title: Bumetanide, an Inhibitor of NKCC1 (Na-K-2Cl Cotransporter Isoform 1), Enhances Propofol-Induced Loss of Righting Reflex but Not Its Immobilizing Actions in Neonatal Rats.
abstract: Gamma-aminobutyric acid (GABA) has been shown to induce excitation on immature neurons due to increased expression of Na+-K+-2Cl- co-transporter isoform 1 (NKCC1), and the transition of GABAergic signaling from excitatory to inhibitory occurs before birth in the rat spinal cord and spreads rostrally according to the developmental changes in cation-chloride co-transporter expression. We previously showed that midazolam activates the hippocampal CA3 area and induces less sedation in neonatal rats compared with adolescent rats in an NKCC1-dependent manner. In the present study, we tested the hypothesis that propofol-induced loss of righting reflex (LORR) but not immobilizing actions are modulated by NKCC1-dependent mechanisms and reduced in neonatal rats compared with adolescent rats. We estimated neuronal activity in the cortex, hippocampus and thalamus after propofol administration with or without bumetanide, an NKCC1 inhibitor, by immunostaining of phosphorylated cyclic adenosine monophosphate-response element binding protein (pCREB). We studied effects of bumetanide on propofol-induced LORR and immobilizing actions in postnatal day 7 and 28 (P7 and P28) rats. The pCREB expression in the cortex (P = 0.001) and hippocampus (P = 0.01) was significantly greater in the rats receiving propofol only than in the rats receiving propofol plus bumetanide at P 7. Propofol-induced LORR or immobilizing effects did not differ significantly between P7 and P28. Bumetanide significantly enhanced propofol-induced LORR (P = 0.031) but not immobilization in P7 rats. These results are partially consistent with our hypothesis. They suggest that propofol may activate the rostral but not caudal central nervous system dependently on NKCC1, and these differential actions may underlie the different properties of sedative and immobilizing actions observed in neonatal rats.
authors: Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.|Department of Anesthesiology, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki, Japan.
authors: Yukihide
authors: Y
authors: Koyama
authors: Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.|Department of Anesthesiology, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki, Japan.
authors: Tomio
authors: T
authors: Andoh
authors: Department of Anesthesiology, Niigata University Graduate School of Medicine, Niigata, Japan.
authors: Yoshinori
authors: Y
authors: Kamiya
authors: Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors: Tomoyuki
authors: T
authors: Miyazaki
authors: Department of Anesthesiology, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki, Japan.
authors: Koichi
authors: K
authors: Maruyama
authors: Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors: Takayuki
authors: T
authors: Kariya
authors: Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors: Takahisa
authors: T
authors: Goto
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D002034:Bumetanide / Q000494:pharmacology*; D050882:CREB-Binding Protein / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D057897:Reflex, Righting / Q000187:drug effects*; D064506:Solute Carrier Family 12, Member 2 / Q000737:chemistry* / Q000378:metabolism
chemical_list: C578879:Slc12a2 protein, rat; D064506:Solute Carrier Family 12, Member 2; D002034:Bumetanide; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D015742:Propofol