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Anesthesiology:
doi: 10.1097/ALN.0b013e31829e4b05
Perioperative Medicine

Bumetanide, an Inhibitor of Cation-chloride Cotransporter Isoform 1, Inhibits γ-Aminobutyric Acidergic Excitatory Actions and Enhances Sedative Actions of Midazolam in Neonatal Rats

Koyama, Yukihide M.D.*; Andoh, Tomio M.D.; Kamiya, Yoshinori M.D., Ph.D.; Morita, Satoshi Ph.D.§; Miyazaki, Tomoyuki M.D., Ph.D.; Uchimoto, Kazuhiro M.D.*; Mihara, Takahiro M.D.#; Goto, Takahisa M.D.**

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Abstract

Background: It has been shown that γ-aminobutyric acid exerts excitatory actions on the immature brain due to the increased expression of Na+–K+–2Cl cotransporter isoform 1. The authors sought to clarify whether midazolam, a γ-aminobutyric acid–mimetic hypnotic agent, causes neuronal excitation that can be blocked by bumetanide, a selective inhibitor of Na+–K+–2Cl cotransporter isoform 1. Furthermore, the authors examined whether bumetanide potentiates the sedative effects of midazolam in neonatal rats.
Methods: The authors measured the effects of midazolam with or without bumetanide on the cytosolic Ca2+ concentration ([Ca]2+i) in hippocampal slices (n = 3 in each condition) from rats at postnatal days 4, 7, and 28 (P4, P7, and P28) using fura-2 microfluorometry. Neuronal activity in the hippocampus and thalamus after intraperitoneal administration of midazolam with or without bumetanide was estimated by immunostaining of phosphorylated cyclic adenosine monophosphate–response element–binding protein (n = 12 in each condition). Furthermore, the authors assessed effects of bumetanide on the sedative effect of midazolam by measuring righting reflex latency (n = 6 in each condition).
Results: Midazolam significantly increased [Ca]2+i in the CA3 area at P4 and P7 but not at P28. Bumetanide inhibited midazolam-induced increase in [Ca]2+i. Midazolam significantly up-regulated phosphorylated cyclic adenosine monophosphate–response element–binding protein expression in a bumetanide-sensitive manner in the hippocampus at P7 but not P28. Bumetanide enhanced the sedative effects of midazolam in P4 and P7 but not P28 rats.
Conclusion: These results suggest that γ-aminobutyric acid A receptor–mediated excitation plays an important role in attenuated sedative effects of midazolam in immature rats.

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