Effects of aldehyde/aldose reductase inhibition on neuronal metabolism of norepinephrine.
After norepinephrine (NE) is deaminated by monoamine oxidase (MAO), the aldehyde formed is either metabolized to 3,4-dihydroxy-mandelic acid (DHMA) by aldehyde dehydrogenase or is converted to 3,4-dihydroxyphenylglycol (DHPG) by aldehyde or aldose reductase. The present study examined the effects of inhibition of aldehyde and aldose reductase on production of DHPG and DHMA in rats. Mean (+/- S.E.) baseline plasma concentrations of DHPG (4.73 +/- 0.21 pmol/ml) were 60-fold higher than those of DHMA (0.08 +/- 0.01 pmol/ml). Inhibition of aldose and aldehyde reductase reduced plasma DHPG concentrations to 1.88 +/- 0.14 pmol/ml and increased plasma DHMA to 4.43 +/- 0.29 pmol/ml; additional inhibition of MAO reduced plasma DHPG to 0.16 +/- 0.06 pmol/ml and DHMA to 0.19 +/- 0.02 pmol/ml. Inhibition of aldehyde and aldose reductase also increased brain tissue levels of DHMA from 8 +/- 2 to 384 +/- 47 pmol/g and decreased levels of DHPG from 70 +/- 9 to 44 +/- 5 pmol/g. The results show that DHMA is normally a minor metabolite of NE, but becomes a major metabolite after aldehyde/aldose reductase inhibition.
Kawamura
M
M
Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Kopin
I J
IJ
Kador
P F
PF
Sato
S
S
Tjurmina
O
O
Eisenhofer
G
G
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D008333:Mandelic Acids / Q000097:blood / Q000378:metabolism; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002395:Catecholamines; D004791:Enzyme Inhibitors; D008333:Mandelic Acids; D008734:Methoxyhydroxyphenylglycol; C000989:3,4-dihydroxymandelic acid; D000449:Aldehyde Reductase; C010117:3,4-dihydroxyphenylglycol; D009638:Norepinephrine