Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 321, Issue 3, pp 207–212 | Cite as

Cocaine and neuronal uptake in the canine saphenous vein

  • T. J. Verbeuren
  • P. M. Vanhoutte
Article

Summary

This study was designed to investigate the effects of the neuronal uptake inhibitor, cocaine on the adrenergic neuroeffector interaction in the canine saphenous vein. Tissues were incubated with 3H-noradrenaline in control solution or in presence of the cocaine. The tissue content of 3H-noradrenaline and its metabolites was determined after the incubation. As the concentration of cocaine in the incubation medium increased gradually less 3H-noradrenaline and DOPEG were detected in the tissue, while the content of DOMA, NMN, MOPEG and, in particular that of VMA increased; comparable results were obtained with high concentrations of cocaine and desmethylimipramine (DMI). Helical strips of canine saphenous veins were incubated with 3H-noradrenaline and mounted for isometric tension recording and for measurement of the efflux of labelled transmitter and its metabolites. Cocaine, but not DMI, slightly increased the spontaneous efflux of DOPEG, suggesting that cocaine enters the nerve terminals and displaces noradrenaline from its storage sites. During electrical stimulation, cocaine at 3×10−5 mol/l increased the contractile response and the overflow of 3H-noradrenaline, DOMA, NMN and MOPEG and decreased the appearance of DOPEG. Similar results were obtained with DMI (10−6 mol/l) except that it did not increase the overflow of DOMA and MOPEG. During electrical stimulation in presence of DMI, cocaine did not affect the contractile response and decreased the appearance of intact labelled transmitter. Electrical stimulation, cocaine and DMI did not affect the overflow of VMA. The present experiments indicate that in the canine saphenous vein: (1) DOPEG is formed intraneuronally, but DOMA, MOPEG, NMN and VMA extraneuronally; (2) VMA is retained in the tissue much longer than the other metabolites; (3) determination of total 3H-content after incubation with 3H-noradrenaline in presence of inhibitors of neuronal uptake underestimates the degree of inhibition of the neuronal amine carrier; and (4) the quantification of the effect of cocaine on the neuronal uptake of released transmitter is complicated by several other actions of the drug (local anesthetic properties, displacement of stored transmitter, activation of effector cells) and that of the effect of DMI by its inhibitory effect on monoamine oxidase, in particular at extraneuronal sites.

