Neural 5-HT 4 receptors in the human isolated detrusor muscle

Effects of indole, benzimidazolone and substituted benzamide agonists and antagonists

S. M. Candura, Eliana Messori, G. P. Franceschetti, G. D'Agostino, D. Vicini, Monica Tagliani, M. Tonini

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

1. In strips of human isolated detrusor muscle, the 5-hydroxytryptamine (5-HT) receptor (5-HT 4) that mediates facilitation of neuromuscular cholinergic transmission was further characterized by using 5-HT and a series of ligands known for their 5-HT 4 agonist (5-methoxytryptamine: 5-MeOT, cisapride, (R,S)-zacopride, BIMU 8) or antagonist (RS 23597, GR 125487, DAU 6285) properties. 2. In the presence of methysergide (1 μM) and ondansetron (3 μM) to isolate pharmacologically the 5-HT 4 receptors, 5-HT (0.3 nM-1 μM), 5-MeOT (10 nM-30 μM), BIMU 8 (10 nM-3 μM), cisapride (0.1-10 μM) and (R,S)-zacopride (0.1-30 μM) potentiated cholinergic contractions to electrical held stimulation in a concentration-dependent manner. RS 23597 (10 nM-10 μM), a competitive 5-HT 4 receptor antagonist in other systems, also showed agonist properties. The following rank order of potency as an agonist was obtained: 5-HT (pEC 50 = 8.0) > RS 23597 (7.0) = BIMU 8 (6.9) ≤ cisapride (6.6) > 5-MeOT (6.0) ≤ (R,S)-zacopride (5.7). Relative to 5-HT (intrinsic activity = 1), 5-MeOT acted as a full agonist (1.03), while BIMU 8 (0.76), (R,S)-zacopride (0.61), RS 23597 (0.60) and cisapride (0.41) behaved as partial agonists. 3. The potentiation by 5-HT was competitively antagonized by the selective 5-HT 4 receptor antagonist GR 125487 (0.3-3 nM) with a pA 2 estimate of 9.75 (Schild slope of 1.09), and by DAU 6285 (1 μM; pK(B) = 6.45). Additionally, GR 125487 (3 nM) antagonized the responses to 5-MeOT (pK(B) = 9.72) and reversed the potentiation induced by RS 23597. As an antagonist, RS 23597 (10, 30 and 100 nM) inhibited the response to 5-HT. In addition, 30 and 100 nM RS 23597 reduced the 5-HT response maximum by 30 and 50%, respectively. The pK(B) value calculated at 10 nM was 8.0. 4. Thus, in the human isolated detrusor muscle, the 5-HT 4 receptors mediating facilitation of cholinergic neuromuscular transmission are activated by indoleamines (5-HT, 5-MeOT), substituted benzamide (cisapride, (R,S)-zacopride), benzoate (RS 23597) and benzimidazolone (BIMU 8) derivatives. The activities (in terms of both potency and efficacy) of most agonists, as well as the affinity estimates of the antagonists GR 125487 and DAU 6285, are comparable to those found in other peripheral tissues. Exceptions are RS 23597, which acted either as a partial agonist or as an antagonist of the response to 5-HT, and 5-MeOT that showed an unusually low potency. The latter findings may be ascribed to differences in the efficiency of receptor coupling mechanisms and/or in the molecular structure (i.e. splice variants) of the 5-HT 4 receptor.

Original languageEnglish
Pages (from-to)1965-1970
Number of pages6
JournalBritish Journal of Pharmacology
Volume118
Issue number8
Publication statusPublished - 1996

Fingerprint

Receptors, Serotonin, 5-HT4
Serotonin
Cisapride
Muscles
Cholinergic Agents
5-Methoxytryptamine
benzamide
indole
benzimidazolone
Methysergide
Ondansetron
Serotonin Receptor Agonists
Benzoates
Molecular Structure
Electric Stimulation

Keywords

  • 5-HT receptor agonists
  • 5-hydroxytryptamine
  • DAU 6285
  • Detrusor strips
  • GR 125487
  • Human urinary bladder
  • Neuromuscular cholinergic transmission
  • RS 23597

ASJC Scopus subject areas

  • Pharmacology

Cite this

Neural 5-HT 4 receptors in the human isolated detrusor muscle : Effects of indole, benzimidazolone and substituted benzamide agonists and antagonists. / Candura, S. M.; Messori, Eliana; Franceschetti, G. P.; D'Agostino, G.; Vicini, D.; Tagliani, Monica; Tonini, M.

