Ketamine interacts with the noradrenaline transporter at a site partly overlapping the desipramine binding site.
Effects of the intravenous anaesthetic ketamine on the desipramine-sensitive noradrenaline transporter (NAT) were examined in cultured bovine adrenal medullary cells and in transfected Xenopus laevis oocytes expressing the bovine NAT (bNAT). Incubation (1-3 h) of adrenal medullary cells with ketamine (10-300 microM) caused an increase in appearance of catecholamines in culture medium. Ketamine (10-1000 microM) inhibited desipramine-sensitive uptake of [3H]noradrenaline (NA) (IC50=97 microM). Saturation analysis showed that ketamine reduced Vmax of [3H]NA uptake without changing Km, indicating a non-competitive inhibition. Other inhibitors of NAT, namely cocaine and desipramine, showed a competitive inhibition of [3H]NA uptake while a derivative of ketamine, phencyclidine, showed a mixed type of inhibition. Ketamine (10-1000 microM) also inhibited the specific binding of [3H]desipramine to plasma membranes isolated from bovine adrenal medulla. Scatchard analysis of [3H]desipramine binding revealed that ketamine increased Kd without altering Bmax, indicating a competitive inhibition. In transfected Xenopus oocytes expressing the bNAT, ketamine attenuated [3H]NA uptake with a kinetic characteristic similar to that of cultured adrenal medullary cells. These findings are compatible with the idea that ketamine non-competitively inhibits the transport of NA by interacting with a site which partly overlaps the desipramine binding site on the NAT.
Hara
K
K
Department of Anaesthesiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Fukuoka, Japan.
Yanagihara
N
N
Minami
K
K
Ueno
S
S
Toyohira
Y
Y
Sata
T
T
Kawamura
M
M
Brüss
M
M
Bönisch
H
H
Shigematsu
A
A
Izumi
F
F
D000313:Adrenal Medulla / Q000187:drug effects* / Q000378:metabolism; D018759:Adrenergic Uptake Inhibitors / Q000378:metabolism*; D000700:Analgesics / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology; D003891:Desipramine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004837:Epinephrine / Q000302:isolation & purification; D006213:Hallucinogens / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D009638:Norepinephrine / Q000302:isolation & purification / Q000378:metabolism*; D010622:Phencyclidine / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000700:Analgesics; D000779:Anesthetics, Local; D006213:Hallucinogens; D007649:Ketamine; D003042:Cocaine; D010622:Phencyclidine; D003891:Desipramine; D009638:Norepinephrine; D004837:Epinephrine