title: Stretch current-induced abnormal impulses in CaMKIIδ knockout mouse ventricular myocytes.
abstract: BACKGROUND
  CaMKII activation is proarrhythmic in heart failure where myocardium is stretched. However, the arrhythmogenic role of CaMKII in stretched ventricle has not been well understood.
  
  
  OBJECTIVE
  We tested abnormal impulse inducibility by stretch current in myocytes isolated from CaMKIIδ knockout (KO) mouse left ventricle (LV) where CaMKII activity is reduced by ≈ 62%.
  
  
  RESULTS
  Action potentials were recorded by whole-cell patch clamp, and abnormal impulses were induced in LV myocytes by a simulation of stretch-activated channel (SAC) current. SAC activation failed to induce abnormal impulses in wild type (WT) myocytes but steadily produced early after-depolarizations and automaticity in KO myocytes in which an increase in L-type calcium channel (LTCC) current (I(Ca)) and a reduction of sarcoplasmic reticulum Ca(2+) leak and action potential duration (APD) were observed. The abnormal impulses were not suppressed by CaMKII inhibitor AIP whereas a low concentration of nifedipine eliminated abnormal impulses without shortening APD, implicating I(Ca) in promoting stretch-induced abnormal impulses. In addition, APD prolongation by LTCC opener S(-)Bay K 8644 or isoproterenol facilitated abnormal impulse induction in WT ventricular myocytes even in the presence of CaMKII inhibitor AIP, whereas APD prolongation by K(+) channel blocker 4-aminopyridine promoted abnormal impulses in KO myocytes but not in WT myocytes.
  
  
  CONCLUSIONS
  I(Ca) activation plays a central role in stretch-induced abnormal impulses and APD prolongation is arrhythmogenic only when I(Ca) is highly activated. At increased I(Ca) activation, CaMKII inhibition cannot suppress abnormal impulse induction.
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
authors.forename: Dongwu
authors.initials: D
authors.lastname: Lai
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.forename: Arnaud B
authors.initials: AB
authors.lastname: Guilbert
authors.forename: Hyun Joung
authors.initials: HJ
authors.lastname: Lim
authors.forename: Guosheng
authors.initials: G
authors.lastname: Fu
authors.forename: Yanggan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D004789:Enzyme Activation; D005071:Evoked Potentials; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology*; D008465:Mechanoreceptors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000201:enzymology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013997:Time Factors
chemical_list: D000318:Adrenergic beta-Agonists; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517673:Camk2d protein, mouse; D002118:Calcium