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 [H-3]norepinephrine uptake, bovine adrenal medullary cells in culture were incubated with [H-3]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 [H-3]desipramine to the plasma membrane was examined. To study the long-term effect of anesthetics, [H-3]norepinephrine uptake by cells pretreated with propofol for 6-24 h and [H-3]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 [H-3]norepinephrine uptake In a concentration-dependent manner. The active concentrations of propofol (1-3 muM) and thiamylal (less than or equal to 30 muM) were Similar to those encountered clinically. The kinetic analysis revealed that all the anesthetics noncompetitively inhibited [H-3]norepinephrine uptake. Propofol inhibited [H-3]desipramine binding with a potency similar to that observed in [H-3]norepinephrine uptake. Scatchard analysis showed that propofol competitively inhibited [H-3]desipramine binding. On the other hand, long-term treatment of cells with propofol (10 mum) 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.