Inhibition of Noradrenaline Release Via Presynaptic 5-HT1D Alpha Receptors in Human Atrium

Overview

Journal Naunyn Schmiedebergs Arch Pharmacol

Specialty Pharmacology

Date 1996 Feb 1

PMID 8692281

Citations 8

Authors

G J Molderings

D Frolich

J Likungu

M Gothert

Affiliations

Soon will be listed here.

Abstract

In segments of human right atrial appendages preincubated with [3H]noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone, we determined the effects of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on tritium overflow evoked by transmural electrical stimulation (2 Hz). Tritium overflow was inhibited by 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole succinate (RU 24969) and sumatriptan. Yohimbine and oxymetazoline (in the presence of idazoxan) also inhibited tritium overflow. The inhibitory potency of the drugs was significantly correlated with their affinity for 5-HTID receptors in human brain and for cloned human 5-HT1D alpha and 5-HT1D beta receptors, but not with their affinity for 5-HT1B, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5A, 5-HT5B and 5-HT7 receptors. The potency order 5-CT > 5-HT > 5-MeOT is opposite to the order of affinities reported for 5-HT6 binding sites. The preferential 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (up to 0.3 microM) and the selective 5-HT4 receptor agonist cisapride (up to 1 microM) failed to inhibit tritium overflow. L-694,247, a potent 5-HT1D beta receptor agonist, did not inhibit tritium overflow, but counteracted the inhibitory effect of 5-HT. Ketanserin at a concentration which should block 5-HT1D alpha but not 5-HT1D beta receptors and methiothepin at a concentration which may be assumed to block both 5-HT1D alpha and 5-HT1D beta receptors antagonized the inhibitory effect of 5-HT. Propranolol and ondansetron did not modify the 5-HT-induced inhibition of release. In conclusion, noradrenaline release in human right atrial appendages is inhibited via 5-HT receptors which are located on the noradrenergic axon terminals. These inhibitory presynaptic 5-HT receptors belong to the 5-HT1D subfamily. The ability of ketanserin to antagonize the inhibitory effect induced by activation of these receptors suggests that they can be subclassified as 5-HT1D alpha.

Citing Articles

The metabolic and cardiovascular effects of amphetamine are partially mediated by the central melanocortin system.

Simonds S, Pryor J, Lam B, Dowsett G, Mustafa T, Munder A Cell Rep Med. 2025; 6(2):101936.

PMID: 39914386 PMC: 11866487. DOI: 10.1016/j.xcrm.2025.101936.

Serotonergic Modulation of Neurovascular Transmission: A Focus on Prejunctional 5-HT Receptors/Mechanisms.

Gonzalez-Hernandez A, Marichal-Cancino B, MaassenVanDenBrink A, Villalon C Biomedicines. 2023; 11(7).

PMID: 37509503 PMC: 10377335. DOI: 10.3390/biomedicines11071864.

Serotonin and beyond-a tribute to Manfred Göthert (1939-2019).

Bonisch H, Fink K, Malinowska B, Molderings G, Schlicker E Naunyn Schmiedebergs Arch Pharmacol. 2021; 394(9):1829-1867.

PMID: 33991216 PMC: 8376721. DOI: 10.1007/s00210-021-02083-5.

International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function.

Barnes N, Ahern G, Becamel C, Bockaert J, Camilleri M, Chaumont-Dubel S Pharmacol Rev. 2020; 73(1):310-520.

PMID: 33370241 PMC: 7770494. DOI: 10.1124/pr.118.015552.

Further characterization of the 5-HT1 receptors mediating cardiac sympatho-inhibition in pithed rats: pharmacological correlation with the 5-HT1B and 5-HT1D subtypes.

Sanchez-Lopez A, Centurion D, Vazquez E, Arulmani U, Saxena P, Villalon C Naunyn Schmiedebergs Arch Pharmacol. 2003; 369(2):220-7.

PMID: 14673512 DOI: 10.1007/s00210-003-0842-0.

References

Molderings G, Werner K, Likungu J, Gothert M . Inhibition of noradrenaline release from the sympathetic nerves of the human saphenous vein via presynaptic 5-HT receptors similar to the 5-HT 1D subtype. Naunyn Schmiedebergs Arch Pharmacol. 1990; 342(4):371-7. DOI: 10.1007/BF00169451. View

Hoyer D, Clarke D, Fozard J, Hartig P, Martin G, Mylecharane E . International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev. 1994; 46(2):157-203. View

Hoyer D, Schoeffter P . 5-HT receptors: subtypes and second messengers. J Recept Res. 1991; 11(1-4):197-214. DOI: 10.3109/10799899109066399. View

Hartig P, Branchek T, Weinshank R . A subfamily of 5-HT1D receptor genes. Trends Pharmacol Sci. 1992; 13(4):152-9. DOI: 10.1016/0165-6147(92)90053-9. View

