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Characterization of receptors mediating contraction induced by tachykinins in the guinea‐pig isolated common bile duct
Author(s) -
Patacchini Riccardo,
Barthó Lorand,
Maggi Carlo Alberto
Publication year - 1997
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701560
Subject(s) - tachykinin receptor , neurokinin a , substance p , receptor , agonist , guinea pig , medicine , endocrinology , neurokinin b , chemistry , tachyphylaxis , biology , pharmacology , neuropeptide
1 We studied the effect of the natural tachykinins and of synthetic agonists selective for the tachykinin NK 1 , NK 2 and NK 3 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 NK 1 and NK 3 receptor‐selective agonists. 3 Among the natural tachykinins neurokinin B (EC 50 =3.2 n m ; 95% c.l.=2.0–5.1; n =4) was the most potent, being about 40 and 25 fold more potent than substance P (EC 50 =121.6 n m ; 95% c.l.=94–157; P <0.01; n =4) and neurokinin A (EC 50 =83.4 n m ; 95% c.l.=62–112; P <0.01; n =4), respectively. Among the synthetic analogues the NK 3 receptor‐selective agonist senktide (EC 50 =1.1 n m ; 95% c.l.=0.7–1.8; n =8) was the most potent, being about 120, 110 and 20 fold more potent than [Sar 9 ]substance P sulfone (NK 1 receptor‐selective) (EC 50 =130.4 n m ; 95% c.l.=99–172; P <0.01; n =8), [βAla 8 ]NKA (4–10) (NK 2 receptor‐selective) (EC 50 =120.1 n m ; 95% c.l.=95–151; P <0.01; n =8) and septide (NK 1 receptor‐selective) (EC 50 =22.6 n m ; 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 m m ). 4 Atropine (1 μ m ) did not affect the responses to either NK 1 or NK 2 receptor‐selective agonists, whereas it reduced the E max of senktide by about 50%, without affecting its potency (EC 50 ). Tetrodotoxin (1 μ m ) totally blocked senktide‐induced contractions, as did the combined pretreatment with atropine plus the tachykinin NK 1 and NK 2 receptor‐selective antagonists GR 82334 and MEN 11420 (1 μ m each), respectively. 5 GR 82334 (1 μ m ) blocked with apparent competitive kinetics septide‐ (apparent p K B =7.46±0.10; n =5) and [Sar 9 ]substance P sulfone‐ (apparent p K B =6.80±0.04; n =4) induced contractions. MEN 11420 (30–300 n m ), a novel potent NK 2 receptor antagonist, potently antagonized [βAla 8 ]NKA (4–10), with competitive kinetics (p K B =8.25±0.08; n =12: Schild plot slope=−0.90; 95% c.l.=−1.4; −0.35). The NK 3 receptor‐selective antagonist SR 142801 (30 n m ) 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 μ m ). 6 We conclude that tachykinins produce contraction of the guinea‐pig isolated common bile duct by stimulating NK 1 , NK 2 and NK 3 receptors. The responses obtained by activating NK 1 and NK 2 receptors are atropine‐resistant. The contraction obtained by stimulating NK 3 receptors is totally neurogenic, being mediated by the release of endogenous acetylcholine and tachykinins; the latter act, in turn, on postjunctional tachykinin NK 1 /NK 2 receptors. The role of the NK 3 receptor as prejunctional mediator of the excitatory transmission operated by tachykinins is discussed.