Impairment of hyperpolarization-activated, cyclic nucleotide-gated channel function by the intravenous general anesthetic propofol.
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.
Cacheaux
Luisa P
LP
CV Starr Laboratory for Molecular Neuropharmacology, Department of Anesthesiology, Weill Medical College, Cornell University, New York, NY 10021, USA.
Topf
Norbert
N
Tibbs
Gareth R
GR
Schaefer
Ulrich R
UR
Levi
Roberto
R
Harrison
Neil L
NL
Abbott
Geoffrey W
GW
Goldstein
Peter A
PA
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects; D054815:Cyclic Nucleotide-Gated Cation Channels; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015640:Ion Channel Gating / Q000187:drug effects*; D007473:Ion Channels / Q000187:drug effects*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009124:Muscle Proteins / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000187:drug effects*; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D015221:Potassium Channels; D015742:Propofol / Q000494:pharmacology*; D012849:Sinoatrial Node / Q000166:cytology / Q000187:drug effects; D014982:Xenopus laevis / Q000502:physiology
D018686:Anesthetics, Intravenous; D054815:Cyclic Nucleotide-Gated Cation Channels; D018076:DNA, Complementary; C578665:HCN1 protein, human; C578710:HCN2 protein, human; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D015742:Propofol