Linaclotide increases cecal pH, accelerates colonic transit, and increases colonic motility in irritable bowel syndrome with constipation.

BACKGROUND: Linaclotide is efficacious in the management of irritable bowel syndrome with constipation (IBS-C), yet relatively little is known regarding its effect on human gastrointestinal physiology. The primary aim of the study was to examine the effect of linaclotide on change in pH across the ileocecal junction (ICJ), a proposed measure of cecal fermentation, and its relationship to symptoms and quality of life (QoL) in IBS-C. METHODS: A total of 13 participants with Rome III IBS-C underwent a standardized wireless motility capsule (WMC). Stool consistency was measured using the Bristol stool form scale (BSFS) and frequency with spontaneous bowel movements (SBM). Gastrointestinal symptoms and QoL were assessed using validated questionnaires. The WMC and questionnaires were repeated after 28 days of linaclotide 290 g po od. KEY RESULTS: Linaclotide reduced the change in pH across the ICJ (-2.4 ± 0.2 vs -2.1 ± 0.4, P = 0.01) as a function of a relative alkalinization of the cecum (5.2 ± 0.2 vs 5.5 ± 0.3, P = 0.02). Linaclotide accelerated colonic transit time (2650 minutes (2171-4038) vs. 1757 (112-3011), P = 0.02), increased colonic log motility index (15 ± 1.8 vs. 16.5 ± 1.8, P = 0.004) but had no effect of gastric emptying or small bowel transit. Change in pH across the ICJ correlated with improvement in symptom intensity, unpleasantness, and visceral sensitivity index (r = 0.62, P = 0.03, r = 0.63, P = 0.02, r = 0.62, P = 0.02) and with increases in BSFS type and SBM (r = 0.9, P < 0.0001, r = 0.6, P = 0.02). CONCLUSIONS & INFERENCES: Linaclotide's effects are confined to the colon where it increases cecal pH, potentially representing a reduction in cecal fermentation and accelerates colonic motility.

[Mechanisms of serotonin effect on motility of ileocaecal zone in alert rabbits].

I.V. administration of serotonin (2 mg kg(-1)) to alert rabbits changed the ileal, caecal, and colon motility including excitatory and inhibitory components. Initial rise of contractile activity was quickly replaced by its diminishing followed by a longer enhancement of the motility, and then by the final, inhibitory, phase. Under blockade of beta1- and beta2-adrenoreceptors with propranolol inhibition of ileal and caecal contractile activity with serotonin was preserved, the effect of circulating catecholamines on beta-adrenoreceptors of smooth muscle cells seems to be excluded as a cause of the serotonin inhibitory effect. In conditions of blockade of pre- and postsynaptic alpha-adrenoreceptors with phentolamine, there was no significant diminishing of the contractile activity in the ileo-caecal zone below the initial level induced by serotonin in control experiments. Intensification of the ileo-caecal zone contractile activity under the effect of serotonin persisted in conditions of blockade of muscarinic cholinoreceptors and was proceeding with participation of non-cholinergic excitatory mechanism.

Effects of gastrin-releasing peptide (GRP) on the mechanical activity of the human ileocaecal region in vitro.

Mechanical activity was recorded in muscle preparations isolated from the human ileocaecal region. Gastrin-releasing peptide (GRP, 10(-9)-10(-7) mol L-1) produced two types of response in the different muscle layers. Longitudinally cut strips showed a concentration-dependent increase in the rhythmic activity, whereas the circularly orientated layers generally reacted with a small decrease in tone. These effects could not be influenced by blockade of adrenergic or cholinergic receptors or nerve blockade with tetrodotoxin (TTX). Application of pentagastrin did not mimic the action of GRP. These findings suggest a direct action of GRP on smooth muscle via distinct receptors which have already been demonstrated to exist in human gastrointestinal tract. The opposite effects on circular and longitudinal strips might indicate a modulatory role of GRP in the control of ileocolonic transit.

Role of nitric oxide in mediating non-adrenergic non-cholinergic relaxation of the cat ileocecal sphincter.

