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.
T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T24 T2 T3 T4 T5 T6 T7 T8 T9
CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
[3H]DMI nisoxetine DMI DMI nisoxetine DMI nisoxetine desipramine norepinephrine NET DMI hNET NET NET NET norepinephrine transporter [3H]NE DMI [3H]NE DMI [3H]DMI [3H]DMI nisoxetine desipramine