title: Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts.
abstract: BACKGROUND
  Enhanced late inward Na current (INa-L) modulates action potential duration (APD) and plays a key role in the genesis of early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) and triggered activity.
  
  
  OBJECTIVE
  The purpose of this study was to define the influence of selective block of INa-L on EAD- and DAD-mediated triggered ventricular tachycardia (VT) and ventricular fibrillation (VF) in intact hearts using (GS967), a selective and potent (IC50 = 0.13 ± 0.01 μM) blocker of INa-L.
  
  
  METHODS
  VT/VF were induced either by local aconitine injection (50 μg) in the left ventricular muscle of adult (3-4 months) male rats (N = 21) or by arterial perfusion of 0.1 mM hydrogen peroxide (H2O2) in aged male rats (24-26 months, N = 16). The left ventricular epicardial surface of the isolated-perfused hearts was optically mapped using fluorescent voltage-sensitive dye, and microelectrode recordings of action potentials were made adjacent to the aconitine injection site. The suppressive and preventive effects of GS967 (1 μM) against EAD/DAD-mediated VT/VF were then determined.
  
  
  RESULTS
  Aconitine induced VT in all 13 hearts studied. Activation map (N = 6) showed that the VT was initiated by a focal activity arising from the aconitine injection site (cycle length [CL] 84 ± 12) that degenerated to VF (CL 52 ± 8 ms) within a few seconds. VF was maintained by multifocal activity with occasional incomplete reentrant wavefronts. Administration of GS967 suppressed the VT/VF in 10 of 13 hearts (P < .001). Preexposure to GS967 for 15 minutes before aconitine injection prevented initiation of VT/VF in 5 of 8 additional hearts (P < .02). VF reoccurred within 10 minutes on washout of GS967. Microelectrode recordings (N = 7) showed that VT/VF was initiated by EAD- and DAD-mediated triggered activity at CL of 86 ± 14 ms (NS from VT CL) that preceded the VF. GS967 shortened APD, flattened the slope of the dynamic APD restitution curve, and reduced APD dispersion from 42 ± 12 ms to 8 ± 3 ms (P < .01). H2O2 perfusion in eight fibrotic aged hearts promoted EAD-mediated focal VT/VF, which was suppressed by GS967 in five hearts (P < .02).
  
  
  CONCLUSIONS
  The selective INa-L blocker GS967 effectively suppresses and prevents aconitine and oxidative stress-induced EADs, DADs, and focal VT/VF. Suppression of EADs, DADs, and reduction of APD dispersion make GS967 a potentially useful antiarrhythmic drug in conditions of enhanced INa-L.
authors.affiliation: Translational Arrhythmia Research Section, UCLA Cardiovascular Research Laboratory, Department of Medicine Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Arash
authors.initials: A
authors.lastname: Pezhouman
authors.affiliation: Translational Arrhythmia Research Section, UCLA Cardiovascular Research Laboratory, Department of Medicine Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Sepideh
authors.initials: S
authors.lastname: Madahian
authors.affiliation: Translational Arrhythmia Research Section, UCLA Cardiovascular Research Laboratory, Department of Medicine Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Hayk
authors.initials: H
authors.lastname: Stepanyan
authors.affiliation: Translational Arrhythmia Research Section, UCLA Cardiovascular Research Laboratory, Department of Medicine Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Hayk
authors.initials: H
authors.lastname: Ghukasyan
authors.affiliation: Translational Arrhythmia Research Section, UCLA Cardiovascular Research Laboratory, Department of Medicine Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
authors.affiliation: Gilead Sciences Inc., Foster City, California.
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: Translational Arrhythmia Research Section, UCLA Cardiovascular Research Laboratory, Department of Medicine Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California. Electronic address: hkaragueuzian@mednet.ucla.edu.
authors.forename: Hrayr S
authors.initials: HS
authors.lastname: Karagueuzian
mesh_terms: D000157:Aconitine / Q000008:administration & dosage; D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000188:drug therapy*; D014230:Triazoles / Q000494:pharmacology*; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: C578456:6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine; D000889:Anti-Arrhythmia Agents; D011725:Pyridines; D014230:Triazoles; D000157:Aconitine
keywords: Aconitine; Early afterdepolarization; Late I(Na); Late afterdepolarization; Optical mapping; Oxidative stress; Ventricular fibrillation; Ventricular tachycardia