Normetanephrine (NMN) and metanephrine (MN) are produced by the actions of catechol-O-methyltransferase on norepinephrine (NE) and epinephrine (E). Because catechol-O-methyltransferase is not present appreciably in neurons, plasma concentrations of NMN and MN provide a marker of extraneuronal catecholamine metabolism. In the present study, plasma NMN and MN were examined in rats before and during immobilization stress or i.v. infusion of NE and E to compare the extraneuronal metabolism of circulating and neuronally released catecholamines. At rest, plasma concentrations of NMN (0.44 +/- 0.03 pmol/ml) were 34% those of NE (1.40 +/- 0.11 pmol/ml) and MN concentrations (0.15 +/- 0.02 pmol/ml) were 33% those of E (0.48 +/- 0.11 pmol/ml). Immobilization and catecholamine infusion both increased plasma NMN and MN in parallel with increases in the precursor amines. Relative to increases in precursor amines, the MN response to infusion of catecholamines was 50% greater than the NMN response. Increases in plasma MN, relative to those in E, were similar during infusion of catecholamines and immobilization stress. In contrast, the NMN response to immobilization, relative to the NE response, was 3-fold larger than the NMN response to catecholamine infusion. Larger MN responses than NMN responses to infusion of catecholamines may reflect preferential extraneuronal uptake or O-methylation of E over NE or more efficient metabolism of NMN than MN. The larger NMN response to release of endogenous stores than to infusion of exogenous amine indicated that 30% of NMN is derived from circulating NE and 70% from NE in transit from sites of release to the circulation.