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GW24-e0050 Stretch current-induced abnormal impulses in CaMKII & knockout mouse ventricular myocytes
  1. Wang Yanggan,
  2. Yanggan Wang
  1. Zhongnan Hospital of Wuhan University

Abstract

Objectives CaMKII activation is pro-arrhythmic in heart failure where myocardium is stretched. However, the arrhythmogenic role of CaMKII in stretched ventricle has not been well understood. 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%.

Methods Action potentials (APs) were recorded by whole-cell patch clamp, and abnormal impulses were induced in LV myocytes by a simulation of stretch-activated-channel (SAC) current.

Results SAC activation failed to induce abnormal impulses in wild type (WT) myocytes but steadily produced early after depolarizations (EADs) and automaticity in KO myocytes in which an increase in L-type calcium channel (LTCC) current (ICa) and a reduction of sarcoplasmic reticulum (SR) Ca2+ 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 ICa 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 ICa activation plays a central role in stretch-induced abnormal impulses and APD prolongation is arrhythmogenic only when ICa is highly activated. At increased ICa activation, CaMKII inhibition cannot suppress abnormal impulse induction.

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