title: Inhibitions of late INa and CaMKII act synergistically to prevent ATX-II-induced atrial fibrillation in isolated rat right atria.
abstract: 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.
  
  
  
  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.
  
  
  
  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.affiliation: Gilead Sciences, Inc., Fremont, CA 94555, United States. Electronic address: faquan_liang@yahoo.com.
authors.forename: Faquan
authors.initials: F
authors.lastname: Liang
authors.affiliation: Gilead Sciences, Inc., Fremont, CA 94555, United States.
authors.forename: Peidong
authors.initials: P
authors.lastname: Fan
authors.affiliation: Gilead Sciences, Inc., Fremont, CA 94555, United States.
authors.forename: Jessie
authors.initials: J
authors.lastname: Jia
authors.affiliation: Gilead Sciences, Inc., Fremont, CA 94555, United States.
authors.forename: Suya
authors.initials: S
authors.lastname: Yang
authors.affiliation: Gilead Sciences, Inc., Fremont, CA 94555, United States.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Gilead Sciences, Inc., Fremont, CA 94555, United States.
authors.forename: Serge
authors.initials: S
authors.lastname: Karpinski
authors.affiliation: Gilead Sciences, Inc., Fremont, CA 94555, United States.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Kornyeyev
authors.affiliation: Gilead Sciences, Inc., Fremont, CA 94555, United States.
authors.forename: Nikos
authors.initials: N
authors.lastname: Pagratis
authors.affiliation: Gilead Sciences, Inc., Fremont, CA 94555, United States.
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: Gilead Sciences, Inc., Fremont, CA 94555, United States.
authors.forename: Lina
authors.initials: L
authors.lastname: Yao
mesh_terms: D000200:Action Potentials; D000818:Animals; D000067698:Ataxin-2 / Q000378:metabolism*; D001281:Atrial Fibrillation / Q000209:etiology* / Q000378:metabolism*; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D012964:Sodium / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000067698:Ataxin-2; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D012964:Sodium; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides
keywords: Arrhythmia; Atrial fibrillation; Ca(2+)/calmodulin-dependent protein kinase; Late sodium current