Key words

Noradrenaline Desmethylimipramine Saphenous vein Cocaine Electrical stimulation 

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References

  1. Brandão F (1977) Inactivation of norepinephrine in an isolated vein. J Pharmacol Exp Ther 203:23–29Google Scholar
  2. Brandão F, Paiva MQ, Guimaraes S (1980) The role of neuronal and extraneuronal systems in the metabolism, of adrenaline and noradrenaline released from nerve terminals by electrical stimulation. Naunyn-Schmiedeberg's Arch Pharmacol 311:1–7Google Scholar
  3. Cubeddu L, Weiner N (1975) Release of norepinephrine and dopamine-β-hydroxylase by nerve stimulation. V. Enhanced release associated with a granular effect of a benzoquinolizine derivative with reserpine-like properties. J Pharmacol Exp Ther 193:757–774Google Scholar
  4. Cubeddu LX, Barnes EM, Langer SZ, Weiner N (1974) Release of norepinephrine and dopamine-β-hydroxylase by nerve stimulation. I. Role of neuronal and extraneuronal uptake and of alphapresynaptic receptors. J Pharmacol Exp Ther 190:431–450Google Scholar
  5. De Mey JG, Vanhoutte PM (1980) Comparison of the responsiveness of cutaneous veins of dog and rabbit to adrenergic and cholinergic stimulation. Blood Vessels 17:27–43Google Scholar
  6. Endo T, Starke K, Bangerter A, Taube HD (1977) Presynaptic receptor systems on the noradrenergic neurones of the rabbit pulmonary artery. Naunyn-Schmiedeberg's Arch Pharmacol 296:229–247Google Scholar
  7. Henseling M, Graefe KH, Trendelenburg U (1978) The rate constants for the efflux of the metabolites of noradrenaline from rabbit aortic strips. Naunyn-Schmiedeberg's Arch Pharmacol 302:207–215Google Scholar
  8. Hukovic S, Muscholl E (1962) Die Noradrenalin-Abgabe aus dem isolierten Kaninchenherzen bei sympathischen Nervenreizungen und ihre pharmakologische Beeinflussung. Naunyn-Schmiedeberg's Arch Pharmacol 244:81–96Google Scholar
  9. Iversen LL, (1967) The uptake and storage of noradrenaline in sympathetic nerves. Cambridge University Press, Cambridge, p 253Google Scholar
  10. Kalsner S, Nickerson M (1969) Mechanism of cocaine potentiation of responses to amines. Brit J Pharmacol 35:428–439Google Scholar
  11. Langer SZ (1970) The metabolism of 3H-noradrenaline released by electrical stimulation from the isolated nictitating membrane of the cat and from the vas deferens of the rat. J Physiol (Lond) 208:515–546Google Scholar
  12. Langer SZ (1974) Selective metabolic pathways for noradrenaline in the peripheral and in the central nervous system. Medic Biol 52:372–383Google Scholar
  13. Langer SZ, Enero MA (1974) The potentiation of responses to adrenergic nerve, stimulation in the presence of cocaine: its relationship to the metabolic fate of released norepinephrine. J Pharmacol Exp Ther 191:431–443Google Scholar
  14. Levin JA (1974) The uptake and metabolism of 3H-l- and 3H-dl-norepinephrine by intact rabbit aorta and by isolated adventitia and media. J Pharmacol Exp Ther 190:210–226Google Scholar
  15. Lorenz RR, Powis DA, Vanhoutte PM, Shepherd JT (1980) The effects of acetylstrophantidin and ouabain on the sympathetic adrenergic neuroeffector junction in canine vascular smooth muscle. Circ Res 47:845–854Google Scholar
  16. Maxwell RA, Wastila WB, Eckhardt SB (1966) Some factors determining the response of rabbit aortic strips to dl-norepinephrine-7-H3 hydrochloride and the influence of cocaine, guanethidine and methylphenidate on these factors. J Pharmacol Exp Ther 151:253–261Google Scholar
  17. McGrath MA, Vanhoutte PM (1978) Vasodilatation caused by peripheral inhibition of adrenergic neurotransmission. In: Vanhoutte PM, Leusen E (eds) Mechanisms of vasodilatation. Karger, Basel, pp 248–257Google Scholar
  18. Muldoon SM, Vanhoutte PM, Tyce GM (1978) Norepinephrine metabolism in canine saphenous veins: prevalence of glycol metabolites. Am J Physiol 236:H235-H243Google Scholar
  19. Paiva MQ, Guimaraes S (1978) A comparative study of the uptake and metabolism of noradrenaline by the isolated saphenous vein of the dog. Naunyn-Schmiedeberg's Arch Pharmacol 303:221–228Google Scholar
  20. Reiffenstein RJ (1968) Effects of cocaine on the rate of contraction to noradrenaline in the cat spleen strip: mode of action of cocaine. Br J Pharmacol 32:591–597Google Scholar
  21. Rorie DK, Muldoon SM Tyce GM (1980) The specific activity of retained and released norepinephrine in dog saphenous vein prelabeled with radioactive norepinephrine. Life Sci 26:707–714Google Scholar
  22. Roth JA, Gillis CN (1975) Some structural requirements for inhibition of type A and B forms of rabbit monoamine oxidase by tricyclic psychoactive drugs. Mol Pharmacol 11:28–35Google Scholar
  23. Starke K, Steppeler A, Zumstein A, Henseling, M, Trendelenburg U (1980) False labelling of commercially available 3H-catecholamines. Naunyn-Schmiedeberg's Arch Pharmacol 311:109–112Google Scholar
  24. Trendelenburg U (1968) The effect of cocaine on the pacemaker of the isolated guinea-pig atria. J Pharmacol Exp Ther 161:222–231Google Scholar
  25. Trendelenburg U (1972) Classification of sympathomimetic amines. In: Blaschko H, Muscholl E (eds) Catecholamines. Springer, Berlin Heidelberg New York (Handbook of experimental pharmacology, vol 33, pp 336–362)Google Scholar
  26. Trendelenburg U (1980) A kinetic analysis of the extraneuronal uptake and metabolism of catecholamines. Rev Physiol Biochem Pharmacol 87:33–115Google Scholar
  27. Trendelenburg U, Bonisch H, Graefe KH, Henseling M (1980) The rate constants for the efflux of metabolites of catecholamines and phenethylamines. Pharmacol Rev 31:179–203Google Scholar
  28. Vanhoutte PM, Lorenz RR, Tyce GM (1973) Inhibition of norepinephrine-3H-release from sympathetic nerve endings in veins by acetylcholine. J Pharmacol Exp Ther 185:386–394Google Scholar
  29. Vanhoutte PM, Verbeuren TJ, Webb RC (1981) Local modulation of the adrenergic neuroeffector interaction in the blood vessel wall. Physiol Rev 61:151–247Google Scholar
  30. Verbeuren TJ, Vanhoutte PM (1982) Deamination of released 3H-noradrenaline in the canine saphenous vein. Naunyn-Schmiedeberg's Arch Pharmacol 318:148–157Google Scholar
  31. Verbeuren TJ, Coen E, Vanhoutte PM (1977) Determination of 3H-norepinephrine and its metabolites in superfusate from isolated blood vessels. Arch Int Pharmacodyn 227:171–174Google Scholar
  32. Verbeuren TJ, Janssens WJ, Vanhoutte PM, (1978) Effects of moderate acidosis on adrenergic neurotransmission in canine saphenous veins. J Pharmacol Exp Ther 206:105–114Google Scholar
  33. Webb RC, Vanhoutte PM (1981) Cocaine and contractile responses of vascular smooth muscle from spontaneously hypertensive rats. Arch Int Pharmacodyn Ther 253:241–256Google Scholar
  34. Webb RC, Vanhoutte PM (1982) Cocaine-induced release of noradrenaline in rat tail artery. J Pharm Pharmacol 34:134–136Google Scholar

Copyright information

© Springer-Verlag 1982

Authors and Affiliations

  • T. J. Verbeuren
    • 1
  • P. M. Vanhoutte
    • 2
  1. 1.Division of Pharmacology, Department of MedicineUniversitaire Instelling AntwerpenWilrijkBelgium
  2. 2.Department of Physiology and BiophysicsMayo ClinicRochesterUSA

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