The Selective Cardiac Late Sodium Current Inhibitor GS-458967 Suppresses Autonomically Triggered Atrial Fibrillation in an Intact Porcine Model.
BACKGROUND
The anti-atrial fibrillation (AF) effects of GS-458967 (GS-967), a selective, potent inhibitor of cardiac late Na(+) current (I(Na)), were evaluated in a novel model of AF induction that does not require electrical stimuli.


RESULTS
In 6 closed-chest anesthetized pigs, AF was induced by intrapericardial acetylcholine (1 mL of 100 mM solution) followed within 1 minute by epinephrine (20 μg/kg, i.v., bolus over 1 min). Effects of GS-967 (0.4 mg/kg, i.v., infused over 30 min) on inducibility and duration of AF were analyzed. Administration of acetylcholine followed by epinephrine elicited spontaneous AF that persisted for 12.03 ± 1.22 minutes (mean ± SEM) in all 6 pigs. Following GS-967, AF did not occur in 5 of 6 pigs when plasma concentration was 383 ± 150 nM. In the single animal in which AF could still be induced, the arrhythmia lasted 6.3 minutes. Partial return of AF inducibility occurred in 2 of 6 animals at 90 minutes, when plasma concentration of GS-967 was 228 ± 35 nM. GS-967 reduced the QT interval (P = 0.004), consistent with cardiac late I(Na) inhibition, but did not affect heart rate, mean arterial pressure, QRS duration, or PR interval. Epinephrine infusion alone, tested in a separate group (N = 6), did not provoke AF.


CONCLUSIONS
Selective cardiac late I(Na) inhibition with GS-967 suppresses spontaneous induction of AF in a novel model that does not require provocative electrical stimuli. Because this mode of action has only a mild on effect on contractility, it offers an advantage over contemporary anti-AF agents, which can have negative inotropic actions.
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.|Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Juliana Saran
JS
Carneiro
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.|Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Afonso S Alves
AS
Bento
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.|Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Danilo
D
Bacic
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Bruce D
BD
Nearing
Gilead Sciences, Inc, Foster City, California, USA.
Sridharan
S
Rajamani
Gilead Sciences, Inc, Foster City, California, USA.
Luiz
L
Belardinelli
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Richard L
RL
Verrier
D000109:Acetylcholine; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D062186:Arterial Pressure / Q000187:drug effects; D001281:Atrial Fibrillation / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D001342:Autonomic Nervous System Diseases / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control*; D004558:Electric Stimulation; D004562:Electrocardiography / Q000187:drug effects; D004837:Epinephrine; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D026941:Sodium Channel Blockers / Q000493:pharmacokinetics / Q000627:therapeutic use*; D034421:Sus scrofa; D013552:Swine; D014230:Triazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*
C578456:6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine; D000889:Anti-Arrhythmia Agents; D011725:Pyridines; D026941:Sodium Channel Blockers; D014230:Triazoles; D000109:Acetylcholine; D004837:Epinephrine
QT interval; acetylcholine; atrial fibrillation; cardiac late sodium current; catecholamines; epinephrine; ranolazine