title: Dual effects of intravenous anesthetics on the function of norepinephrine transporters.
abstract: BACKGROUND
  Norepinephrine transporters (NETs) terminate the neuronal transmission of norepinephrine, which is released from noradrenergic neurons. To investigate the interaction with NET, the authors examined the effects of short- and long-term treatment with anesthetics on the activity and mRNA level of NET.
  
  
  METHODS
  To assay [3H]norepinephrine uptake, bovine adrenal medullary cells in culture were incubated with [3H]norepinephrine in the presence of intravenous anesthetics, including propofol, thiamylal, and diazepam. To study the direct interaction between the anesthetics and NET, the effect of propofol on the binding of [3H]desipramine to the plasma membrane was examined. To study the long-term effect of anesthetics, [3H]norepinephrine uptake by cells pretreated with propofol for 6-24 h and [3H]desipramine binding after pretreatment for 12 h were measured. Simultaneously, we examined the effect of anesthetics on the expression of NET mRNA using the reverse transcriptase-polymerase chain reaction.
  
  
  RESULTS
  All of the intravenous anesthetics inhibited [3H]norepinephrine uptake in a concentration-dependent manner. The active concentrations of propofol (1-3 microm) and thiamylal (< or = 30 microm) were similar to those encountered clinically. The kinetic analysis revealed that all the anesthetics noncompetitively inhibited [3H]norepinephrine uptake. Propofol inhibited [3H]desipramine binding with a potency similar to that observed in [3H]norepinephrine uptake. Scatchard analysis showed that propofol competitively inhibited [3H]desipramine binding. On the other hand, long-term treatment of cells with propofol (10 microm) enhanced the NET functional activity and [3H]desipramine binding, and also increased the level of NET mRNA.
  
  
  CONCLUSIONS
  These results suggest that intravenous anesthetics have a dual effect on NET; short-term treatment causes inhibition, whereas long-term treatment leads to up-regulation. The interaction of intravenous anesthetics with NET may modulate the neuronal transmission of norepinephrine during anesthesia.
authors.affiliation: Departments of Anesthesiology, Pharmacology, and Biochemistry, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hara
authors.forename: N
authors.initials: N
authors.lastname: Yanagihara
authors.forename: K
authors.initials: K
authors.lastname: Minami
authors.forename: H
authors.initials: H
authors.lastname: Hirano
authors.forename: T
authors.initials: T
authors.lastname: Sata
authors.forename: A
authors.initials: A
authors.lastname: Shigematsu
authors.forename: F
authors.initials: F
authors.lastname: Izumi
mesh_terms: D000313:Adrenal Medulla / Q000187:drug effects / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000778:Anesthetics, Dissociative / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003891:Desipramine / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D004334:Drug Administration Schedule; D007649:Ketamine / Q000494:pharmacology; D007700:Kinetics; D009638:Norepinephrine / Q000378:metabolism / Q000493:pharmacokinetics; D050484:Norepinephrine Plasma Membrane Transport Proteins; D015742:Propofol / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D027981:Symporters; D013840:Thiamylal / Q000494:pharmacology; D014316:Tritium
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000778:Anesthetics, Dissociative; D018686:Anesthetics, Intravenous; D002352:Carrier Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D027981:Symporters; D013840:Thiamylal; D014316:Tritium; D007649:Ketamine; D003975:Diazepam; D003891:Desipramine; D009638:Norepinephrine; D015742:Propofol