Advertisement

Pharmaceutisch weekblad

, Volume 1, Issue 1, pp 245–255 | Cite as

De presynaptische α- receptor, een mogelijk aangrijpingspunt voor farmaca

  • B. Wilffert
  • P. B. M. W. M. Timmermans
  • P. A. van Zweeten
Overzichtsartikelen

Samenvatting

Dit artikel bevat een overzicht van de huidige kennis aangaande presynaptische mechanismen in het algemeen en het model van de presynaptischeα-receptor in het bijzonder. Er wordt aandacht besteed aan (dier)modellen waarin presynaptischeα-receptoren zijn onderzocht. Uit deze onderzoekingen wordt geconcludeerd dat de verhouding tussen pre- en postsynaptische activiteit vanα-adrenerge agonisten en antagonisten sterk afhangt van de experimentele opzet, dat de presynaptische α-receptoren speciesverschillen vertonen maar ook in één species kunnen verschillen, en dat presynaptischeα-receptoren niet identiek zijn aan postsynaptische. Het effect van de presynaptische a-receptor komt tot stand door een beperking van het vrije intraneuronale ionogene calcium, hetgeen tevens de frequentie-afhankelijkheid van het presynaptische effect verklaart. De invloed van de nor-adrenaline-concentratie in de synaptische spleet wordt beschouwd, evenals het belang van de remming van de neuronale opname, de breedte van de synaptische spleet, de stimulatie-frequentie en het aantal stimuli.

De mogelijke rol van centrale presynaptischeα-receptoren in het mechanisme van het antihypertensieve effect van clonidine wordt besproken. Tenslotte wordt geconcludeerd dat de fysiologische betekenis van presynaptischeα-receptoren in de periferie nog niet duidelijk is, alhoewel deze betekenis bij een lage activiteit van het zenuwstelsel zeer waarschijnlijk lijkt te zijn. In het centrale zenuwstelsel zijn de presynaptischeα-receptoren misschien van belang voor gedragsprocessen maar waarschijnlijk niet voor een bloeddrukverlagend effect. Het belang van de presynaptische receptoren als aangrijpingspunt van geneesmiddelen die via het perifere of centrale zenuwstelsel werken, wordt besproken.

The presynaptic α- adrenoceptor, a possible target for drugs

Abstract

The actual knowledge regarding presynaptic mechanisms in general and the model of the presynapticα-adrenoceptor in particular is reviewed in this paper. Attention is being paid to (animal) models in which presynapticα-adrenoceptors have been studied.

From these investigations it is concluded, that the ratio of the activities ofα-adrenoceptor agonists and antagonists at pre- and postsynaptically locatedα-adrenoceptors considerably depends upon the experimental model used. It is also clear that the presynapticα-adrenoceptors differ in various species and also show a dissimilarity within one species. Furthermore, presynapticα-adrenoceptors are not identical to postsynaptic ones. The effect of the presynapticα-adrenoceptor is brought about by a limitation of the concentration of the free, intraneuronal calcium. This also accounts for the frequency-dependence of the presynaptic response. The influence of the concentration of noradrenaline in the synaptic cleft, the inhibition of the neuronal uptake, the width of the synaptic cleft, the frequency of stimulation and the number of stimuli will be discussed.

The possible role which central, presynapticα-adrenoceptors may play in the mechanism of the antihypertensive effect of clonidine is discussed. Finally, it is concluded that the physiological significance of presynapticα-adrenoceptors in the periphery is not yet clear. However, an involvement is plausible at low activity of the nervous system. Central presynapticα-adrenoceptors are presumably of importance in determining behavioural processes but they probably play no substantial part in the central mechanism which induces a decrease in blood pressure. The importance of the presynaptic receptors as a target for drugs which owe their action on the peripheral or central nervous system is discussed.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatuur

