Characterization of receptors mediating contraction induced by tachykinins in the guinea-pig isolated common bile duct

Riccardo Patacchini, L. Barthó, Carlo Alberto Maggi

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Abstract

1. We studied the effect of the natural tachykinins and of synthetic agonists selective for the tachykinin NK1, NK2 and NK3 receptors, on the motility of guinea-pig isolated common bile duct longitudinally-oriented smooth muscle. 2. All the tachykinins tested (both natural and synthetic) produced a concentration-dependent contractile response of the guinea-pig isolated common bile duct: these effects underwent a marked tachyphylaxis, especially the responses elicited by NK1 and NK3 receptor-selective agonists. 3. Among the natural tachykinins neurokinin B (EC50 = 3.2 nM; 95% c.l. = 2.0-5.1; n = 4) was the most potent, being about 40 and 25 fold more potent than substance P (EC50 = 121.6 nM; 95% c.l. = 94-157; P <0.01; n = 4) and neurokinin A (EC50 = 83.4 nM; 95% c.l. = 62-112; P <0.01; n = 4), respectively. Among the synthetic analogues the NK3 receptor-selective agonist senktide (EC50 = 1.1 nM; 95% c.l. = 0.7-1.8; n = 8) was the most potent, being about 120, 110 and 20 fold more potent than [Sar9]substance P sulfone (NK1 receptor-selective) (EC50 = 130.4 nM; 95% c.l. = 99-172; P <0.01; n = 8), [βAla8]NKA (4-10) (NK2 receptor-selective) (EC50 = 120.1 nM; 95% c.l. = 95-151; P <0.01; n = 8) and septide (NK1 receptor-selective) (EC50 = 22.6 nM; 95% c.l. = 18-28; P <0.01, n = 8), respectively. All tachykinins (natural or synthetic receptor agonists) produced a similar E(max), averaging about 50% of that produced by KCl (80 mM). 4. Atropine (1 μM) did not affect the responses to either NK1 or NK2 receptor-selective agonists, whereas it reduced the E(max) of senktide by about 50%, without affecting its potency (EC50). Tetrodotoxin (1 μM) totally blocked senktide-induced contractions, as did the combined pretreatment with atropine plus the tachykinin NK1 and NK2 receptor-selective antagonists GR 82334 and MEN 11420 (1 μM each), respectively. 5. GR 82334 (1 μM) blocked with apparent competitive kinetics septide- (apparent pK(B) = 7.46 ± 0.10; n = 5) and [Sar9]substance P sulfone- (apparent pK(B) = 6.80 ± 0.04; n = 4) induced contractions. MEN 11420 (30-300 nM), a novel potent NK2 receptor antagonist, potently antagonized [βAla8]NKA (4-10), with competitive kinetics (pK(B) = 8.25 ± 0.08; n = 12: Schild plot slope = -0.90; 95% c.l. = -1.4; -0.35). The NK3 receptor-selective antagonist SR 142801 (30 nM) produced insurmountable antagonism of the senktide-induced contractions (E(max) inhibited by 64%). None of the above antagonists, tested at the highest concentrations employed against tachykinins, affected the concentration-response curve to methacholine (0.1-300 μM). 6. We conclude that tachykinins produce contraction of the guinea-pig isolated common bile duct by stimulating NK1, NK2 and NK3 receptors. The responses obtained by activating NK1 and NK2 receptors are atropine-resistant. The contraction obtained by stimulating NK3 receptors is totally neurogenic, being mediated by the release of endogenous acetylcholine and tachykinins; the latter act, in turn, on postjunctional tachykinin NK1/NK2 receptors. The role of the NK3 receptor as prejunctional mediator of the excitatory transmission operated by tachykinins is discussed.

