Effects of catechol-O-methyltransferase inhibition on the plasma clearance of noradrenaline and the formation of 3,4-dihydroxyphenylglycol in the rabbit.
The purpose of this study was to elucidate the finding of Friedgen et al. (1993 b) that catechol-O-methyltransferase (COMT) inhibition is much more effective in increasing the plasma concentration of endogenous dihydroxyphenylglycol (DOPEG) than in increasing the plasma concentration of infused DOPEG. To this end, reserpine-pretreated rabbits were anaesthetized and infused with noradrenaline and/or DOPEG, and the plasma clearances of infused noradrenaline (ClNA) and DOPEG (ClDOPEG) as well as the plasma DOPEG response to noradrenaline infusion [as reflected by the ratio of the steady-state increase in plasma DOPEG (delta DOPEG) to that in plasma noradrenaline (delta NA)] were determined before and after blockade of neuronal uptake by desipramine. Experiments were carried out either under control conditions or after COMT inhibition by i.v. administration of 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Ro 40-7592). On the assumption that rates of neuronal noradrenaline uptake equal steady-state rates of neuronal DOPEG formation, the desipramine-sensitive components of ClNA and delta DOPEG/delta NA were used to estimate the apparent plasma clearance of DOPEG formed intraneuronally (Clf-DOPEG) in response to noradrenaline infusion. ClNA was 83.6 ml kg-1 min-1 in the absence and 48.1 ml kg-1 min-1 in the presence of desipramine. Neither the former nor the latter value was altered after COMT inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Halbrügge
T
T
Institut für Pharmakologie und Toxikologie, Universität Würzburg, Federal Republic of Germany.
Friedgen
B
B
Ludwig
J
J
Graefe
K H
KH
D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D002394:Catechol O-Methyltransferase / Q000097:blood / Q000502:physiology; D065098:Catechol O-Methyltransferase Inhibitors; D003891:Desipramine / Q000494:pharmacology; D005260:Female; D007262:Infusions, Intravenous; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000097:blood; D009474:Neurons / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009596:Nitrophenols; D009638:Norepinephrine / Q000097:blood*; D011817:Rabbits; D012110:Reserpine / Q000494:pharmacology; D000077867:Tolcapone
D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D009596:Nitrophenols; D008734:Methoxyhydroxyphenylglycol; D012110:Reserpine; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase; D003891:Desipramine; C010117:3,4-dihydroxyphenylglycol; D009638:Norepinephrine