  1. Ambache, N., L. P. Dunk, J. Verney enM. A. Zar (1973) An inhibition of post-ganglionic motor-transmission in the mammalian vas deferens byd-lysergic acid diethylamide,J. Physiol. 231, 251–270.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Andén, N. E., enM. Grabowska (1977)Fla 136: Selective agonist at central alpha-adrenoceptors mediating changes in the turnover of noradrenaline,Naunyn-Schmiedebergs Arch. Pharmakol. 298, 239–243.CrossRefGoogle Scholar
  3. Andén, N. E., M. Grabowska enU. Strömbom (1976) Different alpha-adrenoceptors in the central nervous system mediating biochemical and functional effects of clonidine and receptor blocking agents,Naunyn-Schmiedebergs Arch. Pharmakol. 292, 43–52.CrossRefGoogle Scholar
  4. Beani, L., L. Bianchi enA. Crema (1969) The effect of catecholamines and sympathetic stimulation on the release of acetylcholine from the guinea-pig colon,Brit. J. Pharmacol. 36, 1–17.CrossRefGoogle Scholar
  5. Bock, K. D., P. Merguet, T. Murata enV. Heimsoth (1968) Klinisch-experimentelle Untersuchungen über die Wirkungen von Dichlorphenylaminoimidazolin, in: (Heilmeyer, L., H. J. Holtmeier enE. F. Pfeiffer)Hochdrucktherapie. G. Thieme-Verlag, Stuttgart.Google Scholar
  6. Borowski, E., H. Ehrl enK. Starke (1976) Relative pre- and postsynaptic potencies ofα-adrenolytic drugs,Naunyn-Schmiedebergs Arch. Pharmakol. 293, R2.Google Scholar
  7. Brown, G. L., enJ. S. Gillespie (1957) The output of sympathetic transmitter from the spleen of the cat,J. Physiol. 138, 81–102.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Cavero, J., F. Lefèvre enA. G. Roach (1977) Differential effects of prazosin on the pre- and postsynapticα-adrenoceptors in the rat and dog,Brit. J. Pharmacol. Proceedings, C 25.Google Scholar
  9. Cubeddu, L. X., E. M. Barnes, S. Z. Langer enN. Weiner (1974) Release of norepinephrine and dopamine-Β-hydroxylase by nerve stimulation, I. Role of neuronal and extraneuronal uptake and of alpha presynaptic receptors,J. Pharmacol. Exptl. Therap. 190, 431–450.Google Scholar
  10. Cubeddu, L. X., enN. Weiner (1975) Nerve stimulation mediated overflow of norepinephrine and dopamine-Β-hydroxylase. III. Effects of norepinephrine depletion on the alpha presynaptic regulation of release,J. Pharmacol. Exptl. Therap. 192, 1–14.Google Scholar
  11. Dismukes, R. K., enA. H. Mulder (1976) CyclicAmp and α-receptor-mediated modulation of noradrenaline release from rat brain slices,Europ. J. Pharmacol. 39, 383–388.CrossRefGoogle Scholar
  12. Drew, G. M. (1976) Effects ofα-adrenoceptor agonists and antagonists on pre- and postsynaptically locatedα-adrenoceptors,Europ. J. Pharmacol. 36, 313–320; (1977) Pharmacological characterization of the presynapticα-adrenoceptor in the rat vas deferens,Ibidem 42, 123–130.CrossRefGoogle Scholar
  13. Dubocovich, M. L., enS. Z. Langer (1974) Negative feedback regulation of noradrenaline release by nerve stimulation in the perfused cat's spleen: Differences in potency of phenoxybenzamine in blocking the pre- and postsynaptic adrenergic receptors,J. Physiol. 237, 505–519.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Endo, T., K. Starke, A. Bangerter enH. D. Taube (1977) Presynaptic receptor systems on the noradrenergic neurones of the rabbit pulmonary artery,Naunyn-Schmiedebergs Arch. Pharmakol. 296, 229–247.CrossRefGoogle Scholar
  15. Enero, M. A., enS. Z. Langer (1973) Influence of reserpine-induced depletion of noradrenaline on the negative feed-back mechanism for transmitter release during nerve stimulation,Brit. J. Pharmacol. 49, 214–225; (1975) Inhibition by dopamine of3H-noradrenaline release elicited by nerve stimulation in the isolated cat's nictitating membrane,Naunyn-Schmiedebergs Arch. Pharmakol. 289, 179–203.CrossRefGoogle Scholar
  16. Farnebo, L.-O., enB. Hamberger (1970) Effects of desipramine, phentolamine and phenoxybenzamine on the release of noradrenaline from isolated tissues,J. Pharm. Pharmacol. 22, 855–857; (1971) Drug-indueed changes in the release of (3H)-noradrenaline from field stimulated rat iris,Brit. J. Pharmacol. 43, 97–106.CrossRefPubMedGoogle Scholar
  17. Farnebo, L.-O., B. Hamberger enG. Jonsson (1971) Release of (3H)-dopamine from field stimulated cerebral cortex slices-effect of tyrosine-hydroxylase and dopamine-Β-hydroxylase,J. Neurochem. 18, 2491–2500.CrossRefPubMedGoogle Scholar
  18. Franklin, K. B. J., enL. J. Herberg (1977) Presynaptic-α-adrenoceptors: The depression of self-stimulation by clonidine and its restoration by piperoxane but not by phentolamine or phenoxybenzamine,Europ. J. Pharmacol. 43, 33–38.CrossRefGoogle Scholar
  19. Graubner, W., enM. Wolf (1966) Kritische Betrachtungen zum Wirkungsmechanismus des 2-(2,6-Dichlorphenylamino)-2-imidazolin-hydrochloride,Arzneimittel-Forsch. 16, 1055–1058.Google Scholar
  20. Haeusler, G. (1974) Clonidine-induced inhibition of sympathetic nerve activity: No indication for central presynaptic or an indirect sympathomimetic mode of action,Naunyn-Schmiedebergs Arch. Pharmakol. 286, 97–111.CrossRefGoogle Scholar
  21. Hughes, J. (1973) Inhibition of noradrenaline release by lysergic acid diethylamide,Brit. J. Pharmacol. 49,706–708.CrossRefGoogle Scholar
  22. Hunt, G. E., D. M. Atrens, G. B. Chesher enF. T. Becker (1976)α-Noradrenergic modulation of hypothalamic self-stimulation: Studies employing clonidine, L-phenylephrine anda-methyl-p-tyrosine.Europ. J. Pharmacol. 37, 105–111.CrossRefGoogle Scholar
  23. Kirpekar, S. M., R. F. Furchgott, A. R. Wakade enJ. C. Prat (1973) Inhibition by sympathomimetic amines of the release of norepinephrine evoked by nerve stimulation in the cat spleen,J. Pharmacol. Exptl. Therap. 187, 529–538.Google Scholar
  24. Kirpekar, S. M., J. C. Prat enA. R. Wakade (1975) Effect of calcium on the relationship between frequency of stimulation and release of noradrenaline from the perfused spleen of the cat,Naunyn-Schmiedebergs Arch. Pharmakol. 287, 205–212.CrossRefGoogle Scholar
  25. Kirpekar, S. M., enM. Puig (1971) Effect of flow-stop on noradrenaline release from normal spleens and spleens treated with cocaine, phentolamine or phenoxybenzamine,Brit. J. Pharmacol. 43, 359–369.CrossRefGoogle Scholar
  26. Knoll, J., enE. S. Vizi (1971) Effect of frequency of stimulation on the inhibition by noradrenaline of the acetylcholine output from parasympathetic nerve terminals,Brit. J. Pharmacol. 41, 263–272.CrossRefGoogle Scholar
  27. Kobinger, W. (1973) Pharmacological basis of the cardiovascular actions of clonidine,Onesti, G, K E Kim enJ. H. Moyer,Hypertension: Mechanisms and Management. Grune and Stratton, Inc., blz. 369–380.Google Scholar
  28. Kobinger, W., enL. Pichler (1976) Centrally induced reduction in sympathetic tone — a postsynapticα-adrenoceptor stimulating action of imidazolines,Europ. J. Pharmacol. 40, 311–320.CrossRefGoogle Scholar
  29. Kobinger, W., enA. Walland (1971) Involvement of adrenergic receptors in central vagus activity,Europ. J. Pharmacol. 16, 120–122.CrossRefGoogle Scholar
  30. Kosterlitz, H. W., R. J. Lydon enA. J. Watt (1970) The effects of adrenaline, noradrenaline and isoprenaline on inhibitoryα- and Β-adrenoceptors in the longitudinal muscle of the guinea-pig ileum,Brit. J. Pharmacol. 39, 398–413.CrossRefGoogle Scholar
  31. Langer, S. Z. (1977) Presynaptic receptors and their role in the regulation of transmitter release,Brit. J. Pharmacol. 60, 481–497.CrossRefGoogle Scholar
  32. Lassen, J. B. (1978) Piperoxane reduces the effects of clonidine on aggression in mice and noradrenaline dependent hypermobility in rats,Europ. J. Pharmacol. 47, 45–49.CrossRefGoogle Scholar
  33. Lokhandwala, M. F., enJ. P. Buckley (1977) Presynapticα-adrenoceptor blockade on responses to cardiac nerve stimulation in anesthetized dogs,Europ. J. Pharmacol. 40, 183–186.CrossRefGoogle Scholar
  34. Lokhandwala, M. F., J. T. Coats enJ. P. Buckley (1977) Effects of several catecholamines on sympathetic transmission to the myocardium; role of presynapticα-adrenoceptors,Europ. J. Pharmacol. 42, 257–265.CrossRefGoogle Scholar
  35. Pacha, W., R. Salzmann enG. Choltysik (1975) Inhibitory effects of clonidine and BS 100–141 on responses to sympathetic nerve stimulation in cats and rabbits,Brit. J. Pharmacol. 53, 512–516.CrossRefGoogle Scholar
  36. Paton, W. D. M., enE. S. Vizi (1969) The inhibitory action of noradrenaline and adrenaline on acetylcholine output by guinea-pig ileum longitudinal muscle strip,Brit. J. Pharmacol. 35, 10–28.CrossRefGoogle Scholar
  37. Pelayo, F., M. Dubocovich enS. Z. Langer (1977) Regulation of noradrenaline release in the rat pineal through a negative feedback mechanism mediated by presynapticα-adrenoceptors,Europ. J. Pharmacol. 45, 317–318.CrossRefGoogle Scholar
  38. Robson, R. D., enM. J. Antonaccio (1974) Effect of clonidine on responses to cardiac nerve stimulation as a function of impulse frequency and stimulus duration in vagotomized dogs,Europ. J. Pharmacol. 29, 182–186.CrossRefGoogle Scholar
  39. Robson, R. D., M. J. Antonaccio, J. K. Saelens enJ. Liebman (1978) Antagonism by mianserin and classicalα-adrenoceptor blocking drugs of some cardiovascular and behavioural effects of clonidine,Europ. J. Pharmacol. 47, 431–442.CrossRefGoogle Scholar
  40. Schmitt, H. (1971) Actions des alpha-sympathomimétiques sur les structures nerveuses,Actualités Pharmacol. 24, 93–131.PubMedGoogle Scholar
  41. Schmitt, H., enH. Schmitt (1970) Interactions between 2-(2,6-dichlorphenylamino)-2-imidazoline hydrochloride (St 155, Catapresan®) andα-adrenergic blocking drugs,Europ. J. Pharmacol. 9, 7–13.CrossRefGoogle Scholar
  42. Schmitt, H., H. Schmitt enS. Fénard (1971) Evidence for anα-sympathomimetic component in the effects of catapresan on vasomotor centres: antagonism by piperoxane,Europ. J. Pharmacol. 14, 98–100; (1973) Action ofα-adrenergic blocking drugs on the sympathetic centres and their interactions with the central sympatho-inhibitory effect of clonidine,ArzneimittelForsch. 23, 40–45.CrossRefGoogle Scholar
  43. Starke, K. (1972) Alpha-sympathomimetic inhibition of adrenergic and cholinergic transmission in the rabbit heart,Naunyn-Schmiedebergs Arch. Pharmakol. 274, 18–45; (1975)Neue Befunde zur Regelung und Beeinflussung der noradrenerge Erregungsübertragung. Voordracht gehouden op de ‘Mitgliederversammlung der Deutschen Liga zur Bekämpfung des hohen Blutdruckes’, Bonn, 26 november, blz. 14–24.CrossRefGoogle Scholar
  44. Starke, K., T. Endo enH. D. Taube (1975) Relative pregic neurotransmission by clonidine: An action on prejunctionalα-receptors,Neuropharmacology 12, 339–347; (1975) Relative pre- and postsynaptic potencies ofα-adrenoceptor agonists in the rabbit pulmonary artery,Naunyn-Schmiedebergs Arch. Pharmakol. 291, 55–78.CrossRefGoogle Scholar
  45. Starke, K., enH. Montel (1973a) Alpha- receptor- mediated modulation of transmitter release from central noradrenergic neurones,Naunyn-Schmiedebergs Arch. Pharmakol. 279, 53–60; (1973b) Involvement ofα-receptors in clonidine-induced inhibition of transmitter release from central monoamine neurones,Neuropharmacology 12, 1073–1080; (1974) Influence of drugs with affinity forα-adrenoceptors on noradrenaline release by potassium, tyramine and dimethylpiperazinum,Europ. J. Pharmacol. 27, 273–280.CrossRefGoogle Scholar
  46. Starke, K., H. Montel, W. Gayk enR. Merker (1974) Comparison of the effects of clonidine on pre- and postsynaptic adrenoceptors in the rabbit pulmonary artery,Naunyn-Schmiedebergs Arch. Pharmakol. 285, 133–150.CrossRefGoogle Scholar
  47. Starke, K., H. D. Taube enE. Borowski (1977) Presynaptic receptor systems in catecholaminergic transmission,Biochem. Pharmacol. 26, 259–268.CrossRefPubMedGoogle Scholar
  48. Stjärne, L. (1973) Frequency dependence of dual negative feedback control of secretion of sympathetic neurotransmitter in guinea-pig vas deferens,Brit. J. Pharmacol. 49, 358–360; (1975) Selectivity for catecholamines of presynaptic alpha-receptors involved in feedback control of sympathetic neurotransmitter secretion in guinea-pig vas deferens,Naunyn-Schmiedebergs Arch. Pharmakol. 288, 296–303.CrossRefGoogle Scholar
  49. Taube, H. D., K. Starke enE. Borowski (1977) Presynaptic receptor systems on the noradrenergic neurones of rat brain,Naunyn-Schmiedebergs Arch. Pharmakol. 299, 123–141.CrossRefGoogle Scholar
  50. Timmermans, P. B. M. W. M. (1978) Central hypotensive activity as a function of peripheral hypertensive potency and lipophilicity,Naunyn-Schmiedebergs Arch. Pharmakol. 302, R40.Google Scholar
  51. Timmermans, P. B. M. W. M., E. Lam enP. A. van Zwieten (1978) Mutual interactions between clonidine, fla-136 and prazosine on pre- and postsynapticα-adrenoceptors 7th International Congress of Pharmacology, Paris 1978, Proc. p. 1410.Google Scholar
  52. Timmermans, P. B. M. W. M., enP. A. Van Zwieten (1977) Central and peripheralα-adrenergic effects of some imidazolidines,Europ. J. Pharmacol. 45, 229–236.CrossRefGoogle Scholar
  53. Vizi, E. S., enJ. Knoll (1971) The effects of sympathetic nerve stimulation and guanethidine on parasympathetic neuroeffector transmission: the inhibition of acetylcholine release,J. Pharm. Pharmacol. 23, 918–925.CrossRefPubMedGoogle Scholar
  54. Vizi, E. S., G. T. Somogyi, P. Hadházy enJ. Knoll (1973) Effect of duration and frequency of stimulation on the presynaptic inhibition byα-adrenoceptor stimulation of the adrenergic transmission,Naunyn-Schmiedebergs Arch. Pharmakol. 280, 79–91.CrossRefGoogle Scholar
  55. Warnke, E., enW. Hoefke (1977) Influence of central pretreatment with 6-hydroxy-dopamine on the hypotensive effect of clonidine,Arzneimittel-Forsch. 27, 2311–2313.Google Scholar
  56. Westfall, T. C. (1977) Local regulation of adrenergic neurotransmission,Physiol. Rev. 57, 659–728.PubMedGoogle Scholar
  57. Westfall, T. C., enLeighton H. J. (1976) Effect of decentralization on presynaptic receptor regulation ofNe release,Pharmacologist 18, 208.Google Scholar
  58. Yamaguchi, N., J. De Champlain enA. Nadeau (1977) Regulation of norepinephrine release from sympathetic fibers in the dog by presynapticα- andΒ-receptors,Circulation res., 41, 108–117.CrossRefPubMedGoogle Scholar
  59. Zwieten, P. A. Van (1975) Antihypertensive Drugs with a Central Action, inProgr. Pharmacol. Vol.I, Nr. I. Gustav Fischer Verlag, Stuttgart.Google Scholar
  60. Zwieten, P. A. van, E. Lam enP. B. M. W. M. Timmermans (1978) The interaction between prazosine and clonidine,Proc. Fifth scientific meeting of the international society of hypertension, Parijs, blz. 282.Google Scholar

Copyright information

© Bohn, Scheltema & Holkema 1979

Authors and Affiliations

  • B. Wilffert
    • 1
  • P. B. M. W. M. Timmermans
    • 1
  • P. A. van Zweeten
    • 1
  1. 1.Vakgroep Farmacotherapie, Laboratorium voor FarmacieUniversiteit van AmsterdamAmsterdam

Personalised recommendations