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*Department of Anesthesiology, University Hospital Hamburg-Eppendorf; and
Institute of Neural Signal Transduction, University of Hamburg, Hamburg, Germany
Address correspondence and reprint requests to Patrick Friederich, MD, Department of Anesthesiology, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. Address e-mail to patrick.friederich{at}zmnh.uni-hamburg.de
Human TWIK-related K+ channels (TREK-1) stabilize the membrane potential (mp) of neurons and have a major role in the regulation of membrane excitability. In view of their physiological significance, interaction of bupivacaine with TREK-1 channels may be clinically important. Our aim was to characterize with the patch-clamp technique the properties of human TREK-1 channels and the effects of bupivacaine on these channels expressed in Chinese hamster ovary (CHO) cells. Transfection of CHO cells with TREK-1 channels (CHOTREK-1 cells) hyperpolarized the mp from -33 ± 13 to -78 ± 4 mV. The channels were stimulated by intracellular acidosis. Inhibition of TREK-1 channels by bupivacaine was reversible, concentration-dependent, voltage-independent, and increased with intracellular acidosis. Bupivacaine depolarized the mp of CHOTREK-1 cells in a reversible and concentration-dependent manner. Concentrations for channel inhibition and membrane depolarization were not linearly related (50% inhibitory concentration value for channel inhibition 370 ± 20 µM, Hill coefficient 1.8 ± 0.1, n = 51; 50% inhibitory concentration value for membrane depolarization 856 ± 14 µM, Hill coefficient 2.4 ± 0.1, mean ± SEM, n = 27). The results suggest that protonated bupivacaine elicits the observed effects via a site of interaction accessible from the intracellular space. Inhibition of TREK-1 channels and consecutive depolarization of the cell membrane by bupivacaine may contribute to blockade of neuronal signal conduction during regional anesthesia.
IMPLICATIONS: The interaction of bupivacaine with human TREK-1 channels was studied with the patch-clamp technique. Bupivacaine inhibited TREK-1 channels and depolarized the membrane potential of cells expressing TREK-1 channels in a concentration-dependent and reversible manner. Both effects may contribute to conductance block caused by bupivacaine.
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