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ANESTHETIC PHARMACOLOGY

General Anesthetic Actions on Norepinephrine, Dopamine, and -Aminobutyric Acid Transporters in Stably Transfected Cells

Departments of Anesthesiology and Pharmacology, Weill Medical College of Cornell University, New York, New York

Address correspondence to Hugh C. Hemmings Jr, MD, PhD, Box 50, LC-203A, Weill Medical College of Cornell University, 525 E. 68th St., New York, NY 10021. Address e-mail to hchemmi{at}med.cornell.edu Reprints will not be available from the authors.

The effects of general anesthetics on neurotransmitter uptake by plasma membrane transporters are controversial. We analyzed the effects of representative volatile and IV general anesthetics on recombinant transporters for norepinephrine (human NET), dopamine (rat DAT), or -aminobutyric acid (rat GAT-1) stably expressed in a porcine kidney cell line (LLC-PK₁). This approach avoids complicating factors associated with neuronal preparations, such as the involvement of multiple transporters and the indirect effects of membrane potential. At clinical concentrations, human NET was inhibited only by halothane (50% inhibitory concentration [IC₅₀] = 0.54 mM), rat DAT was sensitive to both halothane and isoflurane (IC₅₀ = 0.60 and 0.64 mM, respectively), and rat GAT-1 was insensitive to both volatile anesthetics. Human NET was inhibited in a dose-dependent fashion by propofol (IC₅₀ = 41 µM), ketamine (IC₅₀ = 150 µM), and etomidate (IC₅₀ > 200 µM), but not by pentobarbital. Only propofol inhibited NET at a clinically relevant concentration (5 µM). Rat DAT was inhibited in a dose-dependent fashion by propofol (IC₅₀ = 120 µM), etomidate (IC₅₀ = 100 µM), and ketamine (IC₅₀ = 210 µM), but not by pentobarbital. None of these anesthetics was predicted to inhibit DAT at concentrations that produce anesthesia. Propofol inhibited rat GAT-1, but only at the largest concentration tested. General anesthetics have drug- and subtype-selective actions on neurotransmitter transporters. We conclude that effects on catecholamine, but not -aminobutyric acid, transporters may contribute to secondary synaptic actions of certain anesthetics but are unlikely to be essential to their anesthetic properties.

IMPLICATIONS: Previous studies have implicated neurotransmitter transporters as targets for general anesthetic effects on synaptic transmission. Recombinant transporters for norepinephrine and dopamine were sensitive to certain volatile and IV anesthetics, whereas -aminobutyric acid transporters were insensitive. These anesthetic- and neurotransmitter-specific effects may underlie some of the secondary effects of general anesthetics.

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