Original languageEnglish
Pages (from-to)1633-1638
Number of pages6
JournalBritish Journal of Pharmacology
Volume122
Issue number8
DOIs
Publication statusPublished - 1997

Fingerprint

Tachykinins
Common Bile Duct
Guinea Pigs
Substance P
Atropine
Sulfones
Neurokinin B
Artificial Receptors
Tachykinin Receptors
Neurokinin A
Tachyphylaxis
Multiple Endocrine Neoplasia Type 1
Methacholine Chloride
Tetrodotoxin
Acetylcholine
Smooth Muscle

Keywords

  • Guinea-pig common bile duct
  • MEN 11420
  • Tachykinin receptor antagonists
  • Tachykinin receptors
  • Tachykinins

ASJC Scopus subject areas

  • Pharmacology

Cite this

Characterization of receptors mediating contraction induced by tachykinins in the guinea-pig isolated common bile duct. / Patacchini, Riccardo; Barthó, L.; Maggi, Carlo Alberto.

In: British Journal of Pharmacology, Vol. 122, No. 8, 1997, p. 1633-1638.

Research output: Contribution to journalArticle

@article{01a3e43c01724d999ee75dd26cc24ab5,
title = "Characterization of receptors mediating contraction induced by tachykinins in the guinea-pig isolated common bile duct",
abstract = "1. We studied the effect of the natural tachykinins and of synthetic agonists selective for the tachykinin NK1, NK2 and NK3 receptors, on the motility of guinea-pig isolated common bile duct longitudinally-oriented smooth muscle. 2. All the tachykinins tested (both natural and synthetic) produced a concentration-dependent contractile response of the guinea-pig isolated common bile duct: these effects underwent a marked tachyphylaxis, especially the responses elicited by NK1 and NK3 receptor-selective agonists. 3. Among the natural tachykinins neurokinin B (EC50 = 3.2 nM; 95{\%} c.l. = 2.0-5.1; n = 4) was the most potent, being about 40 and 25 fold more potent than substance P (EC50 = 121.6 nM; 95{\%} c.l. = 94-157; P <0.01; n = 4) and neurokinin A (EC50 = 83.4 nM; 95{\%} c.l. = 62-112; P <0.01; n = 4), respectively. Among the synthetic analogues the NK3 receptor-selective agonist senktide (EC50 = 1.1 nM; 95{\%} c.l. = 0.7-1.8; n = 8) was the most potent, being about 120, 110 and 20 fold more potent than [Sar9]substance P sulfone (NK1 receptor-selective) (EC50 = 130.4 nM; 95{\%} c.l. = 99-172; P <0.01; n = 8), [βAla8]NKA (4-10) (NK2 receptor-selective) (EC50 = 120.1 nM; 95{\%} c.l. = 95-151; P <0.01; n = 8) and septide (NK1 receptor-selective) (EC50 = 22.6 nM; 95{\%} c.l. = 18-28; P <0.01, n = 8), respectively. All tachykinins (natural or synthetic receptor agonists) produced a similar E(max), averaging about 50{\%} of that produced by KCl (80 mM). 4. Atropine (1 μM) did not affect the responses to either NK1 or NK2 receptor-selective agonists, whereas it reduced the E(max) of senktide by about 50{\%}, without affecting its potency (EC50). Tetrodotoxin (1 μM) totally blocked senktide-induced contractions, as did the combined pretreatment with atropine plus the tachykinin NK1 and NK2 receptor-selective antagonists GR 82334 and MEN 11420 (1 μM each), respectively. 5. GR 82334 (1 μM) blocked with apparent competitive kinetics septide- (apparent pK(B) = 7.46 ± 0.10; n = 5) and [Sar9]substance P sulfone- (apparent pK(B) = 6.80 ± 0.04; n = 4) induced contractions. MEN 11420 (30-300 nM), a novel potent NK2 receptor antagonist, potently antagonized [βAla8]NKA (4-10), with competitive kinetics (pK(B) = 8.25 ± 0.08; n = 12: Schild plot slope = -0.90; 95{\%} c.l. = -1.4; -0.35). The NK3 receptor-selective antagonist SR 142801 (30 nM) produced insurmountable antagonism of the senktide-induced contractions (E(max) inhibited by 64{\%}). None of the above antagonists, tested at the highest concentrations employed against tachykinins, affected the concentration-response curve to methacholine (0.1-300 μM). 6. We conclude that tachykinins produce contraction of the guinea-pig isolated common bile duct by stimulating NK1, NK2 and NK3 receptors. The responses obtained by activating NK1 and NK2 receptors are atropine-resistant. The contraction obtained by stimulating NK3 receptors is totally neurogenic, being mediated by the release of endogenous acetylcholine and tachykinins; the latter act, in turn, on postjunctional tachykinin NK1/NK2 receptors. The role of the NK3 receptor as prejunctional mediator of the excitatory transmission operated by tachykinins is discussed.",
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T1 - Characterization of receptors mediating contraction induced by tachykinins in the guinea-pig isolated common bile duct

