title: The Inhibitory Effects of Ketamine on Human Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and Action Potential in Rabbit Sinoatrial Node.
abstract: OBJECTIVE
  To investigate the effects of ketamine on human hyperpolarization-activated cyclic nucleotide-gated (hHCN) 1, 2, 4 channel currents expressed in Xenopus oocytes and spontaneous action potentials (APs) of rabbit sinoatrial node (SAN).
  
  
  METHODS
  The 2-electrode voltage clamp and standard microelectrode techniques were respectively applied to record hHCN channels currents expressed in Xenopus oocytes and APs of SAN separated from rabbit heart.
  
  
  RESULTS
  Ketamine (1-625 µmol/L) blocked hHCN1, 2, and 4 currents with IC50 of 67.0, 89.1, and 84.0 µmol/L, respectively, in a concentration-dependent manner. The currents were rapidly blocked by ketamine and partially recovered after washout. The steady-state activation curves of hHCN1, 2, and 4 currents demonstrated a concentration-dependent shift to the left and the rates of activation were significantly decelerated. But ketamine blocked hHCN channels in a voltage-independence and non-use-dependent manner, and did not modify the voltage dependence of activation and reversal potentials. Furthermore, ketamine suppressed phase-4 spontaneous depolarization rate in isolated rabbit SAN and decreased the beat rates in a concentration-dependent manner.
  
  
  CONCLUSIONS
  Ketamine could inhibit hHCN channels expressed in Xenopus oocytes in a concentration-dependent manner as a close-state blocker and decrease beat rates of isolated rabbit SAN. This study may provide novel insights into other unexplained actions of ketamine.
authors.affiliation: Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Junlian
authors.initials: J
authors.lastname: Xing
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Wanzhen
authors.initials: W
authors.lastname: Jiang
authors.forename: Jie
authors.initials: J
authors.lastname: Hao
authors.forename: Zhipei
authors.initials: Z
authors.lastname: Liu
authors.forename: Antao
authors.initials: A
authors.lastname: Luo
authors.forename: Peihua
authors.initials: P
authors.lastname: Zhang
authors.forename: Xinrong
authors.initials: X
authors.lastname: Fan
authors.forename: Jihua
authors.initials: J
authors.lastname: Ma
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors*; D007649:Ketamine / Q000494:pharmacology*; D009865:Oocytes; D011817:Rabbits; D012849:Sinoatrial Node / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007649:Ketamine