• Logan J Voss, Sebastian Karalus, Vilhelm Englund, and James W Sleigh.
• From the Anaesthesia Department, Waikato District Health Board, Hamilton, New Zealand (L.J.V., S.K.) the School of Science and Engineering, University of Waikato, Hamilton, New Zealand (V.E.) the University of Auckland Waikato Clinical School, Hamilton, New Zealand (J.W.S.).
• Anesthesiology. 2018 Jun 1; 128 (6): 1167-1174.

BackgroundKetamine is a general anesthetic thought to act by antagonizing N-methyl-D-aspartate receptors. However, ketamine acts on multiple channels, many of which are potential targets-including hyperpolarization-activated cyclic nucleotide-gated and potassium channels. In this study we tested the hypothesis that potassium leak channels contribute to the anesthetic action of ketamine.MethodsAdult mouse cortical slices (400 µm) were exposed to no-magnesium artificial cerebrospinal fluid to generate seizure-like event activity. The reduction in seizure-like event frequency after exposure to ketamine (n = 14) was quantified as a signature of anesthetic effect. Pharmacologic manipulation of hyperpolarization-activated cyclic nucleotide-gated and potassium channels using ZD7288 (n = 11), cesium chloride (n = 10), barium chloride (n = 10), low-potassium (1.5 mM) artificial cerebrospinal fluid (n = 10), and urethane (n = 7) were investigated.ResultsKetamine reduced the frequency of seizure-like events (mean [SD], -62 [22]%, P < 0.0001). Selective hyperpolarization-activated cyclic nucleotide-gated channel block with ZD7288 did not significantly alter the potency of ketamine to inhibit seizure-like event activity. The inhibition of seizure-like event frequency by ketamine was fully antagonized by the potassium channel blockers cesium chloride and barium chloride (8 [26]% and 39 [58%] increase, respectively, P < 0.0001, compared to ketamine control) and was facilitated by the potassium leak channel opener urethane (-93 [8]%, P = 0.002 compared to ketamine control) and low potassium artificial cerebrospinal fluid (-86 [11]%, P = 0.004 compared to ketamine control).ConclusionsThe results of this study show that mechanisms additional to hyperpolarization-activated cyclic nucleotide-gated channel block are likely to explain the anesthetic action of ketamine and suggest facilitatory action at two-pore potassium leak channels.

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