AU - Patacchini, Riccardo

AU - Barthó, L.

AU - Maggi, Carlo Alberto

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N2 - 1. We studied the effect of the natural tachykinins and of synthetic agonists selective for the tachykinin NK1, NK2 and NK3 receptors, on the motility of guinea-pig isolated common bile duct longitudinally-oriented smooth muscle. 2. All the tachykinins tested (both natural and synthetic) produced a concentration-dependent contractile response of the guinea-pig isolated common bile duct: these effects underwent a marked tachyphylaxis, especially the responses elicited by NK1 and NK3 receptor-selective agonists. 3. Among the natural tachykinins neurokinin B (EC50 = 3.2 nM; 95% c.l. = 2.0-5.1; n = 4) was the most potent, being about 40 and 25 fold more potent than substance P (EC50 = 121.6 nM; 95% c.l. = 94-157; P <0.01; n = 4) and neurokinin A (EC50 = 83.4 nM; 95% c.l. = 62-112; P <0.01; n = 4), respectively. Among the synthetic analogues the NK3 receptor-selective agonist senktide (EC50 = 1.1 nM; 95% c.l. = 0.7-1.8; n = 8) was the most potent, being about 120, 110 and 20 fold more potent than [Sar9]substance P sulfone (NK1 receptor-selective) (EC50 = 130.4 nM; 95% c.l. = 99-172; P <0.01; n = 8), [βAla8]NKA (4-10) (NK2 receptor-selective) (EC50 = 120.1 nM; 95% c.l. = 95-151; P <0.01; n = 8) and septide (NK1 receptor-selective) (EC50 = 22.6 nM; 95% c.l. = 18-28; P <0.01, n = 8), respectively. All tachykinins (natural or synthetic receptor agonists) produced a similar E(max), averaging about 50% of that produced by KCl (80 mM). 4. Atropine (1 μM) did not affect the responses to either NK1 or NK2 receptor-selective agonists, whereas it reduced the E(max) of senktide by about 50%, without affecting its potency (EC50). Tetrodotoxin (1 μM) totally blocked senktide-induced contractions, as did the combined pretreatment with atropine plus the tachykinin NK1 and NK2 receptor-selective antagonists GR 82334 and MEN 11420 (1 μM each), respectively. 5. GR 82334 (1 μM) blocked with apparent competitive kinetics septide- (apparent pK(B) = 7.46 ± 0.10; n = 5) and [Sar9]substance P sulfone- (apparent pK(B) = 6.80 ± 0.04; n = 4) induced contractions. MEN 11420 (30-300 nM), a novel potent NK2 receptor antagonist, potently antagonized [βAla8]NKA (4-10), with competitive kinetics (pK(B) = 8.25 ± 0.08; n = 12: Schild plot slope = -0.90; 95% c.l. = -1.4; -0.35). The NK3 receptor-selective antagonist SR 142801 (30 nM) produced insurmountable antagonism of the senktide-induced contractions (E(max) inhibited by 64%). None of the above antagonists, tested at the highest concentrations employed against tachykinins, affected the concentration-response curve to methacholine (0.1-300 μM). 6. We conclude that tachykinins produce contraction of the guinea-pig isolated common bile duct by stimulating NK1, NK2 and NK3 receptors. The responses obtained by activating NK1 and NK2 receptors are atropine-resistant. The contraction obtained by stimulating NK3 receptors is totally neurogenic, being mediated by the release of endogenous acetylcholine and tachykinins; the latter act, in turn, on postjunctional tachykinin NK1/NK2 receptors. The role of the NK3 receptor as prejunctional mediator of the excitatory transmission operated by tachykinins is discussed.

