Impairment of hyperpolarization-activated, cyclic nucleotide-gated channel function by the intravenous general anesthetic propofol

J Pharmacol Exp Ther. 2005 Nov;315(2):517-25. doi: 10.1124/jpet.105.091801. Epub 2005 Jul 20.


Propofol (2,6-diisopropylphenol) is a widely used intravenous general anesthetic, which has been reported to produce bradycardia in patients at concentrations associated with profound sedation and loss of consciousness. Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels conduct a monovalent cationic current I(h) (also known as I(q) or I(f)) that contributes to autorhythmicity in both the brain and heart. Here we studied the effects of propofol on recombinant HCN1, HCN2, and HCN4 channels and found that the drug inhibits and slows activation of all three channels at clinically relevant concentrations. In oocyte expression studies, HCN1 channel activation was most sensitive to slowing by propofol (EC(50) values of 5.6 +/- 1.0 microM for fast component and 31.5 +/- 7.5 microM for slow component). HCN1 channels also showed a marked propofol-induced hyperpolarizing shift in the voltage dependence of activation (EC(50) of 6.7 +/- 1.0 microM) and accelerated deactivation (EC(50) of 4.5 +/- 0.9 microM). Furthermore, propofol reduced heart rate in an isolated guinea pig heart preparation over the same range of concentrations. These data suggest that propofol modulation of HCN channel gating is an important molecular mechanism that can contribute to the depression of central nervous system function and also lead to bradyarrhythmias in patients receiving propofol during surgical anesthesia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anesthetics, Intravenous / pharmacology*
  • Animals
  • Biological Clocks / drug effects
  • Cyclic Nucleotide-Gated Cation Channels
  • DNA, Complementary / biosynthesis
  • DNA, Complementary / genetics
  • Electrocardiography / drug effects
  • Electrophysiology
  • Heart / drug effects
  • Heart / physiology
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channel Gating / drug effects*
  • Ion Channels / drug effects*
  • Kinetics
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Muscle Proteins / drug effects*
  • Nerve Tissue Proteins / drug effects*
  • Oocytes / drug effects
  • Patch-Clamp Techniques
  • Potassium Channels
  • Propofol / pharmacology*
  • Sinoatrial Node / cytology
  • Sinoatrial Node / drug effects
  • Xenopus laevis / physiology


  • Anesthetics, Intravenous
  • Cyclic Nucleotide-Gated Cation Channels
  • DNA, Complementary
  • HCN1 protein, human
  • HCN2 protein, human
  • HCN4 protein, human
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Muscle Proteins
  • Nerve Tissue Proteins
  • Potassium Channels
  • Propofol