Human norepinephrine metabolism: Its evaluation by administration of tritiated norepinephrine

It has become increasingly apparent that evaluation of human norepinephrine metabolism simply by assay of catecholamines in urine is inadequate for differentiation of many physiological or pathological states. In an attempt to examine norepinepherine metabolism in the human subject, tritium-labeled d,l-norepinephrine was administered to 11 normal adults and the definitive turnover rates and relative specific activities of norepinephrine and its major catabolites, vanillylmandelic acid, 3-methoxy-4-hydroxyphenylethyleneglycol, and normetanephrine, as well as the cumulative 24 hr isotope excretion were determined. The major endogenous norepinephrine catabolites were also quantitatively assayed. In order to verify the reliability of the isotope label, parallel studies were carried out in two patients to whom norepinephrine-14C was administered. Metabolic studies were repeated after the administration of reserpine to gain further insight into the distribution of the label. All studies demonstrated a consistent difference between the relative specific activities of the amines and their deaminated congeners, thereby indicating an uneven distribution of the labeled material. The marked decrease in the relative specific activities of the deaminated catabolites after the administration of reserpine showed that the present experimental technique succeeded in labeling, though to a limited extent, the storage or reserpine-releasable pool. A dose of reserpine known to interfere with sympathetic activity but failing to elicit a change in excretion of endogenous catecholamine catabolites, nonetheless resulted in a marked abnormality in the metabolic handling of labeled norepinephrine. It is anticipated that such studies may not only be of value in measuring sympathetic activity in the intact human subject during physiologic variations and pathologic states associated with abnormalities in catecholamine metabolism, but may serve as a technique whereby drugs that affect human norepinephrine metabolism may undergo precise pharmacologic evaluation.