Overexpression of the HCN2 channel increases the arrhythmogenicity induced by hypokalemia

• Published in: The journal of physiological sciences Vol. 69; no. 4; pp. 653 - 660
• Main Authors: Oshita, Kensuke, Kozasa, Yuko, Nakagawa, Yasuaki, Kuwabara, Yoshihiro, Kuwahara, Koichiro, Nakagawa, Taku, Nakashima, Noriyuki, Hiraki, Teruyuki, Takano, Makoto
• Format: Journal Article
• Language: English
• Published: Japan Springer 01.07.2019; BioMed Central; Springer Japan
• Subjects: Animals; Arrhythmia; Arrhythmias, Cardiac - metabolism; Automation; Cardiac arrhythmia; Cardiac muscle; Congestive heart failure; Electrocardiography; Fetuses; Genetic engineering; Heart; Heart failure; Heart Failure - metabolism; Heart Ventricles - metabolism; Hyperpolarization; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism; Hypokalemia; Hypokalemia - metabolism; Ion channels; Ion channels (cyclic nucleotide-gated); Ivabradine; Membrane potential; Membrane Potentials - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocytes; Myocytes, Cardiac - metabolism; Original Paper; Perfusion; Potassium; Potassium - metabolism; Potassium Channels - metabolism; Statistical analysis; Transgenic animals; Transgenic mice; Ventricle; United States > US; Heart failure; Hypokalemia; Arrhythmia; HCN2
• ISSN: 1880-6546; 1880-6562
• DOI: 10.1007/s12576-019-00684-7

Hypokalemia, an abnormally low level of potassium (K ), is a electrolyte imbalance that commonly occurs in heart failure patients. Hypokalemia is well known to induce lethal ventricular arrhythmia. However, the effects of hypokalemia in failing hearts that have undergone electrophysiological remodeling, i.e., the reactivation of fetal-type ion channels, remain unexplored. We have examined the effect of hypokalemia in the myocytes of transgenic mice overexpressing the hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channel in the heart (HCN2-Tg mice). Perfusion with a mild hypokalemic solution containing 3 mM K induced ectopic ventricular automaticity in 55.0% of HCN2-Tg mouse myocytes. In the remaining HCN2-Tg mouse myocytes, the resting membrane potential (RMP) was more depolarized than that of wild-type myocytes subjected to the same treatment and could also be hyperpolarized by an HCN channel blocker. We conclude that in hypokalemia in our mice model, the HCN2 channel was constitutively activated at the hyperpolarized RMP, thereby destabilizing the electrophysiological activity of ventricular myocytes.