Ivabradine (IVA) selectively inhibits If current in the sinus node and is used to treat inappropriate sinus tachycardia. Previous studies indicated that IVA also inhibited IKr at concentrations higher than therapeutic range. However, the proarrhythmic risk of IVA has not been fully determined.Objective
Sea anemone toxin (ATX) –II treated hearts have an increased risk of proarrhythmia and therefore was used to detect low-risk QT prolonging drugs. The objective of this study was to determine the effect of IVA on the atrial and ventricular monophasic action potential duration (MAPD) and the arrhythmic activities in the absence and presence of ATX-II.Methods
Female rabbit isolated hearts were perfused by Langendorff mode. Hearts were paced at right atria appendage, and left atrial and ventricular MAPD90 were recorded and analysed.Results
When hearts were paced at 2.8 Hz, the atrial, and endocardial and epicardial ventricular MAPD90 were 49.6 ± 3, 136.3 ± 7 and 127.4 ± 4 ms. IVA (3–10 μm) significantly prolonged them by 15.9 ± 2 (n = 6, p < 0.01), 31.5 ± 4 and 23.9 ± 3 ms, respectively (n = 6, p < 0.01), in a concentration dependent manner. When the pacing rate was increased from 2.5 Hz to 3.5 Hz, IVA (6 μm) reduced LV endocardial and epicardial MAPD90 by 41.2 ± 3 and 31.6 ± 4 ms (n = 5, p < 0.05) in a reverse rate dependent mode. ATX-II (3 nM) prolonged atrial MAPD90 by 36.5 ± 5 ms, and LV endocardial and epicardial MAPD90 by 19.9 ± 3 and 19.5 ± 4 ms. In the continued presence of ATX-II (3 nM), IVA (6–10 μm) reduced the atrial MAPD90 by 14.4 ± 4 ms (n = 6, p < 0.01). Atrial arrhythmias were observed in 4 of 12 (33.3%) hearts treated with 1–10 μm IVA in the presence of 3 nM ATX-II. In contrast, IVA (3–10 μm) caused greater prolongation in presence, compared with it in absence of ATX-II, in LV endo- and epi- cardial MAPD90 by 36.2 ± 7 and 27.5 ± 5 ms (n = 6, p < 0.01). IVA did not increase the BVR of atrial MAPD90 and transmural dispersion of MAPD90, and caused no ventriculararrhythmia both in the absence and presence of ATX-II, (n = 6, p > 0.05; n = 6, p > 0.05).Conclusion
IVA prolongs both atrial and ventricular MAPD and causes atrial arrhythmias in hearts when late sodium current is increased, without proarrhythmic activities in the ventricles. This result may explain the results in clinical research.