Skip to main content
SpringerLink
Log in

Alpha sympathomimetic inhibition of adrenergic and cholinergic transmission in the rabbit heart

  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

Experiments were performed in isolated rabbit hearts to investigate the mode of action of α-receptor stimulants and α-adrenolytic drugs on the release of noradrenaline by adrenergic nerve impulses. In addition, the effect of α-receptor stimulants on parasympathetic transmission has been studied.

  1. 1.

    Dihydroergotamine enhanced the overflow of noradrenaline in response to sympathetic nerve stimulation at a concentration (0.19 μg/ml) which did not interfere with the removal of exogenous noradrenaline from the perfusion fluid by the heart.

  2. 2.

    Phenylephrine (in the presence of cocaine), oxymetazoline, and naphazoline caused a dose-dependent decrease of the stimulation-induced overflow of noradrenaline. During perfusion with oxymetazoline and naphazoline, also the mechanical response to stimulation was diminished. Since the inactivation of noradrenaline by the cardiac tissue was not enhanced by any of the three drugs, it can be concluded that overflow was diminished because of a decreased liberation of noradrenaline from the nerve endings.

  3. 3.

    The degree of inhibition caused by oxymetazoline was inversely related to the absolute overflow of noradrenaline in response to nerve stimulation before the infusion of oxymetazoline.

  4. 4.

    Oxymetazoline and naphazoline at a concentration (100 ng/ml) which maximally inhibited the liberation of noradrenaline were devoid of myocardial effects. In contrast, all the concentrations of phenylephrine (1 μg/ml and above) which diminished the secretion of noradrenaline greatly increased the force of contraction. During perfusion with phenylephrine, but not with oxymetazoline or naphazoline, noradrenaline was released into the venous effluent. The myocardial effects of phenylephrine were diminished by phentolamine, but not by propranolol or cocaine, though cocaine prevented the release of noradrenaline by phenylephrine.

  5. 5.

    The effects of oxymetazoline and cocaine on the overflow of noradrenaline were independent of each other. In contrast, pretreatment with oxymetazoline prevented the increase of transmitter overflow by small concentrations of phentolamine (0.28 μg/ml) or phenoxybenzamine (0.034 μg/ml). The increase of overflow caused by a high concentration of phentolamine (2.8 μg/ml) which, in addition to blocking α-receptors, has cocaine-like effects, was only partly counteracted by oxymetazoline.

  6. 6.

    Surface anaesthesia on the rabbit cornea was induced by oxymetazoline and naphazoline only at very high and systemically toxic concentrations.

  7. 7.

    The results indicate that α-receptors are involved in the regulation of the release of noradrenaline from adrenergic nerve terminals in response to nerve impulses. Stimulation of these receptors by liberated noradrenaline triggers a restriction of transmitter discharge. Receptor occupation by α-receptor-blocking drugs prevents the feed-back inhibition of noradrenaline secretion. α-Stimulants mimic the inhibitory action of noradrenaline. The receptors influencing the secretion of noradrenaline are not identical with the myocardial phenylephrine-receptors; a prejunctional, neuronal localization seems probable.

  8. 8.

    Oxymetazoline and naphazoline inhibit the myocardial response to vagal stimulation, presumably by decreasing the release of acetylcholine.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bartsch, W., Knopf, K. W.: Eine modifizierte Methode zur Prüfung der Oberflächenanästhesie an der Kaninchen-Cornea. Arzneimittel-Forsch. 20, 1140 to 1143 (1970).

    Google Scholar 

  • Boura, A. L. A., Green, A. F.: Adrenergic neurone blocking agents. Ann. Rev. Pharmacol. 5, 183–212 (1965).

    Google Scholar 

  • Brown, G. L.: The release and fate of the transmitter liberated by adrenergic nerves. Proc. roy. Soc. B 162, 1–19 (1965).

    Google Scholar 

  • —, Davies, B. N., Ferry, C. B.: The effect of neuronal rest on the output of sympathetic transmitter from the spleen. J. Physiol. (Lond.) 159, 365–380 (1961).

    Google Scholar 

  • — Gillespie, J. S.: The output of sympathetic transmitter from the spleen of the cat. J. Physiol. (Lond.) 138, 81–102 (1957).

