The role of tachykinin NK1 and NK2 receptors in atropine-resistant colonic propulsion in anaesthetized guinea-pigs.
1. The role of endogenous tachykinins on guinea-pig colonic propulsion was investigated by using potent and selective tachykinin NK1 and NK2 receptor antagonists. Colonic propulsion and contractions were determined by means of a balloon-catheter device, inserted into the rectum of guanethidine (68 micromol 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 microl min(-1)). 2. In control conditions the tachykinin NK1 receptor antagonist SR 140333 (1 micromol kg(-1), i.v.) did not affect either colonic propulsion or the amplitude of contractions. The tachykinin NK2 receptor antagonists MEN 10627 and MEN 11420 (1 micromol 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 micromol kg(-1), i.v.) did not significantly enhance the colonic propulsion. None of these tachykinin NK2 receptor antagonists modified the amplitude of colonic contractions. In contrast, both atropine (6 micromol kg(-1), i.v., plus infusion of 1.8 micromol h(-1)) and hexamethonium (55 micromol kg(-1), i.v., plus infusion of 17 micromol h(-1)) abolished propulsion (81% and 87% inhibition, respectively) and decreased the amplitude of contractions (68% inhibition for either treatment). 3. In atropine-treated animals (6 micromol kg(-1), i.v., plus infusion of 1.8 micromol 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 micromol kg(-1), i.v., plus infusion of 17 micromol h(-1)) abolished the apamin-induced, atropine-resistant colonic propulsion (97% inhibition) and reduced the amplitude of the atropine-resistant contractions (52% inhibition). 4. The apamin-induced, atropine-resistant colonic propulsion was inhibited by SR 140333 (-69% at 1 micromol kg(-1)), SR 48968 (-78% at 1 micromol kg(-1)), MEN 11420 (-59% at 1 micromol kg(-1)) and MEN 10627 (-50% at 1 micromol kg(-1)), although the latter effect was not statistically significant. The combined administration of SR 140,333 and MEN 10,627 (1 micromol 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 micromol kg(-1), i.v.), the less potent enantiomer of SR 140333, was inactive. 5. 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 micromol kg(-1), i.v. plus infusion of 17 micromol 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. 6. 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 micromol kg(-1)) dose-dependently decreased the amplitude of contractions. In apamin- and atropine-pretreated animals, only the highest (1 micromol kg(-1)) dose of SR 140333 or MEN 11420 significantly decreased the amplitude of contractions. The inhibitory potency of atropine (0.3-1 micromol kg(-1)) was similar in apamin-pretreated animals and in controls. 7. 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.
Lecci
A
A
Pharmacology Research Department, Menarini Ricerche s.p.a., Florence, Italy.
Giuliani
S
S
Tramontana
M
M
Giorgio
R D
RD
Maggi
C A
CA
D000758:Anesthesia; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D006168:Guinea Pigs; D018738:Hexamethonium / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic / Q000494:pharmacology; D010528:Peristalsis / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000502:physiology*
D001549:Benzamides; C107754:MEN 11420; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic; D010880:Piperidines; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C085215:SR 140333; C090951:MEN 10627; D001030:Apamin; D018738:Hexamethonium; C073839:SR 48968; D001285:Atropine