Summary
Bretylium and tetracaine when perfused at increasing concentrations inhibited and finally blocked discharges elicited by acetylcholine and KCl in adrenergic nerve endings of the isolated perfused heart and less regularly in the isolated perfused spleen of the cat.
There was a direct correlation between the inhibition of the effects of sympathetic nerve stimulation and the inhibition of KCl-induced discharges by bretylium and tetracaine in the heart with regard to both intensity and time course. Acetylcholine-induced release of noradrenaline in the heart was somewhat more resistant to the action of bretylium than acetylcholine-induced antidromic discharges in cardiac adrenergic nerves.
Bretylium and tetracaine inhibited and blocked discharges in sinus nerve afferents elicited by rises in the perfusion pressure and by injection of KCl.
The concentration for complete block in the perfused carotid sinus preparation was 800–1, 000 times higher for bretylium than for tetracaine, whereas bretylium was equally or more potent (depending on the time of interaction) than tetracaine in the isolated perfused heart. Moreover, the effect of bretylium in the heart and spleen developed slowly, increased continuously during the perfusion period and was very resistant to washing out. In contrast, tetracaine achieved its maximum effect on heart, spleen and carotid sinus preparations very rapidly and was readily washed out. The time course and reversibility of the effect of bretylium on baro-receptor afferents were not drastically different from those of tetracaine.
All observations may be explained by the fact that bretylium is a very weak local anaesthetic causing, however, a marked selective local anaesthesia of adrenergic nerve terminals because of its high accumulation in these endings. The adrenergic nerve blocking effect of bretylium seems to be adequately explained by its stabilizing effect on the membrane of the nerve terminals.
Preliminary results of this report have been communicated to the German Pharmacological Society in Mainz at the Spring Meeting 1969 (Haeusler, G., W. Haefely and A. Huerlimann, 1969).
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Abbs, E.T.: The release of catechol amines by choline 2, 6-Xylylether, bretylium and guanethidine. Brit. J. Pharmacol. 26, 162–171 (1966).
Bhagat, B., Shideman, F.E.: Mechanism of the positive inotropic responses to bretylium and guanethidine. Brit. J. Pharmacol. 20, 56–62 (1963).
Boura, A.L.A., Copp, F.C., Duncombe, W.G., Green, A.F., McCoubrey, A.: The selective accumulation of bretylium in sympathetic ganglia and their postganglionic nerves. Brit. J. Pharmacol. 15, 265–270 (1960).
Copp, F.C., Duncombe, W.G., Green, A.F., McCoubrey, A. — Green, A.F.: The actions of bretylium: Adrenergic neurone blocking and other effects. Brit. J. Pharmacol. 14, 536–548 (1959).
Boyd, H., Chang, W., Rand, M.J.: The local anaesthetic activity of bretylium in relation to its action in blocking sympathetic responses. Arch. int. Pharmacodyn. 131, 10–23 (1961).
Brodie, B.B., Chang, C.C., Costa, E.: On the mechanism of action of guanethidine and bretylium. Brit. J. Pharmacol. 25, 171–178 (1965).
Chang, C.C., Costa, E. — Kuntzman, R.: Pharmacological consequences of selective depletion of catechol amines by antihypertensive agents. Ann. N.Y. Acad. Sci. 88, 939–943 (1960).
Brown, G.L., Gray, J.A.B.: Some effects of nicotine-like substances and their relation to sensory nerve endings. J. Physiol. (Lond.) 107, 306–317 (1948).
Gray, J.A.B. — Macintosh, F.C.: Discharges in nerve fibres produced by potassium ions. J. Physiol. (Lond.) 96, 10 P (1939).
Cabrera, R., Torrance, R.W., Viveros, H.: The action of acetylcholine and other drugs upon the terminal parts of the postganglionic sympathetic fibre. Brit. J. Pharmacol. 27, 51–63 (1966).
Cass, R., Kuntzman, R., Brodie, B.B.: Norepinephrine depletion as a possible mechanism of action of guanethidine (Su 5864), a New Hypotensive Agent. Proc. Soc. exp. Biol. (N.Y.) 103, 871–872 (1960).
Kuntzman, R., Brodie, B.B. — Spriggs, T.L.B.: Tissue amine levels and sympathetic blockade after guanethidine and bretylium. Brit. J. Pharmacol. 17, 442–450 (1961).
Chang, C.C., Chang, J.C., Su, C.Y.: Studies on the interactions of guanethidine and bretylium with noradrenaline stores. Brit. J. Pharmacol. 30, 213–223 (1967).
Davey, M.J., Farmer, J.B.: The mode of action of tyramine. J. Pharm. Pharmacol. 15, 178–182 (1963).
Davey, M.J., Hayden, M.L., Scholfield, P.C.: The effects of bretylium on C fibre excitation and noradrenaline release by acetylcholine and electrical stimulation. Brit. J. Pharmacol. 34, 377–387 (1968).
