The persistent membrane retention of desipramine causes lasting inhibition of norepinephrine transporter function.
The present study examined the potential membrane retention of desipramine (DMI) following exposures of 293-hNET cells to DMI, and its effect on [3H]NE uptake. Incubation of cells with 500 nM DMI for 1 h or 1 day persistently inhibited the uptake of [3H]NE up to 7 days, despite daily repeated washing of cells with drug-free medium. Uptake inhibition was paralleled by persistent retention of DMI associated with cells, as determined by HPLC and by radiotracer experiments using [3H]DMI. [3H]DMI trapped in membranes was displaceable by the structurally unrelated NET inhibitor, nisoxetine, in a concentration-dependent manner, implying interaction of retained [3H]DMI with the NET. A similar cellular retention was observed following incubation of cells with nisoxetine. The results demonstrate that DMI and nisoxetine are persistently retained in cell membranes, at least partly in association with the NET. The retention and slow diffusion of DMI and nisoxetine from membranes may contribute to their pharmacological and modulatory action on NET.
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Meng-Yang
MY
Zhu
Patrick B
PB
Kyle
Arthur S
AS
Hume
Gregory A
GA
Ordway
D018759:Adrenergic Uptake Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D003891:Desipramine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D050484:Norepinephrine Plasma Membrane Transport Proteins; D027981:Symporters / Q000037:antagonists & inhibitors*; D013997:Time Factors
D018759:Adrenergic Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; D027981:Symporters; D005473:Fluoxetine; C011386:nisoxetine; D003891:Desipramine