    Google Scholar 

  • Burgen, A. S. V., Iversen, L. L.: The inhibition of noradrenaline uptake by sympathomimetic amines in the rat isolated heart. Brit. J. Pharmacol. 25, 34–49 (1965).

    Google Scholar 

  • Daly, J. W., Creveling, C. R., Witkop, B.: The chemorelease of norepinephrine from mouse hearts. Structure-activity relationships. I. Sympathomimetic and related amines. J. med. Chem. 9, 273–280 (1966).

    Google Scholar 

  • Govier, W. C.: Myocardial alpha adrenergic receptors and their role in the production of a positive inotropic effect by sympathomimetic agents. J. Pharmacol. exp. Ther. 159, 82–90 (1968).

    Google Scholar 

  • Häggendal, J.: Some further aspects on the release of the adrenergic transmitter. In: H. J. Schümann and G. Kroneberg (eds.): New Aspects of Storage and Release Mechanisms of Catecholamines pp. 100–111. Berlin-Heidelberg-New York: Springer 1970.

    Google Scholar 

  • Heise, A., Kroneberg, G., Schloßmann, K.: α-sympathicomimetische Eigenschaften als Ursache der blutdrucksteigernden und blutdrucksenkenden Wirkung von BAY 1470 [2-(2,6-Xylidino)-5,6-dihydro-4H-1,3-thiazinhydrochlorid). Naunyn-Schmiedebergs Arch. Pharmak. 268, 348–360 (1971).

    Google Scholar 

  • Holtz, P., Palm, D.: Brenzkatechinamine und andere sympathicomimetische Amine. Ergebn. Physiol. 58, 183–188 (1966).

    Google Scholar 

  • Huković, S., Muscholl, E.: Die Noradrenalin-Abgabe aus dem isolierten Kaninchenherzen bei sympathischer Nervenreizung und ihre pharmakologische Beeinflussung. Naunyn-Schmiedebergs. Arch. exp. Path. Pharmak. 241, 81–96 (1962).

    Google Scholar 

  • Koch-Weser, J., Blinks, J. R.: The influence of the interval between beats on myocardial contractility. Pharmacol. Rev. 15, 601–652 (1963).

    Google Scholar 

  • Kroneberg, G., Oberdorf, A., Hoffmeister, F., Wirth, W.: Zur Pharmakologie von 2-(2,6-Dimethylphenylamino)-4H-5,6-dihydro-1,3-thiazin (Bayer 1470), eines Hemmstoffes adrenergischer und cholinergischer Neurone. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 256, 257–280 (1967).

    Google Scholar 

  • Langer, F. Z., Adler, E., Enero, M. A., Stefano, F. J. E.: The role of the alpha receptor in regulating noradrenaline overflow by nerve stimulation. Proc. intern. Union Physiol. Sci. 9, 335 (1971).

    Google Scholar 

  • McEwen, L. M.: The effect on the isolated rabbit heart of vagal stimulation and its modification by cocaine, hexamethonium and ouabain. J. Physiol. (Lond.) 131, 678–689 (1956).

    Google Scholar 

  • Mitchell, J. R., Oates, J. A.: Guanethidine and related agents. I. Mechanism of the selective blockade of adrenergic neurons and its antagonism by drugs. J. Pharmacol. exp. Ther. 172, 100–107 (1970).

    Google Scholar 

  • Mujić, M., van Rossum, J. M.: Comparative pharmacodynamics of sympathomimetic imidazolines; studies on intestinal smooth muscle of the rabbit and the cardiovascular system of the cat. Arch. int. Pharmacodyn. 155, 432–449 (1965).

    Google Scholar 

  • Nishi, S.: Cholinergic and adrenergic receptors at sympathetic preganglionic nerve terminals. Fed. Proc. 29, 1957–1965 (1970).

    Google Scholar 

  • Oberdorf, A., Kroneberg, G.: Alpha- und beta-sympathicomimetische Wirkungen am elektrisch gereizten isolierten Meerschweinchenileum. Naunyn-Schmiedebergs Arch. Pharmak. 267, 195–207 (1970).

    Google Scholar 

  • Palmer, J. F.: The use of β-thiopropionic acid for the analysis of mixtures of adrenaline and noradrenaline in plasma by the fluorometric trihydroxyindole method. West Indian med. J. 13, 38–53 (1964).

