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. 1976 May;57(1):115–125. doi: 10.1111/j.1476-5381.1976.tb07661.x

Mechanism of the indirect sympathomimetic effect of 5-hydroxytrypt-amine on the isolated heart of the rabbit.

J R Fozard, G M Mwaluko
PMCID: PMC1667018  PMID: 1276530

Abstract

1 Rabbit isolated hearts, perfused by the Langendorff technique, were used to investigate the indirect sympathomimetic effects of 5-hydroxytryptamine (5-HT). Comparisons were made with noradrenaline and with two indirectly acting sympathomimetic agents with entirely different mechanisms of action, tyramine and dimethylphenylpiperazinium (DMPP). 2 The cardiac stimulant effects of 5-HT, tyramine and DMPP were inhibited by propranolol and practolol and the pA2 values obtained were similar to those obtained with noradrenaline as the agonist. 3 Responses to 5-HT, tyramine and DMPP were greatly reduced on hearts from rabbits pretreated with 6-hydroxydopamine. Such hearts had less than 7% of their normal catecholamine concentration and no fluorescence characteristic of noradrenaline in the cardiac sympathetic nerves could be demonstrated. 4 Rapid, reversible and selective tachyphylaxis to 5-HT was demonstrated during perfusion with 5-HT. In hearts desensitized to DMPP by perfusion with DMPP, responses to 5-HT were also reduced. 5 Perfusion of hearts with colchicine inhibited stimulant responses to 5-HT and DMPP but had little effect on responses to noradrenaline or tyramine. 6 Desmethylimipramine enhanced cardiac stimulant responses to noradrenaline and to a lesser extent, those to 5-HT and DMPP. Responses to tyramine were consistently inhibited by desmethylimipramine. 7 Tetrodotoxin abolished responses of the heart to electrical nerve stimulation but left responses to noradrenaline, 5-HT and DMPP unaffected. 8 5-HT, tyramine and DMPP evoked 3H-release from hearts whose neuronal noradrenaline stores had been labelled by perfusion with [3H]-(-)-noradrenaline. The pattern of release evoked by 5-HT was similar to that of DMPP but differed from that of tyramine. 9 Reducing the calcium concentration in the Tyrode solution from 3.6 to 0.2 mEq/1 did not affect 3H-overflow after tyramine but greatly inhibited that evoked by 5-HT and DMPP. 10 The results confirm that the stimulatn effects of 5-HT on the rabbit isolated heart are the result of noradrenaline release. They further suggest that the site of the release is the terminal sympathetic nerve network. The mechanism of release shows more similarities to that of DMPP (calcium-dependent depolarization and exocytosis) than to that of tyramine (neuronal uptake and stoichiometric displacement).

