Plasma normetanephrine for examination of extraneuronal uptake and metabolism of noradrenaline in rats.
The importance of neuronal reuptake for terminating the actions of noradrenaline is well established, but the role of extraneuronal uptake is less clear. This study used plasma concentrations of the extraneuronal noradrenaline metabolite, normetanephrine, to estimate rates of extraneuronal removal of noradrenaline in rats. Animals received infusions of 3H-noradrenaline, with and without inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), to examine the extraneuronal removal of noradrenaline and formation of normetanephrine from infused and endogenous noradrenaline. Infusions of 3H-normetanephrine were also carried out to examine the plasma kinetics of normetanephrine before and after inhibition of MAO. Normetanephrine was cleared rapidly from the circulation and had a short plasma halflife (1 min). Spillover of normetanephrine into plasma (79 pmol kg-1 min-1) was a third that of noradrenaline, but increased 2.8-fold after inhibition of MAO; noradrenaline spillover remained unchanged. Combined inhibition of MAO and COMT decreased the plasma clearance of 3H-noradrenaline by 38%, reflecting removal of 3H-noradrenaline by extraneuronal uptake. Division of the rate of extraneuronal removal of 3H-noradrenaline by the specific activity of plasma 3H-normetanephrine during the 3H-noradrenaline infusion indicated that the rate of extraneuronal removal of endogenous noradrenaline was 250 pmol kg-1 min-1; this was close to the spillover of normetanephrine into plasma after inhibition of MAO (219 pmol kg-1 min-1). Forty-five% of plasma normetanephrine was derived from circulating noradrenaline and 55% from noradrenaline before entry into the circulation. Assuming that these proportions reflected the sources of noradrenaline metabolized extraneuronally indicated that the rate of extraneuronal metabolism of noradrenaline before entry into the circulation was 138 pmol kg-1 min-1. Comparison of this with the rates at which noradrenaline was recaptured by sympathetic nerves (2540 pmol kg-1 min-1) or spilled over into plasma (228 pmol kg-1 min-1), indicated that 87% of the noradrenaline released by sympathetic nerves was recaptured, 5% was metabolized extraneuronally and 8% escaped into plasma. Thus, extraneuronal uptake removes much less of the noradrenaline released by sympathetic nerves than neuronal reuptake.
Eisenhofer
G
G
Clinical Neuroscience Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20892.
D000818:Animals; D065098:Catechol O-Methyltransferase Inhibitors; D007262:Infusions, Intravenous; D008297:Male; D008962:Models, Theoretical; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009638:Norepinephrine / Q000008:administration & dosage / Q000378:metabolism*; D009647:Normetanephrine / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium
D065098:Catechol O-Methyltransferase Inhibitors; D008996:Monoamine Oxidase Inhibitors; D009647:Normetanephrine; D014316:Tritium; D009638:Norepinephrine