Use-dependent inhibition of hHCN4 by ivabradine and relationship with reduction in pacemaker activity
| Autor: | Thollon, C, Bedut, S, Villeneuve, N, Cogé, F, Piffard, L, Guillaumin, J-P, Brunel-Jacquemin, C, Chomarat, P, Boutin, J-A, Peglion, J-L, Vilaine, J-P |
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| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Male
Potassium Channels Reverse Transcriptase Polymerase Chain Reaction Swine Action Potentials Cyclic Nucleotide-Gated Cation Channels Muscle Proteins CHO Cells Benzazepines Research Papers Ion Channels Rats Cricetulus Biological Clocks Heart Rate Cricetinae Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Animals Humans Female Ivabradine RNA Messenger Rabbits Rats Wistar |
| Popis: | 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.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.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.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. |
| Databáze: | OpenAIRE |
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