Starke K, Gothert M, Kilbinger H . Modulation of neurotransmitter release by presynaptic autoreceptors. Physiol Rev. 1989; 69(3):864-989. DOI: 10.1152/physrev.1989.69.3.864. View

Peroutka S, McCarthy B . Sumatriptan (GR 43175) interacts selectively with 5-HT1B and 5-HT1D binding sites. Eur J Pharmacol. 1989; 163(1):133-6. DOI: 10.1016/0014-2999(89)90406-8. View

Adham N, Kao H, Schecter L, Bard J, Olsen M, Urquhart D . Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase. Proc Natl Acad Sci U S A. 1993; 90(2):408-12. PMC: 45671. DOI: 10.1073/pnas.90.2.408. View

Kilpatrick G, Butler A, Hagan R, Jones B, Tyers M . [3H] GR67330, a very high affinity ligand for 5-HT3 receptors. Naunyn Schmiedebergs Arch Pharmacol. 1990; 342(1):22-30. DOI: 10.1007/BF00178967. View

Molderings G, Colling E, Likungu J, Jakschik J, Gothert M . Modulation of noradrenaline release from the sympathetic nerves of the human saphenous vein and pulmonary artery by presynaptic EP3- and DP-receptors. Br J Pharmacol. 1994; 111(3):733-8. PMC: 1910075. DOI: 10.1111/j.1476-5381.1994.tb14799.x. View

10.

Sharif N, Wong E, Loury D, Stefanich E, Michel A, Eglen R . Characteristics of 5-HT3 binding sites in NG108-15, NCB-20 neuroblastoma cells and rat cerebral cortex using [3H]-quipazine and [3H]-GR65630 binding. Br J Pharmacol. 1991; 102(4):919-25. PMC: 1917964. DOI: 10.1111/j.1476-5381.1991.tb12277.x. View

11.

Matthes H, Boschert U, Amlaiky N, Grailhe R, Plassat J, Muscatelli F . Mouse 5-hydroxytryptamine5A and 5-hydroxytryptamine5B receptors define a new family of serotonin receptors: cloning, functional expression, and chromosomal localization. Mol Pharmacol. 1993; 43(3):313-9. View

12.

Tsou A, Kosaka A, Bach C, Zuppan P, Yee C, Tom L . Cloning and expression of a 5-hydroxytryptamine7 receptor positively coupled to adenylyl cyclase. J Neurochem. 1994; 63(2):456-64. DOI: 10.1046/j.1471-4159.1994.63020456.x. View

13.

Zgombick J, Schechter L, Kucharewicz S, Weinshank R, Branchek T . Ketanserin and ritanserin discriminate between recombinant human 5-HT1D alpha and 5-HT1D beta receptor subtypes. Eur J Pharmacol. 1995; 291(1):9-15. DOI: 10.1016/0922-4106(95)90183-3. View

14.

Beer M, Stanton J, Bevan Y, Heald A, Reeve A, Street L . L-694,247: a potent 5-HT1D receptor agonist. Br J Pharmacol. 1993; 110(3):1196-200. PMC: 2175804. DOI: 10.1111/j.1476-5381.1993.tb13941.x. View

15.

Schoeffter P, Hoyer D . Interaction of the alpha-adrenoceptor agonist oxymetazoline with serotonin 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors. Eur J Pharmacol. 1991; 196(2):213-6. DOI: 10.1016/0014-2999(91)90432-p. View

16.

Gothert M, Fink K, Frolich D, Likungu J, Molderings G, Schlicker E . Presynaptic 5-HT auto- and heteroreceptors in the human central and peripheral nervous system. Behav Brain Res. 1996; 73(1-2):89-92. DOI: 10.1016/0166-4328(96)00076-9. View

17.

Schmidt A, Peroutka S . Quantitative molecular analysis predicts 5-hydroxytryptamine3 receptor binding affinity. Mol Pharmacol. 1990; 38(4):511-6. View

18.

Weinshank R, Zgombick J, Macchi M, Branchek T, Hartig P . Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT1D alpha and 5-HT1D beta. Proc Natl Acad Sci U S A. 1992; 89(8):3630-4. PMC: 48922. DOI: 10.1073/pnas.89.8.3630. View

19.

Fink K, Zentner J, Gothert M . Subclassification of presynaptic 5-HT autoreceptors in the human cerebral cortex as 5-HT1D receptors. Naunyn Schmiedebergs Arch Pharmacol. 1995; 352(4):451-4. DOI: 10.1007/BF00172785. View

20.

Schoeffter P, Waeber C, Palacios J, Hoyer D . The 5-hydroxytryptamine 5-HT1D receptor subtype is negatively coupled to adenylate cyclase in calf substantia nigra. Naunyn Schmiedebergs Arch Pharmacol. 1988; 337(6):602-8. DOI: 10.1007/BF00175784. View