Cerebral glucose metabolic and plasma catecholamine responses to the alpha(2) adrenoceptor antagonist ethoxyidazoxan given to healthy volunteers.
BACKGROUND
Methods that test for the central effects of alpha(2)-adrenoceptor antagonists can facilitate the clinical development of such compounds. Recently we evaluated the effects of idazoxan (IDX), an alpha(2)-adrenoceptor antagonist with high affinity for imidazoline sites, on a variety of measures potentially sensitive to blockade of alpha(2)-adrenoceptors including regional brain glucose metabolic rate.


OBJECTIVE
To test whether these effects on brain metabolic rate could have been mediated by imidazoline binding sites, single dose challenges of 9 or 12 mcg/kg ethoxyidazoxan (ETX; an alpha(2)-adrenoceptor antagonist which does not bind to imidazoline sites) were given to healthy male volunteers.


METHODS
The effects on brain glucose metabolism, blood pressure, catecholamines, and behavior were assessed.


RESULTS
Blood pressure increased 10-15% after both doses. Plasma catecholamines increased 2- to 2.5-fold and responses were dose dependent. There was no evidence of either dose being anxiogenic. Both doses of ETX produced diffuse increases in brain glucose metabolism.


CONCLUSIONS
Brain glucose metabolic responses were more widespread and monotonic than we had observed with IDX. ETX also produced robust increases in glucose metabolism in cerebellum. While we were unable to exclude the possibility that some of the brain metabolic responses we had observed with IDX were mediated by imidazoline sites, ETX may be sufficiently distinct from IDX in alpha(2)-adrenoceptor affinity that differences in acute metabolic responses occurred.
Schmidt
M E
ME
Section on Clinical Pharmacology, National Institute of Mental Health, Bethesda, MD 20892, USA. mschmidt@lilly.com
Oshinsky
R J
RJ
Kim
H G
HG
Schouten
J L
JL
Folley
B S
BS
Potter
W Z
WZ
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002395:Catecholamines / Q000097:blood*; D004837:Epinephrine / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D019329:Idazoxan / Q000031:analogs & derivatives* / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D054755:Imidazoline Receptors; D007700:Kinetics; D008297:Male; D009638:Norepinephrine / Q000097:blood; D011955:Receptors, Drug / Q000187:drug effects
D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D054755:Imidazoline Receptors; D011955:Receptors, Drug; C065483:ethoxyidazoxan; D005947:Glucose; D009638:Norepinephrine; D019329:Idazoxan; D004837:Epinephrine