Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1971 Apr;50(4):859–865. doi: 10.1172/JCI106557

Human norepinephrine metabolism

Its evaluation by administration of tritiated norepinephrine

Stanley E Gitlow 1, Milton Mendlowitz 1, Laura M Bertani 1, Sherwin Wilk 1, Elizabeth K Wilk 1
PMCID: PMC292000  PMID: 5547279

Abstract

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.

Full text

PDF
859

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ANTON A. H., SAYRE D. F. A study of the factors affecting the aluminum oxide-trihydroxyindole procedure for the analysis of catecholamines. J Pharmacol Exp Ther. 1962 Dec;138:360–375. [PubMed] [Google Scholar]
  2. ARMSTRONG M. D., McMILLAN A., SHAW K. N. 3-Methoxy-4-hydroxy-D-mandelic acid, a urinary metabolite of norepinephrine. Biochim Biophys Acta. 1957 Aug;25(2):422–423. doi: 10.1016/0006-3002(57)90491-2. [DOI] [PubMed] [Google Scholar]
  3. AXELROD J. Metabolism of epinephrine and other sympathomimetic amines. Physiol Rev. 1959 Oct;39:751–776. doi: 10.1152/physrev.1959.39.4.751. [DOI] [PubMed] [Google Scholar]
  4. AXELROD J., WEIL-MALHERBE H., TOMCHICK R. The physiological disposition of H3-epinephrine and its metabolite metanephrine. J Pharmacol Exp Ther. 1959 Dec;127:251–256. [PubMed] [Google Scholar]
  5. BOZZI R., BRUNO A., ALLEGRANZA A. URINARY METABOLITES OF SOME MONOAMINES AND CLINICAL EFFECTS UNDER RESERPINE AND CHLORPROMAZINE. Br J Psychiatry. 1965 Feb;111:176–182. doi: 10.1192/bjp.111.471.176. [DOI] [PubMed] [Google Scholar]
  6. Chidsey C. A., Braunwald E. Sympathetic activity and neurotransmitter depletion in congestive heart failure. Pharmacol Rev. 1966 Mar;18(1):685–700. [PubMed] [Google Scholar]
  7. Costa E., Boullin D. J., Hammer W., Vogel W., Brodie B. B. Interactions of drugs with adrenergic neurons. Pharmacol Rev. 1966 Mar;18(1):577–597. [PubMed] [Google Scholar]
  8. DeQuattro V., Sjoerdsma A. Catecholamine turnover in normotensive and hypertensive man: effects of antiadrenergic drugs. J Clin Invest. 1968 Oct;47(10):2359–2373. doi: 10.1172/JCI105920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. GITLOW S. E., MENDLOWITZ M., KHASSIS S., COHEN G., SHA J. The diagnosis of pheochromocytoma by determination of urinary 3-methoxy-4-hydroxymandelic acid. J Clin Invest. 1960 Jan;39:221–226. doi: 10.1172/JCI104022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. GITLOW S. E., MENDLOWITZ M., WILK E. K., WILK S., WOLF R. L., NAFTCHI N. E. PLASMA CLEARANCE OF DL-BETA-H3-NOREPINEPHRINE IN NORMAL HUMAN SUBJECTS AND PATIENTS WITH ESSENTIAL HYPERTENSION. J Clin Invest. 1964 Oct;43:2009–2015. doi: 10.1172/JCI105075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. GOODALL M., KIRSHNER N., ROSEN L. Metabolism of noradrenaline in the human. J Clin Invest. 1959 Apr;38(4):707–714. doi: 10.1172/JCI103850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gitlow S. E., Mendlowitz M., Wilk E. K., Wilk S., Wolf R. L., Bertani L. M. Excretion of catecholamine catabolites by normal children. J Lab Clin Med. 1968 Oct;72(4):612–620. [PubMed] [Google Scholar]
  13. Goodall M., Alton H. Metabolism of 3-hydroxytyramine (dopamine) in human subjects. Biochem Pharmacol. 1968 Jun;17(6):905–914. doi: 10.1016/0006-2952(68)90350-x. [DOI] [PubMed] [Google Scholar]
  14. Gordon R., Spector S., Sjoerdsma A., Udenfriend S. Increased synthesis of norepinephrine and epinephrine in the intact rat during exercise and exposure to cold. J Pharmacol Exp Ther. 1966 Sep;153(3):440–447. [PubMed] [Google Scholar]
  15. HERTTING G., POTTER L. T., AXELROD J. Effect of decentralization and ganglionic blocking agents on the spontaneous release of H3-norepinephrine. J Pharmacol Exp Ther. 1962 Jun;136:289–292. [PubMed] [Google Scholar]
  16. KOPIN I. J., GORDON E. K. Metabolism of administered and drug-released norepinephrine-7-H3 in the rat. J Pharmacol Exp Ther. 1963 May;140:207–216. [PubMed] [Google Scholar]