In: British Journal of Pharmacology, Vol. 118, No. 8, 1996, p. 1965-1970.

Research output: Contribution to journalArticle

Candura, S. M. ; Messori, Eliana ; Franceschetti, G. P. ; D'Agostino, G. ; Vicini, D. ; Tagliani, Monica ; Tonini, M. / Neural 5-HT 4 receptors in the human isolated detrusor muscle : Effects of indole, benzimidazolone and substituted benzamide agonists and antagonists. In: British Journal of Pharmacology. 1996 ; Vol. 118, No. 8. pp. 1965-1970.
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T1 - Neural 5-HT 4 receptors in the human isolated detrusor muscle

T2 - Effects of indole, benzimidazolone and substituted benzamide agonists and antagonists

AU - Candura, S. M.

AU - Messori, Eliana

AU - Franceschetti, G. P.

AU - D'Agostino, G.

AU - Vicini, D.

AU - Tagliani, Monica

AU - Tonini, M.

PY - 1996

Y1 - 1996

N2 - 1. In strips of human isolated detrusor muscle, the 5-hydroxytryptamine (5-HT) receptor (5-HT 4) that mediates facilitation of neuromuscular cholinergic transmission was further characterized by using 5-HT and a series of ligands known for their 5-HT 4 agonist (5-methoxytryptamine: 5-MeOT, cisapride, (R,S)-zacopride, BIMU 8) or antagonist (RS 23597, GR 125487, DAU 6285) properties. 2. In the presence of methysergide (1 μM) and ondansetron (3 μM) to isolate pharmacologically the 5-HT 4 receptors, 5-HT (0.3 nM-1 μM), 5-MeOT (10 nM-30 μM), BIMU 8 (10 nM-3 μM), cisapride (0.1-10 μM) and (R,S)-zacopride (0.1-30 μM) potentiated cholinergic contractions to electrical held stimulation in a concentration-dependent manner. RS 23597 (10 nM-10 μM), a competitive 5-HT 4 receptor antagonist in other systems, also showed agonist properties. The following rank order of potency as an agonist was obtained: 5-HT (pEC 50 = 8.0) > RS 23597 (7.0) = BIMU 8 (6.9) ≤ cisapride (6.6) > 5-MeOT (6.0) ≤ (R,S)-zacopride (5.7). Relative to 5-HT (intrinsic activity = 1), 5-MeOT acted as a full agonist (1.03), while BIMU 8 (0.76), (R,S)-zacopride (0.61), RS 23597 (0.60) and cisapride (0.41) behaved as partial agonists. 3. The potentiation by 5-HT was competitively antagonized by the selective 5-HT 4 receptor antagonist GR 125487 (0.3-3 nM) with a pA 2 estimate of 9.75 (Schild slope of 1.09), and by DAU 6285 (1 μM; pK(B) = 6.45). Additionally, GR 125487 (3 nM) antagonized the responses to 5-MeOT (pK(B) = 9.72) and reversed the potentiation induced by RS 23597. As an antagonist, RS 23597 (10, 30 and 100 nM) inhibited the response to 5-HT. In addition, 30 and 100 nM RS 23597 reduced the 5-HT response maximum by 30 and 50%, respectively. The pK(B) value calculated at 10 nM was 8.0. 4. Thus, in the human isolated detrusor muscle, the 5-HT 4 receptors mediating facilitation of cholinergic neuromuscular transmission are activated by indoleamines (5-HT, 5-MeOT), substituted benzamide (cisapride, (R,S)-zacopride), benzoate (RS 23597) and benzimidazolone (BIMU 8) derivatives. The activities (in terms of both potency and efficacy) of most agonists, as well as the affinity estimates of the antagonists GR 125487 and DAU 6285, are comparable to those found in other peripheral tissues. Exceptions are RS 23597, which acted either as a partial agonist or as an antagonist of the response to 5-HT, and 5-MeOT that showed an unusually low potency. The latter findings may be ascribed to differences in the efficiency of receptor coupling mechanisms and/or in the molecular structure (i.e. splice variants) of the 5-HT 4 receptor.

