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 language | English |
|---|---|
| Pages (from-to) | 1965-1970 |
| Number of pages | 6 |
| Journal | British Journal of Pharmacology |
| Volume | 118 |
| Issue number | 8 |
| Publication status | Published - 1996 |
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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 journal › Article
}
TY - JOUR
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
UR - http://www.scopus.com/inward/record.url?scp=0029658137&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029658137&partnerID=8YFLogxK
M3 - Article
VL - 118
SP - 1965
EP - 1970
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 8
ER -