Ketamine Action in the In Vitro Cortical Slice Is Mitigated by Potassium Channel Blockade

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Abstract

Background:

Ketamine 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.

Methods:

Adult 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.

Results:

Ketamine 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).

Conclusions:

The 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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