BACKGROUND: There is a clear association between excessive ethanol ( EtOH ) consumption and the risk of sudden cardiac death. The hyperpolarization-activated cyclic nucleotide-gated (HCN) current, I (f) , is known to contribute to spontaneous pacemaker activity of sinoatrial (SA) node cells. However, the exact mechanisms of EtOH on arrhythmia induction are not well understood. METHODS: The preparations of SA node were excised from rabbit heart, transmembrane potentials were recorded by standard glass microelectrode technique, and a whole-cell patch clamp technique was used to record I (f) in enzymatically isolated rabbit SA node pacemaker cells. Human HCN2 (hHCN2) and HCN4 channels were heterologously expressed in Xenopus oocytes and studied using 2-electrode voltage clamp technique. RESULTS: Superfusion of EtOH increased the spontaneous firing frequency of SA node cells in a reversible fashion. Treatment with ivabradine irreversibly depressed basal firing frequency and markedly attenuated the enhancement effect of EtOH on firing. The stimulatory effects of EtOH on I (f) were concentration-dependent in the range of 1 to 100 mM, with an average EC (50) value of 20.81 ± 6.71 mM and Hill coefficient of 1.19 ± 0.10. Furthermore, EtOH reversibly enhanced the HCN currents in a concentration-dependent fashion with an EC (50) value of 18.41 ± 2.75 mM for the HCN2 channel and 21.98 ± 3.54 mM for the HCN4 channel, which was accompanied by the acceleration of activation and deactivation kinetics. In addition, EtOH , at both moderate and high doses, caused a shift in the voltage dependence of hHCN4 channel activation to more depolarizing potentials. However, superfusion of high, not moderate, concentration of EtOH caused a shift in the voltage dependence of hHCN2 channel activation to more hyperpolarizing potentials. CONCLUSIONS: This study provides insight into the molecular interaction of EtOH and the hHCN channels, which may shed light on elucidating the potentially proarrhythmic mechanism of EtOH .
BACKGROUND: There is a clear association between excessive ethanol ( EtOH ) consumption and the risk of sudden cardiac death. The hyperpolarization-activated cyclic nucleotide-gated (HCN) current, I (f) , is known to contribute to spontaneous pacemaker activity of sinoatrial (SA) node cells. However, the exact mechanisms of EtOH on arrhythmia induction are not well understood. METHODS: The preparations of SA node were excised from rabbit heart, transmembrane potentials were recorded by standard glass microelectrode technique, and a whole-cell patch clamp technique was used to record I (f) in enzymatically isolated rabbit SA node pacemaker cells. HumanHCN2 (hHCN2) and HCN4 channels were heterologously expressed in Xenopus oocytes and studied using 2-electrode voltage clamp technique. RESULTS: Superfusion of EtOH increased the spontaneous firing frequency of SA node cells in a reversible fashion. Treatment with ivabradine irreversibly depressed basal firing frequency and markedly attenuated the enhancement effect of EtOH on firing. The stimulatory effects of EtOH on I (f) were concentration-dependent in the range of 1 to 100 mM, with an average EC (50) value of 20.81 ± 6.71 mM and Hill coefficient of 1.19 ± 0.10. Furthermore, EtOH reversibly enhanced the HCN currents in a concentration-dependent fashion with an EC (50) value of 18.41 ± 2.75 mM for the HCN2 channel and 21.98 ± 3.54 mM for the HCN4 channel, which was accompanied by the acceleration of activation and deactivation kinetics. In addition, EtOH , at both moderate and high doses, caused a shift in the voltage dependence of hHCN4 channel activation to more depolarizing potentials. However, superfusion of high, not moderate, concentration of EtOH caused a shift in the voltage dependence of hHCN2 channel activation to more hyperpolarizing potentials. CONCLUSIONS: This study provides insight into the molecular interaction of EtOH and the hHCN channels, which may shed light on elucidating the potentially proarrhythmic mechanism of EtOH .
Authors: Francesco Ferrini; Benjamin Dering; Andrea De Giorgio; Laura Lossi; Alberto Granato Journal: Cell Mol Neurobiol Date: 2017-12-09 Impact factor: 5.046
Authors: Michael C Salling; Mary Jane Skelly; Elizabeth Avegno; Samantha Regan; Tamara Zeric; Elcoma Nichols; Neil L Harrison Journal: J Neurosci Date: 2018-06-18 Impact factor: 6.167