Late sodium current in synergism with Ca2+/calmodulin-dependent protein kinase II contributes to β-adrenergic activation-induced atrial fibrillation

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 INa) 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-Nav1.5 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 Nav1.5 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.

 

Comments:

The study suggests that β-adrenergic stimulation increases late INa and CaMKII activity, leading to triggered activities and episodes of AF. Importantly, the study also shows that the inhibition of both late INa and CaMKII can exert synergistic anti-arrhythmic effects, suggesting that targeting both of these mechanisms may be an effective approach for the treatment of AF associated with β-adrenergic stimulation.

Ranolazine and eleclazine are drugs that are known to inhibit late INa, and KN-93 is a drug that inhibits CaMKII. The study found that all three drugs were able to abolish ISO-induced AF and reverse the increase of late INa and phosphorylation of Nav1.5 and CaMKII in a synergistic mode. This suggests that these drugs may be effective treatments for AF associated with β-adrenergic stimulation.

Overall, this study provides important insights into the mechanisms underlying β-adrenergic stimulation-induced AF and highlights the potential of targeting late INa and CaMKII as a therapeutic strategy. However, further research is needed to confirm these findings and to determine the safety and efficacy of drugs targeting these mechanisms in the treatment of AF.

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Cat.No.	Product Name	Information
S7423	KN-93 Phosphate	KN-93 Phosphate is a potent and specific inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII) with Ki of 0.37 μM, no remarkable inhibitory effects on APK, PKC, MLCK or Ca2+-PDE activities. KN-93 attenuates CaMKII-induced autophagy.This product is not soluble in saline. Please do not dissolve it in saline for administration.

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