PT - JOURNAL ARTICLE AU - J. Richard Crout AU - Cyrus R. Creveling AU - Sidney Udenfriend TI - NOREPINEPHRINE METABOLISM IN RAT BRAIN AND HEART DP - 1961 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 269--277 VI - 132 IP - 3 4099 - http://jpet.aspetjournals.org/content/132/3/269.short 4100 - http://jpet.aspetjournals.org/content/132/3/269.full SO - J Pharmacol Exp Ther1961 Jun 01; 132 AB - Previous studies by others have shown that norepinephrine is metabolized largely by two alternate enzymes: catechol-O-methyl transferase and monoamine oxidase. The present study was undertaken to evaluate which of these enzymes is of greater significance in the metabolism of norepinephrine in the brain and heart of the rat. Monoamine oxidase activity, measured in vitro, was found to be 3.6 and 5 times greater than catechol-O-methyl transferase activity in the brain and heart, respectively. However, in rat liver catechol-O-methyl transferase activity was 15 times greater than monoamine oxidase activity. A significant increase in the catecholamine content of rat brain and heart was produced by the intraperitoneal admimstration of four different monoamine oxidase inhibitors. The intraperitoneal injection of pyrogallol, an inhibitor of catechol-O-methyl transferase, failed to increase the catecholamine content of the brain or heart, even after 18 hours of enzyme inhibition. Norepinephrine was injected intravenously into rats, and the rate of disappearance of the amine from the plasma and heart was determined. In animals pretreated with iproniazid the major finding Was a marked accumulation of amine in the myocardium, relative to the concentration present in plasma; clearance of norepinephrine from the plasma was only moderately prolonged. Rats pretreated with pyrogallol, on the other hand, demonstrated a severe impairment in their ability to metabolize circulating norepinephrine. These experiments show that endogenous norepinephrine accumulates in the brain and heart of the rat when monoamine oxidase is inhibited; exogenous norepinephrine accumulates in the heart under the same conditions. Neither of these effects is produced by a catechol-O-methyl transferase inhibitor. The results suggest that oxidative deamination is the more significant pathway in the metabolism of norepinephrine in the brain and heart of the rat. This conclusion is quite compatible with the observation that O-methylation is the major pathway for circulating norepinephrine if one assumes that the liver participates in the metabolism of circulating amine. The liver is by far the richest source of COMT in the rat, and O-methylating activity in this organ greatly exceeds that of monoamine oxidase. Previous work by others, cited in the discussion, suggests that these findings may not necessarily apply to other species. The relative significance of these two metabolic pathways probably varies considerably from organ to organ and from species to species.