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Selected References

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  1. ANDEN N. E. UPTAKE AND RELEASE OF DEXTRO- AND LAEVO-ADRENALINE IN NORADRENERGIC STORES. Acta Pharmacol Toxicol (Copenh) 1964;21:59–75. [PubMed] [Google Scholar]
  2. ARUNLAKSHANA O., SCHILD H. O. Some quantitative uses of drug antagonists. Br J Pharmacol Chemother. 1959 Mar;14(1):48–58. doi: 10.1111/j.1476-5381.1959.tb00928.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barth N., Manns M., Muscholl E. Arrhythmias and inhibition of noradrenaline uptake caused by tricyclic antidepressants and chlorpromazine on the isolated perfused rabbit heart. Naunyn Schmiedebergs Arch Pharmacol. 1975;288(2-3):215–231. doi: 10.1007/BF00500528. [DOI] [PubMed] [Google Scholar]
  4. Borisy G. G., Taylor E. W. The mechanism of action of colchicine. Binding of colchincine-3H to cellular protein. J Cell Biol. 1967 Aug;34(2):525–533. doi: 10.1083/jcb.34.2.525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chubb I. W., De Potter W. P., De Schaepdryver A. F. Tyramine does not release noradrenaline from splenic nerve by exocytosis. Naunyn Schmiedebergs Arch Pharmacol. 1972;274(3):281–286. doi: 10.1007/BF00501937. [DOI] [PubMed] [Google Scholar]
  6. Commarato M. A., Brody T. M., McNeill J. H. The effect of various drugs on the uptake and metabolism of tyramine-H3 in the rat heart. J Pharmacol Exp Ther. 1969 May;167(1):151–158. [PubMed] [Google Scholar]
  7. Douglas W. W., Rubin R. P. The mechanism of catecholamine release from the adrenal medulla and the role of calcium in stimulus-secretion coupling. J Physiol. 1963 Jul;167(2):288–310. doi: 10.1113/jphysiol.1963.sp007150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Douglas W. W., Sorimachi M. Colchicine inhibits adrenal medullary secretion evoked by acetylcholine without affecting that evoked by potassium. Br J Pharmacol. 1972 May;45(1):129–132. [PMC free article] [PubMed] [Google Scholar]
  9. Fillion G. M., Lluch S., Uvnäs B. Release of noradrenaline from the dog heart in situ after intravenous and intracoronary administration of 5-hydroxytryptamine. Acta Physiol Scand. 1971 Sep;83(1):115–123. doi: 10.1111/j.1748-1716.1971.tb05057.x. [DOI] [PubMed] [Google Scholar]
  10. Fozard J. R., Kelly M. J., Small R. C. Proceedings: Chemical sympathectomy of the rabbit with 6-hydroxydopamine. Br J Pharmacol. 1973 Sep;49(1):182P–183P. [PMC free article] [PubMed] [Google Scholar]
  11. Fozard J. R., Muscholl E. A useful muscarinic parameter and the differential recording of atrial and ventricular tension in the perfused rabbit heart. Naunyn Schmiedebergs Arch Pharmakol. 1971;270(4):319–325. doi: 10.1007/BF01002343. [DOI] [PubMed] [Google Scholar]
  12. GADDUM J. H., PICARELLI Z. P. Two kinds of tryptamine receptor. Br J Pharmacol Chemother. 1957 Sep;12(3):323–328. doi: 10.1111/j.1476-5381.1957.tb00142.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. GILLIS C. N. CHARACTERISTICS OF NOREPINEPHRINE RETENTION BY A SUBCELLULAR FRACTION OF RABBIT HEART. J Pharmacol Exp Ther. 1964 Oct;146:54–60. [PubMed] [Google Scholar]
  14. HUKOVIC S., MUSCHOLL E. [Noradrenalin loss from the isolated rabbit heart following sympathetic nerve irritation and its pharmacological alteration]. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1962;244:81–96. [PubMed] [Google Scholar]
  15. Haefely W. The effects of 5-hydroxytryptamine and some related compounds on the cat superior cervical ganglion in situ. Naunyn Schmiedebergs Arch Pharmacol. 1974;281(2):145–165. doi: 10.1007/BF00503495. [DOI] [PubMed] [Google Scholar]
  16. Haefely W. The effects of l,l-dimethyl-4-phenyl-piperazinium (DMPP) in the cat superior cervical ganglion in situ. Naunyn Schmiedebergs Arch Pharmacol. 1974;281(1):57–91. doi: 10.1007/BF00500612. [DOI] [PubMed] [Google Scholar]
  17. INNES I. R. An action of 5-hydroxytryptamine on adrenaline receptors. Br J Pharmacol Chemother. 1962 Dec;19:427–441. doi: 10.1111/j.1476-5381.1962.tb01447.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. JACOB J., POITE-BEVIERRE M. [Action of serotonin and 1-benzyl-2, 5-dimethylserotonin on the isolated rabbit heart]. Arch Int Pharmacodyn Ther. 1960 Aug 1;127:11–26. [PubMed] [Google Scholar]
  19. Jester J., Horst W. D. Influence of serotonin on adrenergic mechanisms. Biochem Pharmacol. 1972 Feb 1;21(3):333–338. doi: 10.1016/0006-2952(72)90344-9. [DOI] [PubMed] [Google Scholar]
  20. Kraicer J., Milligan J. V. Effect of colchicine on in vitro ACTH release induced by HIGH K+ and by hypothalamus-stalk-median eminance extract. Endocrinology. 1971 Aug;89(2):408–412. doi: 10.1210/endo-89-2-408. [DOI] [PubMed] [Google Scholar]
  21. Krauss K. R., Carpenter D. O., Kopin I. J. Acetylcholine-induced release of norepinephrine in the presence of tetrodotoxin. J Pharmacol Exp Ther. 1970 Jun;173(2):416–421. [PubMed] [Google Scholar]