Dhalla, N.S., Gandhi, S.S., Bhagat, B.: Studies on the mechanism of positive inotropic and chronotropic actions of bretylium and tyramine. Pharmacology 1, 246–252 (1968).
Douglas, W.W.: The effect of a ganglion-blocking drug, hexamethonium, on the response of the cat’s carotid body to various stimuli. J. Physiol. (Lond.) 118, 373–383(1952).
— Gray, J.A.B.: The excitant action of acetylcholine and other substances on cutaneous sensory pathways and its prevention by hexamethonium and D-tubocurarine. J. Physiol. (Lond.) 119, 118–128 (1953).
Exley, K.A.: The persistence of adrenergic nerve conduction after TM 10 or bretylium in the cat. In Adrenergic Mechanisms, CIBA Foundation 158–161. London: Churchill 1960.
Ferry, C.B.: The sympathomimetic effect of acetylcholine on the spleen of the cat. J. Physiol. (Lond.) 167, 487–504 (1963).
Furchgott, R.F., Sanchez-Garcia, P.: Inhibition of monoamine oxidase of adrenergic nerve terminals of bretylium. Pharmacologist 8, 176 (1966).
Haeggendal, J.: An improved method for fluorimetric determination of small amounts of adrenaline and noradrenaline in plasma and tissues. Acta physiol. scand. 59, 242–254 (1963).
Haeusler, G., Haefely, W., Huerlimann, A.: Zum Mechanismus der adrenerg blockierenden Wirkung von Bretylium und Guanethidin. Naunyn-Schmiedebergs Arch. Pharmak. 264, 241–243 (1969 a).
— Thoenen, H.: Chemical sympathectomy of the cat with 6-hydroxydopamine. J. Pharmacol. exp. Ther. (in press).
Haefely, W., Huerlimann, A. — Thoenen, H., Haefely, W.: Chemische Sympathektomie der Katze mit 6-Hydroxydopamin: Veränderungen von Sympathicusreizeffekten und Noradrenalin-empfindlichkeit. Helv. physiol. pharmacol. Acta 26, CR 223–CR 225 (1968a).
Haefely, W., Huerlimann, A. — Huerlimann, A.: Durch Acetylcholin hervorgerufene antidrome Aktivität im kardialen Sympathicus und Noradrenalinfreisetzung unter Guanethidin. Helv. physiol. pharmacol. Acta 26, CR 352–CR 354 (1968b).
Haefely, W., Huerlimann, A. — Electrical events in cardiac adrenergic nerves and noradrenaline release from the heart induced by acetylcholine and KC1. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 261, 389–411 (1968c).
Haefely, W., Huerlimann, A. — Elektrosekretorische Koppelung bei der Noradrenalinfreisetzung aus adrenergen Nervenfasern durch nicotinartig wirkende Substanzen. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 263, 217–218 (1969b).
Hukovic, A., Muscholl, E.: Die Noradrenalinabgabe aus dem isolierten Kaninchenherzen bei sympathischer Nervenreizung und ihre pharmakologische Beeinflussung. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 244, 81–96 (1962).
Kirpekar, S.M., Furchgott, R.F.: The sympathomimetic action of bretylium on isolated atria and aortic smooth muscle. J. Pharmacol. exp. Ther. 143, 64–76 (1964).
Kosterlitz, H.W., Lees, G.M.: Action of bretylium on the isolated guinea pig ileum. Brit. J. Pharmacol. 17, 82–86 (1961).
Rand, M.J., Wilson, J.: The actions of some adrenergic neurone blocking drugs at cholinergic junctions. Europ. J. Pharmacol. 1, 210–221 (1967).
Spriggs, T.L.B.: Peripheral noradrenaline and adrenergic transmission in the rat. Brit. J. Pharmacol. 26, 271–281 (1966).
Thoenen, H., Haefely, W., Staehelin, H.: Potentiation by tetraethylammonium of the response of the cat spleen to postganglionic sympathetic nerve stimulation. J. Pharmacol. exp. Ther. 157, 532–540 (1967).
Haefely, W., Staehelin, H. — Huerlimann, A., Haefely, W.: The effect of postganglionic sympathetic stimulation on the isolated, perfused spleen of the cat. Helv. physiol. pharmacol. Acta 21, 17–26(1963).
Haefely, W., Staehelin, H. — Tranzer, J.P.: Chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-hydroxydopamine. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 261, 271–288 (1968).
Tranzer, J.P., Thoenen, H.: An electron microscopic study of selective, acute degeneration of sympathetic nerve terminals after administration of 6-hydroxydopamine. Experientia (Basel) 24, 155–156 (1968).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1969 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Haeusler, G., Haefely, W., Huerlimann, A. (1969). On the Mechanism of the Adrenergic Nerve Blocking Action of Bretylium. In: Habermann, E., et al. Naunyn Schmiedebergs Archiv für Pharmakologie. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-39718-3_326
Download citation
DOI: https://doi.org/10.1007/978-3-662-39718-3_326
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-38809-9
Online ISBN: 978-3-662-39718-3
eBook Packages: Springer Book Archive