1. Late sodium current in synergism with Ca 2+ /calmodulin-dependent protein kinase II contributes to β-adrenergic activation-induced atrial fibrillation.
- Author
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Liu X, Ren L, Yu S, Li G, He P, Yang Q, Wei X, Thai PN, Wu L, and Huo Y
- Subjects
- Animals, Rabbits, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Calcium-Calmodulin-Dependent Protein Kinase Type 2 pharmacology, Adrenergic Agents metabolism, Adrenergic Agents pharmacology, Sodium metabolism, Heart Atria metabolism, Action Potentials, Calcium metabolism, Atrial Fibrillation chemically induced, Atrial Fibrillation metabolism
- Abstract
Atrial fibrillation (AF) is frequently associated with β-adrenergic stimulation, especially in patients with structural heart diseases. The objective of this study was to determine the synergism of late sodium current (late I
Na ) and Ca2+ /calmodulin-dependent protein kinase (CaMKII)-mediated arrhythmogenic activities in β-adrenergic overactivation-associated AF. Monophasic action potential, conduction properties, protein phosphorylation, ion currents and cellular trigger activities were measured from rabbit-isolated hearts, atrial tissue and atrial myocytes, respectively. Isoproterenol (ISO, 1-15 nM) increased atrial conduction inhomogeneity index, phospho-Nav 1.5 and phospho-CaMKII protein levels and late INa by 108%, 65%, 135% and 87%, respectively, and induced triggered activities and episodes of AF in all hearts studied ( p < 0.05). Sea anemone toxin II (ATX-II, 2 nM) was insufficient to induce any atrial arrhythmias, whereas the propensities of AF were greater in hearts treated with a combination of ATX-II and ISO. Ranolazine, eleclazine and KN-93 abolished ISO-induced AF, attenuated the phosphorylation of Nav 1.5 and CaMKII, and reversed the increase of late INa ( p < 0.05) in a synergistic mode. Overall, late INa in association with the activation of CaMKII potentiates β-adrenergic stimulation-induced AF and the inhibition of both late INa and CaMKII exerted synergistic anti-arrhythmic effects to suppress atrial arrhythmic activities associated with catecholaminergic activation. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.- Published
- 2023
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