Atropine and naloxone block the colonic contraction elicited by cholecystokinin and pentagastrin (original) (raw)
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British Journal of Pharmacology, 2001
1 In the gastrointestinal tract, tachykinin NK 2 receptors are localized both on smooth muscle and nerve ®bres. NK 2 receptor antagonists reduce exaggerated intestinal motility in various diarrhoea models but the site of action contributing to this eect is unknown. In this study we investigated the eects of atropine (1.4 mmol kg 71 , i.v.), hexamethonium (13.5 mmol kg 71 , i.v.), and nepadutant (0.1 mmol kg 71 , i.v.), a selective tachykinin NK 2 receptor antagonist, on distension (0.5 and 1 ml)-, or irritation (acetic acid, 0.5 ml of 7.5% v v 71 )-induced motility in the rat distal colon in vivo. The eects of atropine, hexamethonium or N o -nitro-L-argininemethylester (L-NAME, 1.85 mmol kg 71 , i.v.) on [bAla 8 ]NKA(4-10) (10 nmol kg 71 , i.v.)-induced colonic contractions were also investigated. 2 When the colonic balloon was ®lled with a subthreshold volume (0.5 ml), the intraluminal instillation of acetic acid triggered a high-amplitude phasic colonic motility which was partially reduced by nepadutant and suppressed by either hexamethonium or atropine. Filling of the balloon with 1 ml evoked re¯ex (hexamethonium-sensitive), atropine-sensitive phasic colonic motility: nepadutant had no signi®cant eect on the distension-evoked motility.
2011
Background/Aims It is generally believed that cholecystokinin (CCK) stimulates colonic motility, although there are controversial reports. It has also been suggested that postprandial peptide YY (PYY) release is CCK-dependent. Using a totally isolated, vascularly perfused rat colon, we investigated: (1) the roles of CCK and PYY on colonic motility, (2) to determine if CCK modulates PYY release from the colon to influence the motility and (3) to clarify whether the action of CCK and PYY on colonic motility is mediated via the influence of cholinergic input. Methods An isolated whole rat colon was used. Luminal pressure was monitored via microtip catheter pressure transducers from proximal and distal colon. After a control period, CCK-8 or PYY was administerd intraarterially with or without an anti-PYY serum, loxiglumide or atropine at 12, 60 and 240 pM. Each dose was given for a period of 15-minute and the contractile response was expressed as % changes over basal. PYY concentration in the portal effluent was determined by radioimmunoassay. Results Exogenous CCK-8 increased colonic motility which paralleled the increase in PYY release in the portal effluent. Exogenous PYY also significantly increased colonic motility although it was less potent than CCK. The stimulating effect of CCK-8 was significantly inhibited by an anti-PYY serum, and was completely abolished by loxiglumide, and almost completely abolished by atropine. Conclusions CCK increases colonic motility via CCK1 receptor and it is mediated partly by PYY. Cholinergic input is required for the increased motility by either PYY or CCK.
British Journal of Pharmacology, 1998
1 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 mmol kg 71 , 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 ®lling of the balloon (¯ow rate 5 ml min 71 ). 2 In control conditions the tachykinin NK 1 receptor antagonist SR 140333 (1 mmol kg 71 , i.v.) did not aect either colonic propulsion or the amplitude of contractions. The tachykinin NK 2 receptor antagonists MEN 10627 and MEN 11420 (1 mmol kg 71 , i.v.) increased colonic propulsion at 10 min (+120% and 150%, respectively) but at 60 min the eect was signi®cant only for MEN 10627 (+84%). SR 48968 (1 mmol kg 71 , i.v.) did not signi®cantly enhance the colonic propulsion. None of these tachykinin NK 2 receptor antagonists modi®ed the amplitude of colonic contractions. In contrast, both atropine (6 mmol kg 71 , i.v., plus infusion of 1.8 mmol h 71 ) and hexamethonium (55 mmol kg 71 , i.v., plus infusion of 17 mmol h 71 ) abolished propulsion (81% and 87% inhibition, respectively) and decreased the amplitude of contractions (68% inhibition for either treatment).