The participation of nitric oxide (NO) in field stimulation- or nicotine-evoked non-adrenergic non-cholinergic (NANC) relaxation of cat ileocecal sphincter was studied in vitro. During a 30 microM noradrenaline-induced contraction, both the application of electrical field stimulation (2-20 Hz, 0.2 ms, supramaximal current intensity, 10 s duration) and (-)-nicotine (10-500 microM) produced a tetrodotoxin-sensitive relaxation. The maximal relaxation was observed at 10 Hz or 100 microM (-)-nicotine. In 12 out of 19 strips the pretreatment with N omega-nitro-L-arginine (100 microM) decreased the amplitude of the field stimulation-evoked relaxation, while in the remaining strips the relaxation was transformed into a contraction. By increasing the concentration of N omega-nitro-L-arginine up to 1 mM all strips responded to field stimulation with a frequency-dependent tetrodotoxin-resistant contraction. N omega-Nitro-L-arginine (100 microM) completely inhibited the nicotine-induced relaxation. L-Arginine (1 mM) restored the amplitude of both field stimulation- and nicotine-evoked relaxations. These data indicate that NO appears to be involved in both field stimulation- and nicotine-evoked NANC relaxations. Evidence has been obtained for the existence of tetrodotoxin-resistant NANC contraction in cat ileocecal sphincter.

The ileocaecal junction.

The ileocaecal junction remains a controversial region of the gut. There are still a lot of questions concerning its anatomical structure and function. In this review, a concise overview is given of the recent and older literature on the embryology, anatomy, including the intrinsic and extrinsic innervation, and the pharmacology of this region. Based on the available data from the literature, evidence is accumulating for a sphincteric function.

Substance P: mechanism of action and receptor distribution at the feline ileocecal sphincter region.

The purpose of this study was to determine the mechanism of action of substance P at the distal ileum, ileocecal sphincter (ICS), and proximal colon in the cat and to determine the localization of substance P receptors at these sites by autoradiography. Intraluminal pressures and myoelectric activity were recorded at the feline distal ileum, ICS, and colon. Substance P caused a tonic and phasic spike-dependent contractile response at all three sites. The antagonists propranolol, phentolamine, and naloxone did not affect the contractile response to substance P at the ileum, ICS, or colon. The ganglionic blocker trimethaphan camsylate potentiated the response to substance P at all three sites, P less than 0.05. Both atropine and tetrodotoxin reduced the response of substance P at the ileal site. At the ICS, atropine or tetrodotoxin reduced, but did not obliterate, the effect of substance P. Neither atropine nor tetrodotoxin reduced substance P-induced colonic contractions. By use of autoradiography, specific binding for substance P was determined to be present at all three sites with the greatest concentration of substance P receptors in the circular muscle layer. In conclusion, these studies suggest multiple sites of action of substance P. At the ileum, substance P causes contraction via a cholinergic pathway. At the ICS, substance P has an excitatory action through a cholinergic pathway and also at smooth muscle receptors. In the proximal colon, the excitatory action of substance P is via smooth muscle receptors. An inhibitory ganglionic pathway also exists at all three sites. Substance P receptors exist predominantly in the circular muscle region of the ileum, ICS, and the proximal colon.

[The participation of met-enkephalin in the display of contractile reactions of the large intestine and ileocecal sphincter]. / Ob uchastii met-énkefalina v proiavlenii sokratitel'nykh reaktsii tolstoi kishki i ileotsekal'nogo sfinktera.

Blockade of H-cholinoreceptors, alpha- and beta-adrenoreceptors did not lead to disappearance of the colon and ileocecal sphincter contractile responses to i.a. administration of met-enkephalin (0.05-8.0 micrograms). The responses of the colon, as well as ileum and jejunum were augmented under blockade of alpha-adrenoreceptors whereas the responses of ileocecal sphincter decreased. The latters were augmented under blockade of beta-adrenoreceptors. Met-enkephalin infused into the vascular bed of an isolated portion of the intestine (0.01-5.0 micrograms/ml/min), potentiated the colon and ileocecal sphincter responses to acetylcholine (1.0-20.0 micrograms), the colon responses to stimulation of the n. vagus efferent fibers, and the ileocecal sphincter responses to serotonin (20-100 micrograms).

Mechanism of action of neurotensin at the ileocecal sphincter region.

