期刊
ANESTHESIOLOGY
卷 119, 期 5, 页码 1096-1108出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/ALN.0b013e31829e4b05
关键词
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资金
- Ministry of Education, Culture, Sports, Science, and Technology, Tokyo, Japan [22591712]
- Grants-in-Aid for Scientific Research [22591712] Funding Source: KAKEN
Background: It has been shown that -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 -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 -aminobutyric acid A receptor-mediated excitation plays an important role in attenuated sedative effects of midazolam in immature rats.
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