Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 354, Issue 3, pp 287–294 | Cite as

Disprocynium24, a novel inhibitor of the extraneuronal monoamine transporter, has potent effects on the inactivation of circulating noradrenaline and adrenaline in conscious rat

  • Graeme Eisenhofer
  • Richard McCarty
  • Karel Pacak
  • Hermann Russ
  • Edgar Schömig
  • G. Eisenhofer
Original Articles
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Accepted:

Abstract

The role of extraneuronal uptake in terminating the actions of catecholamines has been difficult to evaluate in vivo, largely because of lack of suitable inhibitors. The compound, 1,1′-diisopropyl-2,4′-cyanine iodide or disprocynium24 (D24), is a novel inhibitor of extraneuronal uptake with a high degree of potency in vitro. This study examined the actions of D24 on the inactivation and metabolism of circulating noradrenaline and adrenaline in conscious rats.

Animals received i.v. infusions of 3H-labelled noradrenaline and adrenaline, and their extraneuronal O-methylated metabolites, normetanephrine and meta nephrine. Plasma concentrations of endogeneous and 3H-labelled catecholamines and metanephrines were measured before and after D24. D24 caused large increases in plasma concentrations of noradrenaline and adrenaline, effects due to both decreases in their plasma clearances and increases in their rates of release into plasma. Plasma concentrations of normetanephrine and metanephrine also increased due to their decreased clearance from plasma. Increased release of normetanephrine into plasma did not contribute to increased plasma concentrations of normetanephrine. In fact, the contribution of extraneuronal O-methylation to noradrenaline clearance decreased substantially after D24.

The data indicate that D24 is a potent inhibitor of the extraneuronal catecholamine transporter in vivo and that this process contributes importantly to the removal of circulating catecholamines and their O-methylated amine metabolites. Increased release of noradrenaline into plasma may reflect an increase in the proportion of transmitter that escapes from sites of release into the circulation. However, increased adrenaline release indicates that the drug also causes sympathoadrenal activation.

Key words

Noradrenaline kinetics Adrenaline kinetics Normetanephrine kinetics Metanephrine kinetics Extraneuronal transporter Monoamine uptake Catechol-O-methyltransferase 
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References