AB - 1. In strips of human isolated detrusor muscle, the 5-hydroxytryptamine (5-HT) receptor (5-HT 4) that mediates facilitation of neuromuscular cholinergic transmission was further characterized by using 5-HT and a series of ligands known for their 5-HT 4 agonist (5-methoxytryptamine: 5-MeOT, cisapride, (R,S)-zacopride, BIMU 8) or antagonist (RS 23597, GR 125487, DAU 6285) properties. 2. In the presence of methysergide (1 μM) and ondansetron (3 μM) to isolate pharmacologically the 5-HT 4 receptors, 5-HT (0.3 nM-1 μM), 5-MeOT (10 nM-30 μM), BIMU 8 (10 nM-3 μM), cisapride (0.1-10 μM) and (R,S)-zacopride (0.1-30 μM) potentiated cholinergic contractions to electrical held stimulation in a concentration-dependent manner. RS 23597 (10 nM-10 μM), a competitive 5-HT 4 receptor antagonist in other systems, also showed agonist properties. The following rank order of potency as an agonist was obtained: 5-HT (pEC 50 = 8.0) > RS 23597 (7.0) = BIMU 8 (6.9) ≤ cisapride (6.6) > 5-MeOT (6.0) ≤ (R,S)-zacopride (5.7). Relative to 5-HT (intrinsic activity = 1), 5-MeOT acted as a full agonist (1.03), while BIMU 8 (0.76), (R,S)-zacopride (0.61), RS 23597 (0.60) and cisapride (0.41) behaved as partial agonists. 3. The potentiation by 5-HT was competitively antagonized by the selective 5-HT 4 receptor antagonist GR 125487 (0.3-3 nM) with a pA 2 estimate of 9.75 (Schild slope of 1.09), and by DAU 6285 (1 μM; pK(B) = 6.45). Additionally, GR 125487 (3 nM) antagonized the responses to 5-MeOT (pK(B) = 9.72) and reversed the potentiation induced by RS 23597. As an antagonist, RS 23597 (10, 30 and 100 nM) inhibited the response to 5-HT. In addition, 30 and 100 nM RS 23597 reduced the 5-HT response maximum by 30 and 50%, respectively. The pK(B) value calculated at 10 nM was 8.0. 4. Thus, in the human isolated detrusor muscle, the 5-HT 4 receptors mediating facilitation of cholinergic neuromuscular transmission are activated by indoleamines (5-HT, 5-MeOT), substituted benzamide (cisapride, (R,S)-zacopride), benzoate (RS 23597) and benzimidazolone (BIMU 8) derivatives. The activities (in terms of both potency and efficacy) of most agonists, as well as the affinity estimates of the antagonists GR 125487 and DAU 6285, are comparable to those found in other peripheral tissues. Exceptions are RS 23597, which acted either as a partial agonist or as an antagonist of the response to 5-HT, and 5-MeOT that showed an unusually low potency. The latter findings may be ascribed to differences in the efficiency of receptor coupling mechanisms and/or in the molecular structure (i.e. splice variants) of the 5-HT 4 receptor.

KW - 5-HT receptor agonists

KW - 5-hydroxytryptamine

KW - DAU 6285

KW - Detrusor strips

KW - GR 125487

KW - Human urinary bladder

KW - Neuromuscular cholinergic transmission

KW - RS 23597

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