Dual effects of intravenous anesthetics on the function of norepinephrine transporters.
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.
Hara
K
K
Departments of Anesthesiology, Pharmacology, and Biochemistry, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
Yanagihara
N
N
Minami
K
K
Hirano
H
H
Sata
T
T
Shigematsu
A
A
Izumi
F
F
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
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