Ivabradine induced a use-dependent inhibition of hHCN4 with an IC50 of 0.5 microM, progressively reducing the frequency of action potentials in isolated sino-atrial nodes across multiple species.
Ivabradine's use-dependent inhibition of hHCN4 channels explains its slow-developing heart rate reduction and greater efficacy in species with faster baseline heart rates.
Effect estimate: IC50 0.5 microM
BACKGROUND AND PURPOSE: Ivabradine, a specific and use-dependent I(f) inhibitor, exerts anti-ischaemic activity purely by reducing heart rate. The aim of this work was to characterize its effect on the predominant HCN channel isoform expressed in human sino-atrial nodes (hSAN), to determine its kinetics in HCN channels from multicellular preparations and rate-dependency of its action. EXPERIMENTAL APPROACH: RT-PCR analysis of the four HCN channel isoforms was carried out on RNAs from hSAN. Patch-clamp and intracellular recordings were obtained from CHO cells stably expressing hHCN4 and isolated SAN, respectively. Beating rate of rat isolated atria was followed using a transducer. KEY RESULTS: hHCN4 mRNAs were predominant in hSAN. Ivabradine induced a time-dependent inhibition of hHCN4 with an IC(50) of 0.5 microM. In rabbit SAN, ivabradine progressively reduced the frequency of action potentials: by 10% after 3 h at 0.1 microM, by 14% after 2 h at 0.3 microM and by 17% after 1.5 h at 1 microM. After 3h, ivabradine reduced the beating rate of rat right atria with an IC(30) of 0.2 microM. The onset of action of ivabradine was use-dependent rather than time-dependent with slower effects than caesium, an extracellular I (f) blocker. Ivabradine 3 microM decreased the frequency of action potentials in SAN from guinea-pig, rabbit and pig by 33%, 21% and 15% at 40 min, respectively. CONCLUSIONS AND IMPLICATIONS: The use-dependent inhibition of hHCN4 current by ivabradine probably contributes to its slow developing effect in isolated SAN and right atria and to its increased effectiveness in species with rapid SAN activity.
Thollon et al. (Mon,) conducted a other in Pacemaker activity. Ivabradine vs. Caesium was evaluated on Inhibition of hHCN4 and reduction in action potential frequency (IC50 0.5 microM). Ivabradine induced a use-dependent inhibition of hHCN4 with an IC50 of 0.5 microM, progressively reducing the frequency of action potentials in isolated sino-atrial nodes across multiple species.