  17. KOPIN I. J., GORDON E. K. Metabolism of norepinephrine-H3 released by tyramine and reserpine. J Pharmacol Exp Ther. 1962 Dec;138:351–359. [PubMed] [Google Scholar]
  18. Kopin I. J., Breese G. R., Krauss K. R., Weise V. K. Selective release of newly synthesized norepinephrine from the cat spleen during sympathetic nerve stimulation. J Pharmacol Exp Ther. 1968 Jun;161(2):271–278. [PubMed] [Google Scholar]
  19. Maas J. W., Landis D. H. In vivo studies of the metabolism of norepinephrine in the central nervous system. J Pharmacol Exp Ther. 1968 Sep;163(1):147–162. [PubMed] [Google Scholar]
  20. Neff N. H., Tozer T. N., Hammer W., Costa E., Brodie B. B. Application of steady-state kinetics to the uptake and decline of H3-NE in the rat heart. J Pharmacol Exp Ther. 1968 Mar;160(1):48–52. [PubMed] [Google Scholar]
  21. PISANO J. J. A simple analysis for normetanephrine and metanephrine in urine. Clin Chim Acta. 1960 May;5:406–414. doi: 10.1016/0009-8981(60)90146-7. [DOI] [PubMed] [Google Scholar]
  22. POTTER L. T., AXELROD J., KOPIN I. J. Differential binding and release of norepinephrine and tachyphylaxis. Biochem Pharmacol. 1962 Mar;11:254–256. doi: 10.1016/0006-2952(62)90082-5. [DOI] [PubMed] [Google Scholar]
  23. Persson T., Waldeck B. A source of error in catecholamine turnover studies with labelled DOPA: slow disappearance of the precursor. Acta Pharmacol Toxicol (Copenh) 1970;28(6):466–476. doi: 10.1111/j.1600-0773.1970.tb00572.x. [DOI] [PubMed] [Google Scholar]
  24. Persson T., Waldeck B. The use of 3H-dopa for studying cerebral catecholamine metabolism. Acta Pharmacol Toxicol (Copenh) 1968;26(4):363–372. doi: 10.1111/j.1600-0773.1968.tb00455.x. [DOI] [PubMed] [Google Scholar]
  25. SPECTOR S., SHORE P. A., BRODIE B. B. Biochemical and pharmacological effects of the monoamine oxidase inhibitors, iproniazid, 1-phenyl-2-hydrazinopropane (JB 516) and 1-phenyl-3-hydrazinobutane (JB 835). J Pharmacol Exp Ther. 1960 Jan;128:15–21. [PubMed] [Google Scholar]
  26. TANIGUCHI K., KAKIMOTO Y., ARMSTRONG M. D. QUANTITATIVE DETERMINATION OF METANEPHRINE AND NORMETANEPHRINE IN URINE. J Lab Clin Med. 1964 Sep;64:469–484. [PubMed] [Google Scholar]
  27. UDENFRIEND S., ZALTZMAN-NIRENBERG P. NOREPINEPHRINE AND 3,4DIHYDROXYPHENETHYLAMINE TURNOVER IN GUINEA PIG BRAIN IN VIVO. Science. 1963 Oct 18;142(3590):394–396. doi: 10.1126/science.142.3590.394. [DOI] [PubMed] [Google Scholar]
  28. WHITBY L. G., AXELROD J., WEIL-MALHERBE H. The fate of H3-norepinephrine in animals. J Pharmacol Exp Ther. 1961 May;132:193–201. [PubMed] [Google Scholar]
  29. WOLFE D. E., POTTER L. T., RICHARDSON K. C., AXELROD J. Localizing tritiated norepinephrine in sympathetic axons by electron microscopic autoradiography. Science. 1962 Oct 19;138(3538):440–442. doi: 10.1126/science.138.3538.440. [DOI] [PubMed] [Google Scholar]
  30. WURTMAN R. J., KOPIN I. J., AXELROD J. Thyroid function and the cardiac disposition of catecholamines. Endocrinology. 1963 Jul;73:63–74. doi: 10.1210/endo-73-1-63. [DOI] [PubMed] [Google Scholar]
  31. Wilk E. K., Gitlow S. E., Bertani L. M. Modification of the Taniguchi method for the determination of normetanephrine and metanephrine. Clin Chim Acta. 1968 Apr;20(1):147–148. doi: 10.1016/0009-8981(68)90397-5. [DOI] [PubMed] [Google Scholar]
  32. Wilk S., Gitlow S. E., Clarke D. D., Paley D. H. Determination of urinary 3-methoxy-4-hydroxyphenyl-ethylene glycol by gas-liquid chromatography and electron capture detection. Clin Chim Acta. 1967 Jun;16(3):403–408. doi: 10.1016/0009-8981(67)90306-3. [DOI] [PubMed] [Google Scholar]
  33. Wilk S., Gitlow S. E., Mendlowitz M., Franklin M. J., Carr H. E., Clarke D. D. A quantitative assay for vanillylmandelic acid (VMA) by gas-liquid chromatography. Anal Biochem. 1965 Dec;13(3):544–551. doi: 10.1016/0003-2697(65)90349-0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES