Retigabine stimulates human KCNQ2/Q3 channels in the presence of bupivacaine.
BACKGROUND
Inhibition of KCNQ2/Q3 channels may cause convulsion in humans. The interaction of bupivacaine with these channels is unknown. The anticonvulsant retigabine activates KCNQ2/Q3 channels and may reverse inhibitory actions of bupivacaine. Potassium channel stimulation may thus constitute a novel approach to treat local anesthetic-induced seizures. The aim of this study was to characterize bupivacaine effects on KCNQ2/Q3 channels and to investigate whether retigabine reverses the effects of the local anesthetic.


METHODS
KCNQ2/Q3 channels were transiently expressed in Chinese hamster ovary cells. The effects of bupivacaine and retigabine were studied with the patch-clamp technique.


RESULTS
Bupivacaine inhibited KCNQ2/Q3 channels in a concentration-dependent and reversible manner. The concentration-response curve was described by a Hill equation (IC50 = 173 +/- 7 microm, Hill coefficient = 1.4 +/- 0.1, mean +/- SEM, n = 37). The inhibitory effect did not differ between bupivacaine and levobupivacaine (42 +/- 4%, n = 7, versus 42 +/- 5%, n = 10; P > 0.05). Ropivacaine was four times less potent than bupivacaine. The inhibition of KCNQ2/Q3 channels by bupivacaine resulted in a significant and reversible depolarization of the membrane potential. Retigabine (300 nm-10 microm) reversed the inhibitory action of bupivacaine on KCNQ2/Q3 channels as well as the depolarization of the membrane potential.


CONCLUSIONS
The anticonvulsant retigabine at nanomolar concentrations reverses the inhibitory effect of micromolar concentrations of bupivacaine. Our results allow the hypothesis that activation of KCNQ2/Q3 channels by retigabine may offer a novel therapeutic approach for the treatment of bupivacaine-induced seizures.
Department of Anesthesiology, University Hospital Hamburg-Eppendorf, 52, 20246 Hamburg, Germany. patrick.friederich@zmnh.uni-hamburg.de
Mark A
MA
Punke
Patrick
P
Friederich
D000779:Anesthetics, Local / Q000633:toxicity; D000818:Animals; D002045:Bupivacaine / Q000633:toxicity; D016466:CHO Cells; D002219:Carbamates / Q000494:pharmacology*; D006224:Cricetinae; D006801:Humans; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000473:pathology; D018408:Patch-Clamp Techniques; D010655:Phenylenediamines / Q000494:pharmacology*; D015221:Potassium Channels / Q000819:agonists*; D024642:Potassium Channels, Voltage-Gated
D000779:Anesthetics, Local; D002219:Carbamates; D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D051659:KCNQ3 Potassium Channel; C496916:KCNQ3 protein, human; D010655:Phenylenediamines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C101866:ezogabine; D002045:Bupivacaine