This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kawaguchi, Y. Articles by Hirota, K. Search for Related Content PubMed Articles by Kawaguchi, Y. Articles by Hirota, K. Related Collections Mechanisms Preclinical Pharmacology Pharmacology

---

ANESTHETIC PHARMACOLOGY

The Effects of Benzodiazepines on Urotensin II-Stimulated Norepinephrine Release from Rat Cerebrocortical Slices

Yoko Kawaguchi, MD^*, Tomoko Ono, MD^*, Mihoko Kudo, PhD^*, Tetsuya Kushikata, MD^*, Eiji Hashiba, MD^*, Hitoshi Yoshida, MD^*, Tsuyoshi Kudo, PhD^*, Kenichi Furukawa, PhD, Stephen A. Douglas, PhD, and Kazuyoshi Hirota, MD, FRCA^*

From the Departments of *Anesthesiology and Pharmacology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; and Cardiovascular and Urogenital Centre of Excellence for Drug Discovery GlaxoSmithKline, King of Prussia, Pennsylvania.

Address correspondence and reprint requests to Kazuyoshi Hirota, MD, FRCA, Department of Anesthesiology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan. Address e-mail to hirotak{at}cc.hirosaki-u.ac.jp.

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 Ca²⁺ concentrations ([Ca²⁺]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 [Ca²⁺]i. The IC₅₀ of midazolam for inhibition of UII-evoked norepinephrine release (0.32 µM, P < 0.01) was significantly lower than that of diazepam (187 µM) or flunitrazepam (40 µM). The inhibitory effects of midazolam on UII-evoked norepinephrine release were significantly attenuated by flumazenil, a benzodiazepine site antagonist.

CONCLUSION: 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.