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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on July 20, 2005; DOI: 10.1124/jpet.105.091801

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Received for publication June 30, 2005.
Revised July 18, 2005.
Accepted for publication July 18, 2005.

Impairment of HCN channel function by the intravenous general anesthetic propofol

Luisa P. Cacheaux 1, Norbert Topf 1, Gareth R. Tibbs 2, Ulrich R. Schaefer 1, Roberto Levi 1, Neil L. Harrison 1, Geoffrey W. Abbott 1*, Peter A. Goldstein 1

1 Weill Medical College of Cornell University 2 Columbia University

* Address correspondence to: E-mail: gwa2001{at}med.cornell.edu

Abstract

Propofol 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. 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, fast component; 31.5 µM, 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). Further, 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 which can contribute to the depression of central nervous system function and also lead to bradyarrhythmias in patients receiving propofol during surgical anesthesia.


Key words: HCN1, HCN2, HCN4, Ih, bradycardia, hyperpolarization-activated


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A. K. Lyashchenko, K. J. Redd, J. Yang, and G. R. Tibbs
Propofol inhibits HCN1 pacemaker channels by selective association with the closed states of the membrane embedded channel core
J. Physiol., August 15, 2007; 583(1): 37 - 56.
[Abstract] [Full Text] [PDF]


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