    Google Scholar 

  • Paton, W. D. M., Vizi, E. S.: The inhibitory action of noradrenaline and adrenaline on acetylcholine output by guinea-pig ileum longitudinal muscle strip. Brit. J. Pharmacol. 35, 10–28 (1969).

    Google Scholar 

  • Perry, W. L. M., Talesnik, J.: The role of acetylcholine in synaptic transmission at parasympathetic ganglia. J. Physiol. (Lond.) 119, 455–469 (1953).

    Google Scholar 

  • Potter, W. P. de, Chubb, I. W., Put, A., de Schaepdryver, A. F.: Facilitation of the release of noradrenaline and dopamine-β-hydroxylase at low stimulation frequencies by α-blocking agents. Arch. int. Pharmacodyn. 193, 191–197 (1971).

    Google Scholar 

  • Schmitt, H., Schmitt, H., Fenard, S.: Evidence for an α-sympathomimetic component in the effects of catapresan on vasomotor centres: antagonism by piperoxane. Europ. J. Pharmacol. 14, 98–100 (1971).

    Google Scholar 

  • Starke, K.: Influence of α-receptor stimulants on noradrenaline release. Naturwissenschaften 58, 420 (1971a).

    Google Scholar 

  • —: Action of angiotensin on uptake, release and metabolism of 14C-noradrenaline by isolated rabbit hearts. Europ. J. Pharmacol. 14, 112–123 (1971b).

    Google Scholar 

  • — Montel, H., Schümann, H. J.: Influence of cocaine and phenoxybenzamine on noradrenaline uptake and release. Naunyn-Schmiedebergs Arch. Pharmak. 270, 210–214 (1971a).

    Google Scholar 

  • ——, Wagner, J.: Effect of phentolamine on noradrenaline uptake and release. Naunyn-Schmiedebergs Arch. Pharmak. 271, 181–192 (1971b).

    Google Scholar 

  • — Wagner, J., Schümann, H. J.: Adrenergic neuron blockade by clonidine: comparison with guanethidine and local anesthetics. Arch. int. Pharmacodyn. 195, 291–308 (1972).

    Google Scholar 

  • — Werner, U., Schümann, H. J.: Wirkung von Angiotensin auf Funktion und Noradrenalinabgabe isolierter Kaninchenherzen in Ruhe und bei Sympathicusreizung. Naunyn-Schmiedebergs Arch. Pharmak. 265, 170–186 (1969).

    Google Scholar 

  • Su, C., Bevan, J. A.: The release of H3-norepinephrine in arterial strips studied by the technique of superfusion and transmural stimulation. J. Pharmacol. exp. Ther. 172, 62–68 (1970).

    Google Scholar 

  • Thoenen, H., Hürlimann, A., Haefely, W.: Wirkungen von Phenoxybenzamin, Phentolamin und Azapetin auf adrenergische Synapsen der Katzenmilz. Helv. physiol. pharmacol. Acta 22, 148–161 (1964).

    Google Scholar 

  • Trendelenburg, U., Muskus, A., Fleming, W. W., de la Sierra, B. G. A.: Modification by reserpine of the action of sympathomimetic amines in spinal cats; a classification of sympathomimetic amines. J. Pharmacol. exp. Ther. 138, 170–180 (1962).

    Google Scholar 

  • Wennmalm, A.: Studies on mechanisms controlling the secretion of neurotransmitters in the rabbit heart. Acta physiol. scand., Suppl. 365 (1971).

  • Werner, U., Starke, K., Schümann, H. J.: Actions of clonidine and 2-(2-methyl-6-ethyl-cyclohexylamino)-2-oxazoline on postganglionic autonomic nerves. Arch. int. Pharmacodyn. 195, 282–290 (1972).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharmakologisches Institut, Klinikum Essen der Ruhr-Universität, Essen, Germany

    K. Starke

Authors
  1. K. Starke
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This work was supported by the Deutsche Forschungsgemeinschaft.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Starke, K. Alpha sympathomimetic inhibition of adrenergic and cholinergic transmission in the rabbit heart. Naunyn-Schmiedeberg's Arch. Pharmacol. 274, 18–45 (1972). https://doi.org/10.1007/BF00501004

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00501004

Key words

Search

Navigation