UNLABELLED: Neurotensin, a neuropeptide identified in the distal small intestine, plays an unclear role in ileocecal sphincter regional function. The purpose of this study was to determine the effect and mechanism of action of neurotensin on the feline ileocecal sphincter (ICS), proximal colon, and distal ileum. Intraluminal pressures were recorded at these sites in anesthetized cats after superior mesenteric artery injection of neurotensin. Dose dependent tonic and phasic contractions were seen at all sites. Peak pressure responses were seen at the maximal dose used and were greater for the ICS than the distal ileum and the proximal colon. The threshold dose for peak pressures for neurotensin was 0.05 microgram/kg for all sites with the maximal peak pressures occurring at the maximal dose used (100 micrograms/kg). The motility index (MI [number of contractions x mean amplitude of contractions]) was determined for three minutes before and after neurotensin injection. The change in the motility index after neurotensin increased at doses above 0.05 micrograms/kg for the ileum and the ICS and 0.25 microgram/kg for the colon. Maximal responses for the motility index were seen at 1 microgram/kg for the distal ileum, and 10 micrograms/kg for the ICS and the proximal colon, with the greatest response seen at the ICS. Neurotensin-induced ICS relaxation was seen at 1 microgram/kg (50 +/- 10%, p less than 0.01) in 33% of cats. The contractile responses of the distal ileum and the proximal colon were not inhibited by naloxone, trimethaphan, tetrodotoxin, or atropine. The ICS contractile response was decreased by tetrodotoxin by 53%, p less than 0.05. The alpha 2 antagonist, yohimbine reduced the neurotensin induced ICS contraction from 31.6 +/- 3.4 to 21.9 +/- 3.3 mm Hg, p less than 0.05. Prazosin had no effect on neurotensin-induced contractions. In the presence of cimetidine and diphenhydramine, trimethaphan did not affect the neurotensin-induced contractile response at all three sites. However, neurotensin inhibited contractions induced by trimethaphan alone at all three sites. CONCLUSIONS: 1. Neurotensin causes a dose-dependent contractile response at the distal ileum, ICS, and proximal colon. 2. Neurotensin has an inhibitory effect at all three sites. 3. The contractile response at the distal ileum and the proximal colon is mediated via smooth muscle receptors. 4. The contractile response of neurotensin at the ICS is mediated partly via alpha 2 receptors and partly via smooth muscle receptors.

The partial opiate receptor agonists, dezocine and ciramadol act as mu receptor antagonists at the feline ileocecal sphincter.

The effects of two novel synthetic narcotic agonist/antagonists dezocine and ciramadol were examined at the ileocecal sphincter (ICS) in the intact anesthetized cat. Changes in blood pressure were seen with higher doses of both dezocine and ciramadol. No ICS pressure changes were seen in the ICS to dezocine and an increase in ICS pressure was seen only to the highest dose of ciramadol examined (10 mg/kg). The antagonist action of the two drugs were examined against submaximal doses of the mu receptor agonist morphine sulfate, delta receptor agonist methionine enkephalin and the k-receptor agonist dynorphin. Both drugs inhibit the ICS response to morphine sulfate. No inhibition of the responses to methionine enkephalin or dynorphin were seen with dezocine and only partial inhibition of the ICS response to dynorphin was seen with ciramadol.

Sites of action of mu-, kappa- and sigma-opiate receptor agonists at the feline ileocecal sphincter.

The sites of action of several opiate agonists at the feline ileocecal sphincter (ICS) were studied. Dose-response curves for the relatively specific ligands for the mu-, kappa-, and sigma-receptors were determined using morphine (mu-receptors), dynorphin-(1-13) (kappa-receptors), and N-allylnormetazocine (sigma-receptors). Each agonist results in a contractile ICS response. The ICS responded stereospecifically to the levo-isomer of N-allylnormetazocine. Atropine (30 micrograms/kg) or naloxone (100 micrograms/kg) antagonized the ICS response to morphine and to (-)-N-allylnormetazocine. Higher doses of naloxone were required to inhibit the ICS response to dynorphin. Neither atropine nor tetrodotoxin inhibited the ICS response to dynorphin. The ICS response to dynorphin was enhanced after tetrodotoxin. Morphine tachyphylaxis inhibited the ICS response to (-)-N-allylnormetazocine and vice versa. The ICS response to morphine was unaffected by vagotomy but inhibited by trimethaphan camsylate. This study suggests that dynorphin (kappa-receptor) acts at a smooth muscle receptor to mediate contraction and a neural receptor to mediate relaxation, while (-)-N-allylnormetazocine acts at the ICS via a mu-receptor. mu-Receptor activation causes ICS contraction via a cholinergic pathway.

Evidence for a direct and indirect action of leucine enkephalin at the feline ileocecal sphincter.

An in vitro whole organ bath preparation was used to examine the effects of leucine enkephalin on the cat ileocecal sphincter (ICS) intraluminal pressure and myoelectric activity. The bath allowed separation of the bathing media surrounding the ICS and the ileum. Leucine enkephalin (2 x 10(-7) M) when added to the ileal bathing medium caused a delayed increase in ICS spike activity and pressure which was blocked by tetrodotoxin (10(-5)M). In contrast, leucine enkephalin (2 x 10(-7)M) added directly to the ICS bathing medium caused an immediate spike-associated contractile response which was tetrodotoxin-resistant. Thus both an indirect and direct opiate action at the ICS was demonstrated.

