The Inhibitory Effects of Ketamine on Human Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and Action Potential in Rabbit Sinoatrial Node

Abstract

Aims: 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. Conclusion: 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.