KETAMINE INTERACTS WITH THE NORADRENALINE TRANSPORTER AT A SITE PARTLY OVERLAPPING THE DESIPRAMINE BINDING-SITE

Effects of the intravenous anaesthetic ketamine on the desipramine-sen sitive noradrenaline transporter (NAT) were examined in cultured bovin e adrenal medullary cells and in transfected Xenopus laevis oocytes ex pressing the bovine NAT (bNAT). Incubation (1-3 h) of adrenal medullar y cells with ketamine (10-300 mu M) caused an in crease in appearance of catecholamines in culture medium. Ketamine (10-1000 mu M) inhibited desipramine-sensitive uptake of [H-3] noradrenaline (NA) (IC50=97 mu M) Saturation analysis showed that ketamine reduced V-max of [H-3]NA u ptake without changing K-m, indicating a non-competitive inhibition. O ther inhibitors of NAT, namely cocaine and desipramine, showed a compe titive inhibition of [H-3]NA uptake while a derivative of ketamine, ph encyclidine, showed a mixed type of inhibition. Ketamine (10-1000 mu M ) also inhibited the specific binding of [H-3]desipramine to plasma me mbranes isolated from bovine adrenal medulla. Scatchard analysis of [H -3]desipramine binding revealed that ketamine increased K-d without al tering B-max, indicating a competitive inhibition. In transfected Xeno pus oocytes expressing the bNAT, ketamine attenuated [H-3]NA uptake wi th a kinetic characteristic similar to that of cultured adrenal medull ary cells. These findings are compatible with the idea that ketamine n on-competitively inhibits the transport of NA by interacting with a si te which partly overlaps the desipramine binding site on the NAT.