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CELLULAR AND MOLECULAR

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

C. V. Starr Laboratory for Molecular Neuropharmacology, Department of Anesthesiology (L.P.C., N.T., N.L.H., P.A.G.), Department of Pharmacology (U.R.S., R.L., N.L.H., G.W.A.), and Greenberg Division of Cardiology, Department of Medicine (G.W.A.), Weill Medical College, Cornell University, New York, New York; and Departments of Anesthesiology and Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York (G.R.T.)

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 (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.

Address correspondence to: Dr. Geoffrey W. Abbott, Greenberg Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University, Starr 463, 520 East 70th Street, New York, NY 10021. E-mail: gwa2001{at}med.cornell.edu

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