AB - 1. We studied the effect of the natural tachykinins and of synthetic agonists selective for the tachykinin NK1, NK2 and NK3 receptors, on the motility of guinea-pig isolated common bile duct longitudinally-oriented smooth muscle. 2. All the tachykinins tested (both natural and synthetic) produced a concentration-dependent contractile response of the guinea-pig isolated common bile duct: these effects underwent a marked tachyphylaxis, especially the responses elicited by NK1 and NK3 receptor-selective agonists. 3. Among the natural tachykinins neurokinin B (EC50 = 3.2 nM; 95% c.l. = 2.0-5.1; n = 4) was the most potent, being about 40 and 25 fold more potent than substance P (EC50 = 121.6 nM; 95% c.l. = 94-157; P <0.01; n = 4) and neurokinin A (EC50 = 83.4 nM; 95% c.l. = 62-112; P <0.01; n = 4), respectively. Among the synthetic analogues the NK3 receptor-selective agonist senktide (EC50 = 1.1 nM; 95% c.l. = 0.7-1.8; n = 8) was the most potent, being about 120, 110 and 20 fold more potent than [Sar9]substance P sulfone (NK1 receptor-selective) (EC50 = 130.4 nM; 95% c.l. = 99-172; P <0.01; n = 8), [βAla8]NKA (4-10) (NK2 receptor-selective) (EC50 = 120.1 nM; 95% c.l. = 95-151; P <0.01; n = 8) and septide (NK1 receptor-selective) (EC50 = 22.6 nM; 95% c.l. = 18-28; P <0.01, n = 8), respectively. All tachykinins (natural or synthetic receptor agonists) produced a similar E(max), averaging about 50% of that produced by KCl (80 mM). 4. Atropine (1 μM) did not affect the responses to either NK1 or NK2 receptor-selective agonists, whereas it reduced the E(max) of senktide by about 50%, without affecting its potency (EC50). Tetrodotoxin (1 μM) totally blocked senktide-induced contractions, as did the combined pretreatment with atropine plus the tachykinin NK1 and NK2 receptor-selective antagonists GR 82334 and MEN 11420 (1 μM each), respectively. 5. GR 82334 (1 μM) blocked with apparent competitive kinetics septide- (apparent pK(B) = 7.46 ± 0.10; n = 5) and [Sar9]substance P sulfone- (apparent pK(B) = 6.80 ± 0.04; n = 4) induced contractions. MEN 11420 (30-300 nM), a novel potent NK2 receptor antagonist, potently antagonized [βAla8]NKA (4-10), with competitive kinetics (pK(B) = 8.25 ± 0.08; n = 12: Schild plot slope = -0.90; 95% c.l. = -1.4; -0.35). The NK3 receptor-selective antagonist SR 142801 (30 nM) produced insurmountable antagonism of the senktide-induced contractions (E(max) inhibited by 64%). None of the above antagonists, tested at the highest concentrations employed against tachykinins, affected the concentration-response curve to methacholine (0.1-300 μM). 6. We conclude that tachykinins produce contraction of the guinea-pig isolated common bile duct by stimulating NK1, NK2 and NK3 receptors. The responses obtained by activating NK1 and NK2 receptors are atropine-resistant. The contraction obtained by stimulating NK3 receptors is totally neurogenic, being mediated by the release of endogenous acetylcholine and tachykinins; the latter act, in turn, on postjunctional tachykinin NK1/NK2 receptors. The role of the NK3 receptor as prejunctional mediator of the excitatory transmission operated by tachykinins is discussed.

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KW - Tachykinin receptors

KW - Tachykinins

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