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Research ArticleCELLULAR AND MOLECULAR

Impairment of Hyperpolarization-Activated, Cyclic Nucleotide-Gated Channel Function by the Intravenous General Anesthetic Propofol

Luisa P. Cacheaux, Norbert Topf, Gareth R. Tibbs, Ulrich R. Schaefer, Roberto Levi, Neil L. Harrison, Geoffrey W. Abbott and Peter A. Goldstein
Journal of Pharmacology and Experimental Therapeutics November 2005, 315 (2) 517-525; DOI: https://doi.org/10.1124/jpet.105.091801
Luisa P. Cacheaux
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Norbert Topf
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Gareth R. Tibbs
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Ulrich R. Schaefer
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Roberto Levi
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Neil L. Harrison
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Geoffrey W. Abbott
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Peter A. Goldstein
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Abstract

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 Ih (also known as Iq or If) 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 (EC50 values of 5.6 ± 1.0 μM for fast component and 31.5 ± 7.5 μM for slow component). HCN1 channels also showed a marked propofol-induced hyperpolarizing shift in the voltage dependence of activation (EC50 of 6.7 ± 1.0 μM) and accelerated deactivation (EC50 of 4.5 ± 0.9 μM). 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.

Footnotes

  • This work was supported by grants from the National Institutes of Health and the Whitehall Foundation.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.105.091801.

  • ABBREVIATIONS: HCN, hyperpolarization-activated, cyclic nucleotide-gated; mHCN, murine HCN; HEK, human embryonic kidney; QTC, corrected QT interval; IKs, slow delayed rectifier potassium current; TEVC, two-electrode voltage clamp; GFP, green fluorescent protein; DMSO, dimethyl sulfoxide.

    • Received June 29, 2005.
    • Accepted July 18, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 315 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 315, Issue 2
1 Nov 2005
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Research ArticleCELLULAR AND MOLECULAR

Impairment of Hyperpolarization-Activated, Cyclic Nucleotide-Gated Channel Function by the Intravenous General Anesthetic Propofol

Luisa P. Cacheaux, Norbert Topf, Gareth R. Tibbs, Ulrich R. Schaefer, Roberto Levi, Neil L. Harrison, Geoffrey W. Abbott and Peter A. Goldstein
Journal of Pharmacology and Experimental Therapeutics November 1, 2005, 315 (2) 517-525; DOI: https://doi.org/10.1124/jpet.105.091801

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Research ArticleCELLULAR AND MOLECULAR

Impairment of Hyperpolarization-Activated, Cyclic Nucleotide-Gated Channel Function by the Intravenous General Anesthetic Propofol

Luisa P. Cacheaux, Norbert Topf, Gareth R. Tibbs, Ulrich R. Schaefer, Roberto Levi, Neil L. Harrison, Geoffrey W. Abbott and Peter A. Goldstein
Journal of Pharmacology and Experimental Therapeutics November 1, 2005, 315 (2) 517-525; DOI: https://doi.org/10.1124/jpet.105.091801
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