European Journal of Clinical Pharmacology

, Volume 17, Issue 6, pp 429–435 | Cite as

Effect of infused L-threo-3,4-dihydroxyphenylserine on adrenergic activity in patients with familial amyloid polyneuropathy

  • T. Suzuki
  • S. Higa
  • I. Tsuge
  • S. Sakoda
  • A. Hayashi
  • Y. Yamamura
  • Y. Takaba
  • A. Nakajima


L-threo-3,4-dihydroxyphenylserine (DOPS), an immediate precursor amino acid of (-)-norepinephrine, was used as a pharmacological tool to investigate the pathophysiology of the peripheral sympathetic nervous system in Type 1 familial amyloid polyneuropathy. Patients with the well-established disorder showed an enhanced pressor reponse to L-threo-DOPS under conditions that produced no change in normal subjects. While octopamine induced a brisk pressor response, L-threo-DOPS produced a slow and prolonged change in blood pressure, with a marked concomitant increase in urinary excretion of norepinephrine. A slight increase in urinary excretion of total metanephrine was observed in both groups, but there was no significant increase in serum dopamine-β-hydroxylase activity. Since infusion of dilute norepinephrine into patients also produced a markedly hypersensitive response, the characteristic pressor response to L-threo-DOPS was indicative of denervation supersensitivity of adrenergic receptors to norepinephrine formed enzymatically from L-threo-DOPS.

