The effects of benzodiazepines on urotensin II-stimulated norepinephrine release from rat cerebrocortical slices.
BACKGROUND
Urotensin II (UII) and its receptor (UT) are implicated in mood disorders, such as stress and anxiety, and this may result, at least in part, from increased norepinephrine release from the cerebral cortex. Benzodiazepines have been widely used as hypnotics and anxiolytics, producing a decrease in cerebrocortical norepinephrine release. We hypothesized that there was some interaction between benzodiazepines and the UII system in the cerebral cortex.


METHODS
In the present study, we have examined the effects of benzodiazepines on UII-increased norepinephrine release from rat cerebrocortical slices and intracellular Ca(2+) concentrations ([Ca(2+)]i) in HEK293 cells expressing rat UT receptor (HEK293-rUT cells).


RESULTS
Midazolam, diazepam and flunitrazepam concentration-dependently inhibited UII-evoked norepinephrine release but did not affect [Ca(2+)]i. The IC(50) of midazolam for inhibition of UII-evoked norepinephrine release (0.32 microM, P < 0.01) was significantly lower than that of diazepam (187 microM) or flunitrazepam (40 microM). The inhibitory effects of midazolam on UII-evoked norepinephrine release were significantly attenuated by flumazenil, a benzodiazepine site antagonist.


CONCLUSIONS
The present study suggests that midazolam, at clinically relevant concentration, significantly inhibited UII-evoked norepinephrine release. This inhibitory effect may be partially mediated via central benzodiazepine receptors.
Kawaguchi
Yoko
Y
Department of Anesthesiology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
Ono
Tomoko
T
Kudo
Mihoko
M
Kushikata
Tetsuya
T
Hashiba
Eiji
E
Yoshida
Hitoshi
H
Kudo
Tsuyoshi
T
Furukawa
Kenichi
K
Douglas
Stephen A
SA
Hirota
Kazuyoshi
K
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001583:Benzoxazoles / Q000494:pharmacology; D020013:Calcium Signaling; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D005445:Flunitrazepam / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D009287:Naphthyridines; D009638:Norepinephrine / Q000378:metabolism*; D064446:Orexin Receptors; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D014579:Urotensins / Q000378:metabolism*
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives; D009287:Naphthyridines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A; D018013:Receptors, Neuropeptide; D014579:Urotensins; C473142:Uts2r protein, rat; D001569:Benzodiazepines; D005442:Flumazenil; D005445:Flunitrazepam; D014508:Urea; C029677:urotensin II; D003975:Diazepam; D008874:Midazolam; D009638:Norepinephrine