  22. Kuriyama H., Osa T., Toida N. Effect of tetrodotoxin on smooth muscle cells of the guinea-pig taenia coli. Br J Pharmacol Chemother. 1966 Aug;27(2):366–376. doi: 10.1111/j.1476-5381.1966.tb01668.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lacy P. E., Howell S. L., Young D. A., Fink C. J. New hypothesis of insulin secretion. Nature. 1968 Sep 14;219(5159):1177–1179. doi: 10.1038/2191177a0. [DOI] [PubMed] [Google Scholar]
  24. Lindmar R., Löffelholz K., Muscholl E. A muscarinic mechanism inhibiting the release of noradrenaline from peripheral adrenergic nerve fibres by nicotinic agents. Br J Pharmacol Chemother. 1968 Feb;32(2):280–294. doi: 10.1111/j.1476-5381.1968.tb00972.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lindmar R., Löffelholz K., Muscholl E. Unterschiede zwischen Tyramin und Dimethylphenylpiperzin in der Ca-Abhangigkeit und im zeitlichen Verlauf der Noradrenalin-Freisetzung am isolierten Kaninchenherzen. Experientia. 1967 Nov 15;23(11):933–934. doi: 10.1007/BF02136230. [DOI] [PubMed] [Google Scholar]
  26. Löffelholz K. Autoinhibition of nicotinic release of noradrenaline from postganglionic sympathetic nerves. Naunyn Schmiedebergs Arch Pharmakol. 1970;267(1):49–63. doi: 10.1007/BF00997114. [DOI] [PubMed] [Google Scholar]
  27. Löffelholz K. Nicotinic drugs and postganglionic sympathetic transmission. Naunyn Schmiedebergs Arch Pharmakol. 1970;267(1):64–73. doi: 10.1007/BF00997115. [DOI] [PubMed] [Google Scholar]
  28. MUSACCHIO J. M., KOPIN I. J., WEISE V. K. SUBCELLULAR DISTRIBUTION OF SOME SYMPATHOMIMETIC AMINES AND THEIR BETA-HYDROXYLATED DERIVATIVES IN THE RAT HEART. J Pharmacol Exp Ther. 1965 Apr;148:22–28. [PubMed] [Google Scholar]
  29. Pluchino S. Direct and indirect effects of 5-hydroxytryptamine and tyramine on cat smooth muscle. Naunyn Schmiedebergs Arch Pharmacol. 1972;272(2):189–224. doi: 10.1007/BF00508769. [DOI] [PubMed] [Google Scholar]
  30. Poisner A. M., Douglas W. W. The need for calcium in adrenomedullary secretion evoked by biogenic amines, polypeptides, and muscarinic agents. Proc Soc Exp Biol Med. 1966 Oct;123(1):62–64. doi: 10.3181/00379727-123-31402. [DOI] [PubMed] [Google Scholar]
  31. ROCHA E SILVA M., VALLE J. R., PICARELLI P. A pharmacological analysis of the mode of action of serotonin (5-hydroxytryptamine) upon the guinea-pig ileum. Br J Pharmacol Chemother. 1953 Dec;8(4):378–388. doi: 10.1111/j.1476-5381.1953.tb01333.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Smith C. B. The role of monoamine oxidase in the intraneuronal metabolism of norepinephrine released by indirectly-acting sympathomimetic amines or by adrenergic nerve stimulation. J Pharmacol Exp Ther. 1966 Feb;151(2):207–220. [PubMed] [Google Scholar]
  33. Sorimachi M., Oesch F., Thoenen H. Effects of colchicine and cytochalasin B on the release of 3 H-norepinephrine from guinea-pig atria evoked by high potassium, nicotine and tyramine. Naunyn Schmiedebergs Arch Pharmacol. 1973;276(1):1–12. doi: 10.1007/BF00500773. [DOI] [PubMed] [Google Scholar]
  34. Spriggs T. L., Lever J. D., Rees P. M., Graham J. D. Controlled formaldehyde-catecholamine condensation in cryostat sections to show adrenergic nerves by fluorescence. Stain Technol. 1966 Nov;41(6):323–327. doi: 10.3109/10520296609116333. [DOI] [PubMed] [Google Scholar]
  35. Starke K. Action of angiotensin on uptake, release and metabolism of 14C-noradrenaline by isolated rabbit hearts. Eur J Pharmacol. 1971 Apr;14(2):112–123. doi: 10.1016/0014-2999(71)90204-4. [DOI] [PubMed] [Google Scholar]
  36. Su C., Bevan J. A. Blockade of the nicotine-induced norepinephrine release by cocaine, phenoxybenzamine and desipramine. J Pharmacol Exp Ther. 1970 Nov;175(2):533–540. [PubMed] [Google Scholar]
  37. TRENDELENBURG U. The action of 5-hydroxytryptamine on the nictitating membrane and on the superior cervical ganglion of the cat. Br J Pharmacol Chemother. 1956 Mar;11(1):74–80. doi: 10.1111/j.1476-5381.1956.tb01031.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. TRENDELENBURG U. The action of histamine and 5-hydroxytryptamine on isolated mammalian atria. J Pharmacol Exp Ther. 1960 Dec;130:450–460. [PubMed] [Google Scholar]
  39. Thoa N. B., Wooten G. F., Axelrod J., Kopin I. J. On the mechanism of release of norepinephrine from sympathetic nerves induced by depolarizing agents and sympathomimetic drugs. Mol Pharmacol. 1975 Jan;11(1):10–18. [PubMed] [Google Scholar]
  40. Thoenen H., Huerlimann A., Haefely W. Cation dependence of the noradrenaline-releasing action of tyramine. Eur J Pharmacol. 1969 Apr;6(1):29–37. doi: 10.1016/0014-2999(69)90061-2. [DOI] [PubMed] [Google Scholar]
  41. Welch A. S., Welch B. L. Solvent extraction method for simultaneous determination of norepinephrine, dopamine, serotonin, and 5-hydroxyindoleacetic acid in a single mouse brain. Anal Biochem. 1969 Aug;30(2):161–179. doi: 10.1016/0003-2697(69)90387-x. [DOI] [PubMed] [Google Scholar]
  42. Westfall T. C., Brasted M. The mechanism of action of nicotine on adrenergic neurons in the perfused guinea-pig heart. J Pharmacol Exp Ther. 1972 Sep;182(3):409–418. [PubMed] [Google Scholar]

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