Late sodium current in synergism with Ca ²⁺ /calmodulin-dependent protein kinase II contributes to β-adrenergic activation-induced atrial fibrillation

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>I</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-Na_v1.5 and phospho-CaMKII protein levels and late <i>I</i>_Na by 108%, 65%, 135% and 87%, respectively, and induced triggered activities and episodes of AF in all hearts studied (<i>p</i> < 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 Na_v1.5 and CaMKII, and reversed the increase of late <i>I</i>_Na (<i>p</i> < 0.05) in a synergistic mode. Overall, late <i>I</i>_Na in association with the activation of CaMKII potentiates β-adrenergic stimulation-induced AF and the inhibition of both late <i>I</i>_Na 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'.