Interactions of metoclopramide and ergotamine with human 5-HT3A receptors and human 5-HT reuptake carriers

被引:27
作者
Walkembach, J
Brüss, M
Urban, BW
Barann, M
机构
[1] Univ Kliniken Bonn, Klin & Poliklin Anasthesiol & Operat Intensivmed, D-53105 Bonn, Germany
[2] Univ Bonn, Inst Pharmakol & Toxikol, D-53113 Bonn, Germany
关键词
5-HT3; receptor; 5-HT reuptake carrier; metoclopramide; migraine; ergotamine; emesis;
D O I
10.1038/sj.bjp.0706351
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
I The actions of metoclopramide and ergotamine, drugs which are used as a combined migraine medication, on human (h)5-HT3A receptors and 5-HT reuptake carriers, stably expressed in HEK-293 cells, were studied with patch-clamp- and ([H-3]5-HT)-uptake techniques. 2 At clinical concentrations, metoclopramide inhibited peak and integrated currents through h5-HT3A receptors concentration-dependently (IC50 = 0.064 and 0.076 mu M, respectively) when it was applied in equilibrium (60 s before and during 5-HT (30 mu M) exposure). The onset and offset time constants of metoclopramide action were 1.3 and 2.1 s, respectively. The potency of metoclopramide when exclusively applied during the agonist pulse decreased more than 200-fold (IC50 = 19.0 mu M, peak current suppression). 3 Metoclopramide (0.10 mu M) did not alter the EC50 of 5-HT-induced peak currents. In contrast to the lack of competitive interaction between metoclopramide and 5-HT in this functional assay, metoclopramide inhibited specific [H-3]GR65630 binding to human h5-HT3A receptors in a surmountable manner. This seeming discrepancy between functional studies and radioligand binding experiments may be accounted for by (1) the slow kinetics of inhibition of peak currents by metoclopramide compared with the fast onset and offset kinetics of 5-HT-induced currents and (2) the low efficacy of metoclopramide in inhibiting radioligand binding (e.g. only 20% binding inhibition compared to 79% peak current suppression by 200 nM metoclopramide). 4 At low concentrations (1-10 nM), ergotamine had no effect on 5-HT (30 mu M)-induced peak currents. Above clinical concentrations, ergotamine (> 3 mu M) inhibited them. 5 When both drugs were applied together (0.10 mu M metoclopramide + 0.001 to 0.01 mu M ergotamine), an inhibition of both, peak and integrated current responses was observed. 6 Neither metoclopramide (<= 30 mu M) nor ergotamine (<= 30 mu M) had an effect on the 5-HT reuptake carrier as they did not alter the citalopram-sensitive [H-3]5-HT uptake.
引用
收藏
页码:543 / 552
页数:10
相关论文
共 43 条
  • [1] 5-HT3 RECEPTOR ANTAGONISTS - AN OVERVIEW OF THEIR PRESENT STATUS AND FUTURE POTENTIAL IN CANCER THERAPY-INDUCED EMESIS
    AAPRO, MS
    [J]. DRUGS, 1991, 42 (04) : 551 - 568
  • [2] Direct inhibition by cannabinoids of human 5-HT3A receptors:: probable involvement of an allosteric modulatory site
    Barann, M
    Molderings, G
    Brüss, M
    Bönisch, H
    Urban, BW
    Göthert, M
    [J]. BRITISH JOURNAL OF PHARMACOLOGY, 2002, 137 (05) : 589 - 596
  • [3] Inhibition of 5-HT3 receptors by propofol:: equilibrium and kinetic measurements
    Barann, M
    Dilger, JP
    Bönisch, H
    Göthert, M
    Dybek, A
    Urban, BW
    [J]. NEUROPHARMACOLOGY, 2000, 39 (06) : 1064 - 1074
  • [4] BARANN M, 2000, N-S ARCH PHARMACOL, V93, P309
  • [5] Barnard EA, 2002, MOLECULAR AND BASIC MECHANISMS OF ANESTHESIA, P44
  • [6] Belelli D, 1995, MOL PHARMACOL, V48, P1054
  • [7] Ion permeation and conduction in a human recombinant 5-HT3 receptor subunit (h5-HT3A)
    Brown, AM
    Hope, AG
    Lambert, JJ
    Peters, JA
    [J]. JOURNAL OF PHYSIOLOGY-LONDON, 1998, 507 (03): : 653 - 665
  • [8] EVIDENCE FOR 5-HT1B 1D RECEPTORS MEDIATING THE ANTIMIGRAINE EFFECT OF SUMATRIPTAN AND DIHYDROERGOTAMINE
    BUZZI, MG
    MOSKOWITZ, MA
    [J]. CEPHALALGIA, 1991, 11 (04) : 165 - 168
  • [9] EXCITATION OF AREA POSTREMA NEURONS BY TRANSMITTERS, PEPTIDES, AND CYCLIC-NUCLEOTIDES
    CARPENTER, DO
    BRIGGS, DB
    KNOX, AP
    STROMINGER, N
    [J]. JOURNAL OF NEUROPHYSIOLOGY, 1988, 59 (02) : 358 - 369
  • [10] ZATOSETRON, A 5-HT3, RECEPTOR ANTAGONIST IN A MULTICENTER TRIAL FOR ACUTE MIGRAINE
    CHAPPELL, AS
    BAY, J
    BOTZUM, GD
    COHEN, ML
    [J]. NEUROPHARMACOLOGY, 1994, 33 (3-4) : 509 - 513