Abstract
Background:Ivabradine (IVA) inhibits hyperpolarization-activated cyclic nucleotide
channel to reduce pacing current with a possible increasing risk of
atrial fibrillation (AF). Objective: To determine the effects
of IVA on atrial action potentials, atrial arrhythmic activities and
intracellular calcium homeostasis. Methods:Langendorff-perfused hearts and atrial myocytes from New Zealand White
rabbits were used to record 12-lead ECGs,left atrial
monophasic APs and
Ca2+ sparks. Ca2+ handing related
protein from left atrium were tested using western blotting.Results: IVA (0.1-10 μM) slowed the HR and prolonged the atrial
MAPD90 (n=8, p <0.05) and induced atrial
arrhythmias in 26% and 77% of hearts paced at cycle lengths of 350 ms
and 570 ms, respectively (n=23 and 13, p <0.05). In
hearts treated with either 0.3 µM acetylcholine (ACh) or 2 nM ATX-II
with modulated atrial MAPDs, IVA (0.1-10 µM) caused either shortening or
prolongation of MAPD90, respectively (n=18 and 21,p <0.05) and atrial arrhythmias in 61.9% and 44.4% of
hearts (p <0.05). IVA induced delayed
afterdepolarizations in 41.7%, 62.5% and 50% of cells in the absence
and presence of either ATX-II or ACh, respectively (n=12, 8 and 8,p <0.05). IVA
(0.03-3 µM) increased the frequency, amplitude and full width at
half-maximum (n=22, p <0.05), and the expression of
ryanodine receptor and Na+/Ca2+exchanger with decreased sarcoplasmic reticulum calcium pump (n=4-5,p <0.05). Conclusion:IVA
caused a blunted HR reduction and increased atrial proarrhythmic risk in
hearts with slow rate, enhanced vagal tone and late INa,
and DADs resulting from enhanced Ca2+ release.
Key words: ivabradine, atrium, proarrhythmia, delayed
afterdepolarization,
Ca2+spark