Inactivation of HCN channels slows rhythm differently in atria and ventricle and improves conduction in the anoxic‐reoxygenated embryonic chick heart

Abstract

Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels control heart rate and are expressed early during cardiogenesis. Distribution of the predominant HCN4 isoform and the involvement of HCN channels in myocardial dysfunction induced by anoxia‐reoxygenation were investigated in the embryonic heart.Expression of HCN4 channels was determined by western blotting in atria (A), ventricle (V) and outflow tract (OT) from hearts of 4‐day‐old chick embryos. Hearts or isolated ventricles were exposed to the selective inhibitor of HCN channels ivabradine. Effects of 0.3μM ivabradine on ECG, excitation‐contraction (EC) coupling and contractility were determined in hearts submitted to 30 min anoxia and 60 min reoxygenation.The distribution of HCN4 was inhomogeneous, i.e. A ≥ V ≫ OT. The intrinsic rate was 164±22 in A and 78±24 bpm in isolated V. Under normoxia, 0.3 μM ivabradine decreased A rate by 20% and V rate by 50% and increased A‐V conduction by 20%. These effects persisted throughout anoxia‐reoxygenation, whereas variations of QT duration, EC coupling, contractility and arrhythmias were not affected.These data indicate that HCN channels are inhomogeneously distributed and control finely atrial and ventricular pacemakers of the embryonic heart. Their inactivation during anoxia‐reoxygenation ameliorates atrial rhythmicity and conduction.Supported by Servier and SNSF n°3100A0‐105901