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

TitleImpairment of hyperpolarization-activated, cyclic nucleotide-gated channel function by the intravenous general anesthetic propofol.
Publication TypeJournal Article
Year of Publication2005
AuthorsCacheaux LP, Topf N, Tibbs GR, Schaefer UR, Levi R, Harrison NL, Abbott GW, Goldstein PA
JournalJ Pharmacol Exp Ther
Volume315
Issue2
Pagination517-25
Date Published2005 Nov
ISSN0022-3565
KeywordsAnesthetics, Intravenous, Animals, Biological Clocks, Cyclic Nucleotide-Gated Cation Channels, DNA, Complementary, Electrocardiography, Electrophysiology, Heart, Humans, Ion Channel Gating, Ion Channels, Kinetics, Membrane Potentials, Muscle Proteins, Nerve Tissue Proteins, Oocytes, Patch-Clamp Techniques, Potassium Channels, Propofol, Sinoatrial Node, Xenopus laevis
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 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.

DOI10.1124/jpet.105.091801
Alternate JournalJ. Pharmacol. Exp. Ther.
PubMed ID16033909