European Journal of Pharmacology, 2007
Cholecystokinin and related peptides are involved in the control of intestinal motility and cholecystokinin receptor ligands might represent new pharmacological tools for the treatment of symptoms associated with functional bowel disorders. However, the respective roles played by cholecystokinin receptor subtypes and the mechanisms underlying these regulatory actions remain undetermined. This study was designed to examine the influence of cholecystokinin receptor subtypes on the motor activity of guinea-pig distal colon. The effects of drugs acting on CCK 1 and CCK 2 receptors were assessed in vitro on the contractile activity of longitudinal smooth muscle, both under basal conditions and in the presence of transmural electrical stimulation or KCl-induced contractions. The application of cholecystokinin octapeptide sulphate (cholecystokinin-8S) to colonic preparations induced concentration-dependent contractions which were prevented by devazepide (CCK 1 receptor antagonist), enhanced by GV150013 (CCK 2 receptor antagonist) or N ω -nitro-L-arginine methylester (L-NAME, nitric oxide synthase inhibitor), and unaffected by tetrodotoxin. The application of gastrin-17 to colonic preparations resulted in relaxant responses which were insensitive to devazepide, and prevented by GV150013, L-NAME or tetrodotoxin. L-NAME, N ω -propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor) or GV150013 enhanced electrically evoked contractile responses, whereas devazepide did not. When tested in the presence of L-NAME or NPA the enhancing effect of GV150013 on electrically induced contractions no longer occurred. In the presence of KCl-induced pre-contractions, cholecystokinin-8S or gastrin-17 evoked concentration-dependent relaxations, which were unaffected by devazepide and were counteracted by GV150013, L-NAME, NPA or tetrodotoxin. In conclusion, the present results indicate that, at level of distal colon, CCK 1 receptors mediate direct contractile effects on smooth muscle, whereas CCK 2 receptors on enteric neurons mediate relaxant responses via nitric oxide release.
European Journal of Pharmacology, 1993
The effects of three tachykinin NK 1 receptor antagonists and a tachykinin NK 2 receptor antagonist against substance P-induced contractions of the guinea-pig proximal colon longitudinal muscle were investigated. Atropine, tetrodotoxin and phosphoramidon did not affect the concentration-response curve for substance P (pECs0 = 7.8). The tachykinin NK1 receptor antagonist, 2S,3S-cis-CP 96345, competitively inhibited the contractions due to substance P (pA 2 = 8.5; constrained pA 2 = 8.9), but at higher concentrations (>_ 3 × 10 -7 M), 2S,3S-cis-CP 96345 also depressed the concentration-response curve for methacholine. The species-selective tachykinin NK~ receptor antagonists, WIN 51708 and WIN 62577 (both 1 × 10 6 M), and the tachykinin NK 2 receptor antagonist, SR 48968 (3 × 10 -7 M), had no effect. It is concluded that substance P induces contractions through the stimulation of tachykinin NK 1 receptors on the smooth muscle cells. In this preparation, tachykinin NK 2 receptors do not seem to be involved in the contractile action of substance P.
Food Funct., 2014
Beta-casomorphin-5 (βCM-5) is a milk-derived bioactive peptide that slows gastro-intestinal transit (GIT) in vivo and blocks the peristaltic reflex in the guinea pig colon in vitro. We wanted to establish an in vitro model system in which effects of dairy-derived substances containing opioid peptides on intestinal motility can be assessed and used to predict in vivo outcomes. Because βCM-5 is an opioid agonist that acts on enteric neurons, we used this substance to compare two different isolated colonic tissue preparations to determine which would more closely mimic the in vivo response previously reported in the literature.
