Inhibitions of late INa and CaMKII act synergistically to prevent ATX-II-induced atrial fibrillation in isolated rat right atria.

Abstract

AIMS:

Increases in late Na(+) current (late INa) and activation of Ca(2+)/calmodulin-dependent protein kinase (CaMKII) are associated with atrial arrhythmias. CaMKII also phosphorylates Nav1.5, further increasing late INa. The combination of a CaMKII inhibitor with a late INa inhibitor may be superior to each compound alone to suppress atrial arrhythmias. Therefore, we investigated the effect of a CaMKII inhibitor in combination with a late INa inhibitor on anemone toxin II (ATX-II, a late INa enhancer)-induced atrial arrhythmias.

METHODS AND RESULTS:

Rat right atrial tissue was isolated and preincubated with either the CaMKII inhibitor autocamtide-2-related inhibitory peptide (AIP), the late INa inhibitor GS458967, or both, and then exposed to ATX-II. ATX-II increased diastolic tension and caused fibrillation of isolated right atrial tissue. AIP (0.3μmol/L) and 0.1μmol/L GS458967 alone inhibited ATX-II-induced arrhythmias by 20±3% (mean±SEM, n=14) and 34±5% (n=13), respectively, whereas the two compounds in combination inhibited arrhythmias by 81±4% (n=10, p<0.05, vs either AIP or GS458967 alone or the calculated sum of individual effects of both compounds). AIP and GS458967 also attenuated the ATX-induced increase of diastolic tension. Consistent with the mechanical and electrical data, 0.3μmol/L AIP and 0.1μmol/L GS458967 each inhibited ATX-II-induced CaMKII phosphorylation by 23±3% and 32±4%, whereas the combination of both compounds inhibited CaMKII phosphorylation completely.

CONCLUSION:

The effects of an enhanced late INa to induce arrhythmic activity and activation of CaMKII in atria are attenuated synergistically by inhibitors of late INa and CaMKII.

• Authors: Faquan Liang, Peidong Fan, Jessie Jia, Suya Yang, Zhan Jiang, Serge Karpinski, Dmytro Kornyeyev, Nikos Pagratis, Luiz Belardinelli, Lina Yao
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 94 Pg. 122-130 (05 2016) ISSN: 1095-8584 [Electronic] England
• PMID: 27066997 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Ataxin-2
• Benzylamines
• Sulfonamides
• KN 93
• Sodium
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Action Potentials
• Animals
• Ataxin-2 (metabolism)
• Atrial Fibrillation (etiology, metabolism)
• Benzylamines (pharmacology)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors, metabolism)
• Heart Atria (drug effects, metabolism)
• Male
• Myocardial Contraction (drug effects)
• Rats
• Sodium (metabolism)
• Sulfonamides (pharmacology)