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Use-dependent inhibition of hHCN4 by ivabradine and relationship with reduction in pacemaker activity.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2007 Jan; Vol. 150 (1), pp. 37-46. Date of Electronic Publication: 2006 Nov 27. - Publication Year :
- 2007
-
Abstract
- 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.<br />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.<br />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.<br />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.
- Subjects :
- Action Potentials drug effects
Animals
CHO Cells
Cricetinae
Cricetulus
Cyclic Nucleotide-Gated Cation Channels
Female
Humans
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Ion Channels genetics
Ivabradine
Male
Muscle Proteins genetics
Potassium Channels
RNA, Messenger genetics
Rabbits
Rats
Rats, Wistar
Reverse Transcriptase Polymerase Chain Reaction
Swine
Benzazepines pharmacology
Biological Clocks drug effects
Heart Rate drug effects
Ion Channels antagonists & inhibitors
Muscle Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 0007-1188
- Volume :
- 150
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 17128289
- Full Text :
- https://doi.org/10.1038/sj.bjp.0706940