cav1.2. [Ca2+]o increase to hypercalcemic levels induced arrhythmia also in the intact SAN tissues, activating ectopic leading regions of pacemaking and impairing conduction towards the atria. We recovered these pacemaker dysfunctions by blocking Ca2+-activated small-conductance K+ (SK) channels.
Conclusions |
Hypercalcemia causes excessive Cav1.2-mediated Ca2+ influx, which alters [Ca2+]i and could hyperactivate SK channels, leading to pacemaker impairment. Cav1.2 or SK modulation may reduce pacemaker dysfunctions, preventing SND progression.
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Vol 12 - N° 2-4
P. 255 - octobre 2020 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.