  1. Axelrod J (1971) The fate of noradrenaline in the sympathetic neurone. The Harvey Lectures 67:175–197Google Scholar
  2. Chang PC, van Der Krogt JA, Van Brummelen P (1987) Demonstration of neuronal and extraneuronal uptake of circulating norepinephrine in the forearm. Hypertension 9:647–653Google Scholar
  3. Eisenhofer G, Finberg JPM (1994) Different metabolism of norepinephrine and epinephrine by catechol-O-methyltransferase and monoamine oxidase in rats. J Pharmacol Exp Ther 268:1242–1251Google Scholar
  4. Eisenhofer G, Goldstein, DS, Stull R, Keiser HR, Sunderland T, Murphy DL, Kopin IJ (1986) Simultaneous liquid-chromatographic determination of 3,4-dihydroxyphenylglycol, catecholamines, and 3,4-dihydroxyphenylalanine in plasma, and their responses to inhibition of monoamine oxidase. Clin Chem 32:2030–2033Google Scholar
  5. Eisenhofer G, Goldstein DS, Kopin IJ (1989) Plasma dihydroxyphenylglycol for estimation of noradrenaline neuronal reuptake in the sympathetic nervous system in vivo. Clin Sci 76:171–181Google Scholar
  6. Eisenhofer G, Friberg P, Pacak K, Golstein DS, Tsigos C, Quyyumi AA, Brunner HG, Lenders JWM (1995) Plasma metadrenalines: do they provide useful information about sympatho-adrenal function and catecholamine metabolism. Clin Sci 88:533–542Google Scholar
  7. Esler M, Jackman G, Bobik A, Kelleher D, Jennings G, Leonard P, Skews H, Korner P (1979) Determination of norepinephrine apparent release rate and clearance in humans. Life Sci 25: 1461–1470Google Scholar
  8. Esler M, Jackman G, Leonard P, Skews H, Bobik A, Jennings G (1981a) The effect of propanolol on noradrenaline kinetics in patients with essential hypertension. Br J Clin Pharmacol 12:375–380Google Scholar
  9. Esler M, Jackman G, Leonard P, Skews H, Bobik A, Korner P (1981b) Effect of norepinephrine uptake blockers on norepinephrine kinetics. Clin Phamacol Ther 29:12–20Google Scholar
  10. Fiebig ER, Trendelenburg U (1978) The neuronal and extraneuronal uptake and metabolism of 3H-(−)-noradrenaline in the perfused rat heart. Naunyn-Schmiedeberg's Arch Pharmacol 303: 21–35Google Scholar
  11. Friedgen B, Wölfel R, Russ H, Schömig E, Graefe K-H (1996) The role of extraneuronal membrane transport systems for the removal of extracellular catecholamines in the rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 354:275–286Google Scholar
  12. Goldstein DS, Eisenhofer G, Stull R, Folio CJ, Keiser HR, Kopin IJ (1988) Plasma dihydroxyphenylglycol and the intraneuronal dispostiion of norepinephrine in humans. J Clin Invest 81:213–220Google Scholar
  13. Graefe K-H, Henseling M (1983) Neuronal and extraneuronal uptake and metabolism of catecholamines. Gen Pharmacol 14:27–33Google Scholar
  14. Gründemann D, Gorboulev V, Gambaryan S, Veyhl M, Koepsell H (1994) Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372:549–552Google Scholar
  15. Gryglewski R, Vane JR (1970) The inactivation of noradrenaline and isoprenaline in dogs. Br J Pharmacol 39:573–584Google Scholar
  16. Halbrügge T, Friedgen B, Ludwig J, Graefe K-H (1993) Effects of catechol-O-methyltransferase inhibition on the plasma clearance of noradrenaline and the formation of 3,4-dihydroxyphenylglycol in the rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 347:162–170Google Scholar
  17. Iversen LL (1965) The uptake of catecholamines at high perfusion concentrations in the rat isolated heart: a novel catecholamine uptake process. Br J Pharmacol 25:18–33Google Scholar
  18. Lappe RW, Henry DP, Willis LR (1980) Mechanism of renal tubular secretion of norepinephrine in the rabbit. J Pharmacol Exp Ther 215:443–449Google Scholar
  19. Lenders JWM, Eisenhofer G, Armando I, Keiser HR, Goldstein DS, Kopin IJ (1993) Determination of plasma metanephrines by liquid chromatography with electrochemical detection. Clin Chem 39:97–103Google Scholar
  20. Luchelli-Fortis MA, Langer SZ (1975) Selective inhibition by hydrocortisone of 3H-normetanephrine formation during 3H-transmitter release elicited by nerve stimulation in the isolated nerve-muscle preparation of the cat nictitating membrane. Naunyn-Schmiedeberg's Arch Pharmacol 287:261–275Google Scholar
  21. Marino V, de la Lande IS, Newlyn M, Parker DAS (1993) Evidence for uptake 2-mediated O-methylation of noradrenaline in the human amnion FL cell-line. Naunyn-Schmiedeberg's Arch Pharmacol 347:371–378Google Scholar
  22. Pacholczyk T, Blakely RD, Amara SG (1991) Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature 350:350–354Google Scholar
  23. Russ H, Engel W, Schömig E (1993a) Isocyanines and pseudoisocyanines as a novel class of potent noradrenaline transport inhibitors: Synthesis, detection, and biological activity. J Med Chem 36:4208–4213Google Scholar
  24. Russ H, Sonna J, Keppler K, Baunach S, Schomig E (1993b) Cyanine-related compounds: a novel class of potent inhibitors of extraneuronal noradrenaline transport. Naunyn-Schmiedeberg's Arch Pharmacol 348:458–465Google Scholar
  25. Russ H, Friedgen B, Königs B, Schumacher C, Graefe K-H, Schömig E (1996) Pharmacokinetic and α1-antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport. Naunyn-Schmiedeberg's Arch Pharmacol (in press)Google Scholar
  26. Salt PJ (1972) Inhibition of noradrenaline uptake2 in the isolated rat heart by steroids, clonidine and methoxylated phenylethylamines. Eur J Pharmacol 20:329–340Google Scholar
  27. Schömig E, Schönfeld C-L (1990) Extraneuronal noradrenaline transport (uptake2) in a human cell line (Caki-1 cells). Naunyn-Schmiedeberg's Arch Pharmacol 341:404–410Google Scholar
  28. Schömig E, Babin-Ebell J, Russ H (1993) 1,1′-diethy- 2,2′-cyanine (decynium22) potently inhibits the renal transport of organic cations. Naunyn-Schmiedeberg's Arch Pharmacol 347:379–383Google Scholar
  29. Trendelenburg U (1988) The extraneuronal uptake and metabolism of catecholamines. In: Trendelenburg U, Weiner N (eds) Catecholamines I. Handbook of experimental pharmacology, vol 90. Springer, Berlin Heidelberg New York Tokyo, pp 279–319Google Scholar
  30. Wallenstein S, Zucker CL, Fleiss JL (1980) Some statistical methods useful in circulation research. Circ Res 47:1–9Google Scholar
  31. Zimlichman R, Goldstein DS, Eisenhofer G, Stull R, Keiser HR (1986) Comparison of noradrenaline and isoprenaline removal in the canine hindlimb and kidney. Clin Exp Pharmacol Physiol 13:777–781Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Graeme Eisenhofer
    • 1
  • Richard McCarty
    • 2
  • Karel Pacak
    • 1
  • Hermann Russ
    • 3
  • Edgar Schömig
    • 4
  • G. Eisenhofer
    • 5
  1. 1.Clinical Neuroscience Branch, National Institute of Neurological Disorders and StrokeNational Institutes of HealthBethesdaUSA
  2. 2.Department of PsychologyUniversity of Virginia, 102 Gilmer Hall, University of VirginiaCharlottesville VirginiaUSA
  3. 3.Neurologische and Psyckiatrische UniversitätsklinikeRegensburgGermany
  4. 4.Institut fur PharmakologieHeidelbergGermany
  5. 5.Building 10, Room 4D18, National Institutes of HealthBethesdaUSA

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