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The role of tachykinin NK 1 and NK 2 receptors in atropine‐resistant colonic propulsion in anaesthetized guinea‐pigs
Author(s) -
Lecci A,
Giuliani S,
Tramontana M,
Giorgio R D,
Maggi C A
Publication year - 1998
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.0701789
Subject(s) - tachykinin receptor , endocrinology , medicine , guanethidine , receptor , atropine , receptor antagonist , chemistry , nk1 receptor antagonist , antagonist , biology , substance p , neuropeptide , stimulation
The role of endogenous tachykinins on guinea‐pig colonic propulsion was investigated by using potent and selective tachykinin NK 1 and NK 2 receptor antagonists. Colonic propulsion and contractions were determined by means of a balloon‐catheter device, inserted into the rectum of guanethidine (68 μmol kg −1 , s.c., 18 and 2 h before)‐pretreated, urethane‐anaesthetized guinea‐pigs. Propulsion of the device (dynamic model) was determined by measuring the length of the catheter expelled during 60 min filling of the balloon (flow rate 5 μl min −1 ). In control conditions the tachykinin NK 1 receptor antagonist SR 140333 (1 μmol kg −1 , i.v.) did not affect either colonic propulsion or the amplitude of contractions. The tachykinin NK 2 receptor antagonists MEN 10627 and MEN 11420 (1 μmol kg −1 , i.v.) increased colonic propulsion at 10 min (+120% and 150%, respectively) but at 60 min the effect was significant only for MEN 10627 (+84%). SR 48968 (1 μmol kg −1 , i.v.) did not significantly enhance the colonic propulsion. None of these tachykinin NK 2 receptor antagonists modified the amplitude of colonic contractions. In contrast, both atropine (6 μmol kg −1 , i.v., plus infusion of 1.8 μmol h −1 ) and hexamethonium (55 μmol kg −1 , i.v., plus infusion of 17 μmol h −1 ) abolished propulsion (81% and 87% inhibition, respectively) and decreased the amplitude of contractions (68% inhibition for either treatment). In atropine‐treated animals (6 μmol kg −1 , i.v., plus infusion of 1.8 μmol h −1 ), apamin (30 nmol kg −1 , i.v.) restored colonic propulsion (+416%) and increased the amplitude of contractions (+367% as compared to atropine alone). Hexamethonium (55 μmol kg −1 , i.v., plus infusion of 17 μmol h −1 ) abolished the apamin‐induced, atropine‐resistant colonic propulsion (97% inhibition) and reduced the amplitude of the atropine‐resistant contractions (52% inhibition). The apamin‐induced, atropine‐resistant colonic propulsion was inhibited by SR 140333 (−69% at 1 μmol kg −1 ), SR 48968 (−78% at 1 μmol kg −1 ), MEN 11420 (−59% at 1 μmol kg −1 ) and MEN 10627 (−50% at 1 μmol kg −1 ), although the latter effect was not statistically significant. The combined administration of SR 140,333 and MEN 10,627 (1 μmol kg −1 for each antagonist) almost completely abolished colonic propulsion (90% inhibition). The amplitude of colonic contractions was also reduced by SR 140333 (−42%), SR 48968 (−29%), MEN 11420 (−45%) but not by MEN 10627 (−16%). The combined administration of SR 140333 and MEN 10,627 reduced the amplitude of contractions by 47%. SR 140603 (1 μmol kg −1 , i.v.), the less potent enantiomer of SR 140333, was inactive. In control animals, apamin (30 nmol kg −1 , i.v.) enhanced colonic propulsion (+84%) and increased the amplitude of contractions (+68%), as compared to the vehicle. Hexamethonium (55 μmol kg −1 , i.v. plus infusion of 17 μmol h −1 ) inhibited propulsion (86% inhibition) and decreased the amplitude of contractions (49% inhibition). SR 140333, SR 48968, MEN 11420, MEN 10627, or the coadministration of SR 140333 and MEN 10627 had no effect. In a separate series of experiments, the mean amplitude of colonic contractions was also recorded under isovolumetric conditions through the balloon‐catheter device kept in place at 75 mm from the anal sphincter (static model). In control conditions, neither SR 140333 nor MEN 11420 modified the amplitude of contractions. In atropine‐pretreated guinea‐pigs, SR 140333 and MEN 11420 (0.1–1 μmol kg −1 ) dose‐dependently decreased the amplitude of contractions. In apamin‐ and atropine‐pretreated animals, only the highest (1 μmol kg −1 ) dose of SR 140333 or MEN 11420 significantly decreased the amplitude of contractions. The inhibitory potency of atropine (0.3–1 μmol kg −1 ) was similar in apamin‐pretreated animals and in controls. It was concluded that, in anaesthetized guinea‐pigs, endogenous tachykinins, acting through both NK 1 and NK 2 receptors, act as non‐cholinergic excitatory neurotransmitters in promoting an apamin‐evoked reflex propulsive activity of the distal colon.