Original ArticleDexmedetomidine Exerts a Negative Chronotropic Action on Sinoatrial Node Cells Through the Activation of Imidazoline ReceptorsIshihara, Mariko MD*,†; Kojima, Akiko MD, PhD†; Ding, Wei-Guang MD, PhD*; Kitagawa, Hirotoshi MD, PhD†; Matsuura, Hiroshi MD, PhD*Author Information *Department of Physiology, Shiga University of Medical Science, Otsu, Shiga, Japan; and †Department of Anesthesiology, Shiga University of Medical Science, Otsu, Shiga, Japan. Correspondence: Wei-Guang Ding, MD, PhD, Department of Physiology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan (e-mail: [email protected]). Supported by JSPS (the Japan Society for the Promotion of Science, Tokyo, Japan) KAKENHI Grant Numbers 17K11050 (to A. Kojima) and 17K08536 (to H. Matsuura). The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jcvp.org). M. Ishihara and H. Matsuura participated in the research design. M. Ishihara and H. Matsuura conducted the experiments. M. Ishihara, W. -G. Ding, A. Kojima, H. Matsuura, and H. Kitagawa performed the data analysis. M. Ishihara, W. -G. Ding, and H. Matsuura wrote the manuscript. All authors revised the final version of manuscript and approved its submission. Data Availability Statement: The data that support the findings of this study are available from the corresponding author on reasonable request. Journal of Cardiovascular Pharmacology: December 2021 - Volume 78 - Issue 6 - p 826-838 doi: 10.1097/FJC.0000000000001133 Buy SDC Metrics Abstract Dexmedetomidine (DEX), an α2-adrenoreceptor (α2-AR) and imidazoline receptor agonist, is most often used for the sedation of patients in the intensive care unit. Its administration is associated with an increased incidence of bradycardia; however, the precise mechanism of DEX-induced bradycardia has yet to be fully elucidated. This study was undertaken to examine whether DEX modifies pacemaker activity and the underlying ionic channel function through α2-AR and imidazoline receptors. The whole-cell patch-clamp techniques were used to record action potentials and related ionic currents of sinoatrial node cells in guinea pigs. DEX (≥10 nM) reduced sinoatrial node automaticity and the diastolic depolarization rate. DEX reduced the amplitude of hyperpolarization-activated cation current (If or Ih) the pacemaker current, even within the physiological pacemaker potential range. DEX slowed the If current activation kinetics and caused a significant shift in the voltage dependence of channel activation to negative potentials. In addition, efaroxan, an α2-AR and imidazoline I1 receptor antagonist, attenuated the inhibitory effects of DEX on sinoatrial node automaticity and If current activity, whereas yohimbine, an α2-AR–selective antagonist, did not. DEX did not affect the current activities of other channels, including rapidly and slowly activating delayed rectifier K+ currents (IKr and IKs), L-type Ca2+ current (ICa,L), Na+/Ca2+ exchange current (INCX), and muscarinic K+ current (IK,ACh). Our results indicate that DEX, at clinically relevant concentrations, induced a negative chronotropic effect on the sinoatrial node function through the downregulation of If current through an imidazoline I1 receptor other than the α2-AR in the clinical setting. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.