Article: article from journal or magazin.
Specific inhibition of HCN channels slows rhythm differently in atria, ventricle and outflow tract and stabilizes conduction in the anoxic-reoxygenated embryonic heart model.
The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are expressed in pacemaker cells very early during cardiogenesis. This work aimed at determining to what extent these channels are implicated in the electromechanical disturbances induced by a transient oxygen lack which may occur in utero. Spontaneously beating hearts or isolated ventricles and outflow tracts dissected from 4-day-old chick embryos were exposed to a selective inhibitor of HCN channels (ivabradine 0.1-10microM) to establish a dose-response relationship. The effects of ivabradine on electrocardiogram, excitation-contraction coupling and contractility of hearts submitted to anoxia (30min) and reoxygenation (60min) were also determined. The distribution of the predominant channel isoform, HCN4, was established in atria, ventricle and outflow tract by immunoblotting. Intrinsic beating rate of atria, ventricle and outflow tract was 164+/-22 (n=10), 78+/-24 (n=8) and 40+/-12bpm (n=23, mean+/-SD), respectively. In the whole heart, ivabradine (0.3microM) slowed the firing rate of atria by 16% and stabilized PR interval. These effects persisted throughout anoxia-reoxygenation, whereas the variations of QT duration, excitation-contraction coupling and contractility, as well as the types and duration of arrhythmias were not altered. Ivabradine (10microM) reduced the intrinsic rate of atria and isolated ventricle by 27% and 52%, respectively, whereas it abolished activity of the isolated outflow tract. Protein expression of HCN4 channels was higher in atria and ventricle than in the outflow tract. Thus, HCN channels are specifically distributed and control finely atrial, ventricular and outflow tract pacemakers as well as conduction in the embryonic heart under normoxia and throughout anoxia-reoxygenation.
Animals, Anoxia/drug therapy, Anoxia/embryology, Anti-Arrhythmia Agents/pharmacology, Arrhythmias, Cardiac/embryology, Arrhythmias, Cardiac/metabolism, Benzazepines/pharmacology, Biological Clocks/drug effects, Blotting, Western, Chick Embryo, Cyclic Nucleotide-Gated Cation Channels/antagonists & inhibitors, Cyclic Nucleotide-Gated Cation Channels/metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Electrocardiography, Excitation Contraction Coupling/drug effects, Heart/drug effects, Heart/embryology, Heart Atria/drug effects, Heart Atria/metabolism, Heart Conduction System/drug effects, Heart Conduction System/embryology, Heart Rate/drug effects, Heart Ventricles/drug effects, Heart Ventricles/metabolism, Myocardial Contraction/drug effects, Oxygen/metabolism, Potassium Channels/metabolism, Time Factors, Tissue Culture Techniques
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