title: Microtubules and angiotensin II receptors contribute to modulation of repolarization induced by ventricular pacing.
abstract: BACKGROUND
  Left ventricular pacing (LVP) in canine heart alters ventricular activation, leading to reduced transient outward potassium current (I(to)), loss of the epicardial action potential notch, and T-wave vector displacement. These repolarization changes, referred to as cardiac memory, are initiated by locally increased angiotensin II (AngII) levels. In HEK293 cells in which Kv4.3 and KChIP2, the channel subunits contributing to I(to), are overexpressed with the AngII receptor 1 (AT1R), AngII induces a decrease in I(to) as the result of internalization of a Kv4.3/KChIP2/AT1R macromolecular complex.
  
  
  OBJECTIVE
  To test the hypothesis that in canine heart in situ, 2h LVP-induced decreases in membrane KChIP2, AT1R, and I(to) are prevented by blocking subunit trafficking.
  
  
  METHODS
  We used standard electrophysiological, biophysical, and biochemical methods to study 4 groups of dogs: (1) Sham, (2) 2h LVP, (3) LVP + colchicine (microtubule-disrupting agent), and (4) LVP + losartan (AT1R blocker).
  
  
  RESULTS
  The T-wave vector displacement was significantly greater in LVP than in Sham and was inhibited by colchicine or losartan. Epicardial biopsies showed significant decreases in KChIP2 and AT1R proteins in the membrane fraction after LVP but not after sham treatment, and these decreases were prevented by colchicine or losartan. Colchicine but not losartan significantly reduced microtubular polymerization. In isolated ventricular myocytes, AngII-induced I(to) reduction and loss of action potential notch were blocked by colchicine.
  
  
  CONCLUSIONS
  LVP-induced reduction of KChIP2 in plasma light membranes depends on an AngII-mediated pathway and intact microtubular status. Loss of I(to) and the action potential notch appear to derive from AngII-initiated trafficking of channel subunits.
authors: Department of Pharmacology, Columbia University, New York, New York 10032, USA.
authors: Nazira
authors: N
authors: Özgen
authors: Zhongju
authors: Z
authors: Lu
authors: Gerard J J
authors: GJ
authors: Boink
authors: David H
authors: DH
authors: Lau
authors: Iryna N
authors: IN
authors: Shlapakova
authors: Yevgeniy
authors: Y
authors: Bobkov
authors: Peter
authors: P
authors: Danilo
authors: Ira S
authors: IS
authors: Cohen
authors: Michael R
authors: MR
authors: Rosen
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001706:Biopsy; D015153:Blotting, Western; D002304:Cardiac Pacing, Artificial; D003078:Colchicine / Q000494:pharmacology; D004285:Dogs; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology*; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008870:Microtubules / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011945:Receptors, Angiotensin / Q000378:metabolism*
chemical_list: D051605:Kv Channel-Interacting Proteins; D015221:Potassium Channels; D011945:Receptors, Angiotensin; D019808:Losartan; D003078:Colchicine