Digestive Diseases and Sciences, 1985
Nociceptive stimulation of the peritoneum inhibits colonic motility via a sympathoadrenergic reflex. This sympathetic reflex most probably induces the inhibition indirectly via a presynaptic blockade of cholinergic transmission. To further clarify this reflex, colonic motility was continuously recorded by a volume method in rats exposed to nociceptive abdominal stimulation and intravenous drug administration. Intraabdominally applied HCl inhibited colonic motility, which was unaffected by nonselective beta-adrenoceptor blockade (propranolol). However, the nonselective alpha-adrenoceptor antagonist phentolamine and the selective alpha 2-adrenoceptor antagonist yohimbine restored motility. Spontaneous colonic motility was unaffected by the nonselective beta-adrenoceptor agonist (isoproterenol) and the selective alpha 1-adrenoceptor agonist (L-phenylephrine). On the other hand, a nonselective alpha-agonist (noradrenaline) and a selective alpha 2-adrenoceptor agonist (clonidine) inhibited spontaneous colonic motility. It is suggested that in the rat sympathetic reflex inhibition of colonic motility caused by abdominal nociception is mediated via presynaptic alpha 2-adrenoceptors inhibiting the excitatory cholinergic neurons.
British Journal of Pharmacology, 2009
Background and purpose: Cholecystokinin is known to exert stimulant actions on intestinal motility via activation of type 1 cholecystokinin receptors (CCK 1 ). However, the role played by cholecystokinin 2 (CCK 2 ) receptors in the regulation of gut motility remains undetermined. This study was designed to examine the influence of CCK 2 receptors on the contractile activity of human distal colon. Experimental approach: The effects of compounds acting on CCK 2 receptors were assessed in vitro on motor activity of longitudinal smooth muscle, under basal conditions as well as in the presence of KCl-induced contractions or transmural electrical stimulation. Key results: Cholecystokinin octapeptide sulphate induced concentration-dependent contractions which were enhanced by GV150013 (CCK 2 receptor antagonist; þ 57% at 0.01 mM). These effects were unaffected by tetrodotoxin. The enhancing actions of GV150013 on contractions evoked by cholecystokinin octapeptide sulphate were unaffected by N o -propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor), while they were prevented by N o -nitro-L-arginine methylester (L-NAME, non-selective nitric oxide synthase inhibitor). In the presence of KCl-induced contractions, cholecystokinin octapeptide sulphate elicited concentration-dependent relaxations (-36%), which were unaffected by NPA, but were counteracted by GV150013 or L-NAME. The application of electrical stimuli evoked phasic contractions which were enhanced by GV150013 ( þ 41 % at 0.01 mM). Conclusions and implications: CCK 2 receptors mediate inhibitory actions of cholecystokinin on motor activity of human distal colon. It is suggested that CCK 2 receptors exert their modulating actions through a nitric oxide pathway, independent of the activity of the neuronal nitric oxide synthase isoform.
The Journal of Physiology, 1985
The action and mechanism of action of cholecystokinin octapeptide (CCK-8) and pentagastrin on isolated segments of guinea-pig duodenum were examined using contractility studies and by intracellular recordings made from smooth muscle cells. 2. Both CCK-8 and pentagastrin caused an excitatory contractile response. The threshold concentration ranged from 5 x 10-11 to 109 M for CCK-8 and 5 x 1010 to 10-8 M for pentagastrin. 3. The excitatory response was abolished by tetrodotoxin (3-1 x 10-6 M) and atropine (1-5 X 10-6 M) and inhibited by d-tubocurarine (up to 2-9 x 10-5 M). 4. In the presence of atropine a proportion of preparations relaxed in response to CCK-8 (nineteen of thirty-one) and pentagastrin (thirteen of seventeen). This response was only seen at high concentrations of the peptides (10-8-10-7 M) and was abolished by tetrodotoxin (3 x 10-6 M). 5. Intracellular recordings from duodenal smooth muscle revealed multiple excitatory junction potentials (e.j.p.s) in response to CCK-8 and to pentagastrin. These e.j.p.s were identical to those evoked by transmural nerve stimulation and were abolished by atropine (1.5 x 10-7 M) and by tetrodotoxin (3 x 10-6 M). Inhibitory junction potentials (i.j.p.s) were not recorded in response to the peptides except on one occasion. 6. It is suggested that CCK-8 and pentagastrin cause an increase in duodenal motility by the selective activation of excitatory pathways in the enteric nervous system.