title: Up-regulation of noradrenaline transporter in response to prolonged exposure to ketamine.
abstract: We previously reported that the intravenous anaesthetic ketamine acutely inhibits the activity of the noradrenaline transporter (NAT) by acting on a site partly overlapping the desipramine binding site. Here we report the effects of a prolonged exposure to ketamine on the functional activity and number of NAT and its mRNA in cultured bovine adrenal medullary cells. Treatment of cells with ketamine (10-1000 microM) for 1-24 h resulted in a transient decrease and subsequent increase in [(3)H]noradrenaline (NA) uptake by the cells. Saturation analysis showed that ketamine (100 microM, 12 h) increased the V(max) value of [(3)H]NA uptake without any change in the K(m) value. Ketamine also increased the specific binding of [(3)H]nisoxetine to plasma membranes isolated from the cells. Scatchard analysis of [(3)H]nisoxetine binding revealed that ketamine increased the B(max) value without altering the K(d) value, suggesting an increase in the number of NAT in the plasma membrane. The stimulatory effect of ketamine on [(3)H]NA uptake was blocked by cycloheximide, an inhibitor of protein synthesis. Treatment of cells with ketamine for 12-24 h enhanced the expression of NAT mRNA. The present findings demonstrated that prolonged exposure to ketamine increases the functional activity of NAT and its mRNA. This may imply that ketamine negatively modulates sympathetic nervous activity through an up-regulation of NAT during long anaesthesia.
authors.affiliation: Department of Anaesthesiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, 807-8555, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Hara
authors.forename: Kouichiro
authors.initials: K
authors.lastname: Minami
authors.forename: Susumu
authors.initials: S
authors.lastname: Ueno
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Toyohira
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
authors.forename: Akio
authors.initials: A
authors.lastname: Shigematsu
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
mesh_terms: D000313:Adrenal Medulla / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology*; D007700:Kinetics; D009638:Norepinephrine / Q000235:genetics / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger / Q000378:metabolism; D027981:Symporters / Q000187:drug effects*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D018686:Anesthetics, Intravenous; D002352:Carrier Proteins; D018691:Excitatory Amino Acid Antagonists; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D027981:Symporters; D007649:Ketamine; D009638:Norepinephrine