Key words

L-threo-3,4-dihydroxyphenylserine norepinephrine octopamine dopamine-β-hydroxylase familial amyloid polyneuropathy denervation supersensitivity autonomic dysfunction 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Glenner GG, Ignaczak TF, Page DL (1978) The inherited systemic amyloidosis and localized amyloid deposits. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, (eds) The metabolic basis of inherited disease. 4th ed. McGraw-Hill, New York, pp 1308–1339Google Scholar
  2. 2.
    Suzuki T, Tsuge I, Higa S, Hayashi A, Yamamura Y, Takaba Y, Nakajima A (1979) Catecholamine metabolism in familial amyloid polyneuropathy. Clin. Genet. 16: 117–124Google Scholar
  3. 3.
    Patil PN, Miller DD, Trendelenburg U (1975) Molecular geometry and adrenergic drug activity. Pharmacol Rev 26: 323–392Google Scholar
  4. 4.
    Axelrod J, Saavedra JM (1977) Octopamine. Nature 265: 501–504Google Scholar
  5. 5.
    Araki S, Mawatari S, Ohta M, Nakajima A, Kuroiwa Y (1968) Polyneuritic amyloidosis in a Japanese family. Arch Neurol 18: 593–602Google Scholar
  6. 6.
    Alexander RW, Gill JR, Yamabe H, Lovenberg W, Keiser H (1974) Effects of dietary sodium and of acute saline infusion on the interrelationship between dopamine excretion and adrenergic activity in man. J Clin Invest 54: 194–200Google Scholar
  7. 7.
    Rubenstein AE, Yahr MD, Mytilineou C, Bajaj K (1978) Peripheral catecholamine depletion in amyloid autonomic neuropathy. Mt Sinai J Med 45: 782–789Google Scholar
  8. 8.
    Nagatsu T, Udenfriend S (1972) Photometric assay of dopamine-β-hydroxylase activity in human blood. Clin Chem 18: 980–983Google Scholar
  9. 9.
    Higa S, Suzuki T, Hayashi A, Tsuge I, Yamamura Y (1977) Isolation of catecholamines in biological fluids by boric acid gel. Anal Biochem 77: 18–24Google Scholar
  10. 10.
    Atack CV (1973) The determination of dopamine by modification of the dihydroxyindole fluorimetric assay. Br J. Pharmacol 48: 699–714Google Scholar
  11. 11.
    Anton AH, Sayre DF (1962) A study of the factors affecting the aluminum oxide-trihydroxyindole procedure for the analysis of catecholamines. J Pharmacol Exp Ther 138: 360–375Google Scholar
  12. 12.
    Pisano JJ (1960) A simple analysis for normetanephrine and metanephrine in urine. Clin Chim Acta 5: 406–414Google Scholar
  13. 13.
    Creveling GR, Daly J, Tokuyama T, Witkop B (1968) The combined use of α-methyltyrosine and threo-dihydroxyphenylserine-selective reduction of dopamine levels in the central nervous system. Biochem Pharmacol 17: 65–70Google Scholar
  14. 14.
    Bartholini G, Constantinidis J, Puig M, Tissot R, Pletcher A (1975) The stereoisomers of 3,4-dihydroxyphenylserine as precursors of norepinephrine. J Pharmacol Exp Ther 193: 523–532Google Scholar
  15. 15.
    Hirai M, Matsuoka Y, Nakajima T, Sano I (1975) Effects of 3,4-dihydroxyphenylserine on the concentration of brain noradrenaline and the level of plasma growth hormon of rats. Med J Osaka Univ 26: 51–59Google Scholar
  16. 16.
    Fujiwara H, Inagaki C, Ikeda Y, Tanaka C (1976) Decarboxylation of stereoisomers of 3,4-dihydroxyphenylserine (DOPS) in vitro. Nippon Yakurigaku Zasshi 72: 891–898Google Scholar
  17. 17.
    Inagaki C, Fujiwara H, Tanaka C (1976) Inhibitory effect of (+)threo-3,4-dihydroxyphenylserine (DOPS) on decarboxylation of (-)threo-DOPS. Jpn J Pharmacol 26: 380–382Google Scholar
  18. 18.
    Gunne LM, Lidvall HF (1966) The urinary output of catecholamines in narcolepsy under resting conditions and following administration of dopamine, dopa and dops. Scand J Clin Lab Invest 18: 425–430Google Scholar
  19. 19.
    Gatlin LA, Gromes GJ, Hiranaka PK, Gallelli JF (1975) Investigational drug information. DL-threo-dihydroxyphenylserine. Drug Intell Clin Pharm 9: 655Google Scholar
  20. 20.
    Andrade C (1975) Hereditary amyloid neuropathy. In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology. Vol 21. North-Holland Amsterdam, pp 119–143Google Scholar
  21. 21.
    Tsukagoshi H, Oguchi K, Shoji S, Yamasaki T, Nakamura H, Beppu H: Autonomic disturbance in familial amyloid polyneuropathy. Autonom Nerv Syst (Jpn) 12: 7–12Google Scholar
  22. 22.
    Burnstock G, Costa M (1975) Adrenergic neurons. Their organization, function and development in the peripheral nervous system. Chapman and Hall, London, pp 125–126Google Scholar
  23. 23.
    Barnett AJ, Wagner GR (1958) Severe orthostatic hypotension: Case report and description of response to sympathomimetic drugs. Am Heart J 56: 412–424Google Scholar
  24. 24.
    Hickler RB, Thomson GR, Fox LM, Hamlin JT (1959) Successful treatment of orthostatic hypotension with 9-alpha-fluorohydrocortisone. N Engl J Med 261: 788–791Google Scholar
  25. 25.
    Engelman K, Mueller PS, Horwitz D, Sjoerdsma A (1964) Denervation hypersensitivity of adipose tissue in idiopathic orthostatic hypotension. Lancet 2: 927–929Google Scholar
  26. 26.
    Chokroverty S, Barron KD, Katz FH, Del Greco F, Sharp JT (1969) The syndrome of primary orthostatic hypotension. Brain 92: 743–768Google Scholar
  27. 27.
    Burns RJ, Downey JA, Frewin DB, Whelan RF (1971) Autonomic dysfunction with orthostatic hypotension. Aust NZ J Med 1: 15–21Google Scholar
  28. 28.
    Kontos HA, Richardson DW, Norvell JE (1975) Norepinephrine depletion in idiopathic orthostatic hypotension. Ann Int Med 82: 336–341Google Scholar
  29. 29.
    Hohl RD, Frame B, Schatz IJ (1965) The Shy-Drager variant of idiopathic orthostatic hypotension. Am J Med 39: 134–141Google Scholar
  30. 30.
    Smith AA, Dancis J (1964) Exaggerated response to infused norepinephrine in familial dysautonomia. N Engl J Med 270: 704–707Google Scholar
  31. 31.
    Young RR, Asbury AK, Corbett JL, Adams RD (1975) Pure pan-dysautonomia with recovery. Brain 98: 613–636Google Scholar
  32. 32.
    Weinshilboum RM, Thoa NB, Johnson DG, Kopin IJ (1971) Proportional release of norepinephrine and dopamine-β-hydroxylase from sympathetic nerves. Science 174: 1349–1351Google Scholar

Copyright information

© Springer-Verlag 1980

Authors and Affiliations

  • T. Suzuki
    • 1
  • S. Higa
    • 1
  • I. Tsuge
    • 1
  • S. Sakoda
    • 1
  • A. Hayashi
    • 1
  • Y. Yamamura
    • 1
  • Y. Takaba
    • 1
  • A. Nakajima
    • 1
  1. 1.Third Department of Internal MedicineOsaka University Hospital, Arao City Hospital, and Nakajima Medical ClinicJapan

Personalised recommendations