Effect of chronic ethanol ingestion on enterocyte turnover in rat small intestine.

Whether chronic ethanol ingestion significantly damages the small intestine remains controversial. To clarify this we have analysed the morphology of the small intestinal epithelium and quantified its renewal in chronically ethanol fed rats. Twenty adult male rats were pair fed for 28 days a nutritionally adequate liquid diet containing either ethanol as 36% of total calories or an isocaloric diet in which fat substituted for ethanol. Crypt cell production rate was determined in the jejunum and ileum by the metaphase arrest method. Weight gain and small intestinal morphology were similar in ethanol fed and control rats, but enterocyte turnover was significantly reduced in the jejunum (p less than 0.05) and ileum (p less than 0.01) of the ethanol fed rats. This effect of ethanol on the small intestine is probably systemic rather than local, because the changes in jejunum and ileum were similar, and it may contribute to the development of malnutrition in chronic alcoholics.

Effects of morphine and atropine on motility and transit in the human ileum.

We examined motility of the ileocecal region, pressures at the ileocecal sphincter, and ileal flow after therapeutic doses of morphine and atropine. Using a factorial design in two cells of 8 (2(3] subjects, drugs were given during fasting and postcibally. Morphine (100 micrograms/kg body wt as a bolus intravenously) and atropine (7 micrograms/kg body wt as a bolus) stimulated migrating bursts of phasic activity (similar to phase III of the migrating motor complex). Morphine initially stimulated ileal flow, but atropine could not be shown to have this effect. Atropine reduced markedly the occurrence of sporadic pressure waves in the ileum, but morphine did not. Whereas atropine delayed mouth-to-ileum transit of polyethylene glycol, given in a mixed meal, morphine did not. Naloxone, in the dosage used (40 micrograms/kg body wt as a bolus, followed by 10 micrograms/kg body wt X h) had no independent effects on motility or flow, but did blunt the stimulatory effects of morphine and atropine on migrating motor complexes. We could not demonstrate an effect of any drug on the transit of lactulose from terminal ileum to cecum. Neither morphine nor atropine had impressive effects on tone at the ileocecal sphincter. These observations, while not specifying the mechanisms for constipation after opiates or anticholinergics, highlight the complexities of small bowel transit in humans and point out that the antidiarrheal effects of drugs are probably multifactorial.

Changes in the responsiveness of the cat ileocecal sphincter to adrenergic agents during the postnatal period.

The changes in the responsiveness of the cat ileocecal sphincter (ICS) to adrenergic agents during the postnatal period were studied by the effect of noradrenaline (applied cumulatively: 0.01-100 mumol) on the mechanical activity:smooth muscle tone and phasic contractions. Noradrenaline contracted the ICS smooth muscle through alpha 1-adrenergic receptors. These receptors were differentiated in the first postnatal days but continue to develop functionally even after 60 days postnatal. An age-determined decrease in the EC50 values of noradrenaline, inducing tonic contractions, was established. Noradrenaline inhibited the phasic contractions of ICS. This effect increased after beta-adrenergic receptor blockers, and disappeared after blocking of alpha 1-adrenergic receptors, which suggests the existence of a postjunctional inhibitory adrenergic receptor of alpha 1 type. The beta-adrenergic receptors in the ICS smooth muscle are not differentiated until 15 days postnatal. They developed functionally towards 30 days postnatal.

Multiple 5-hydroxytryptamine receptors on feline ileum and ileocecal sphincter.

The effects of 5-hydroxytryptamine (5-HT) on the feline ileum and ileocecal sphincter (ICS) were studied in vivo using simultaneous myoelectric and pressure recordings. Both inhibitory and excitatory responses were seen in the ileum and ICS, with the inhibitory response being seen with lower doses of 5-HT (EDmax for inhibition was 5.0 micrograms/kg and EDmax for contractile response was 80.0 micrograms/kg). The inhibitory and excitatory responses were antagonized separately by different 5-HT antagonists. Methysergide inhibited the ICS relaxation response only, whereas cinanserin inhibited the ICS contractile response. Neither effect was inhibited by tetrodotoxin, suggesting that 5-HT acts directly on the smooth muscle at at least two separate receptors. In addition, methysergide alone resulted in a usually tonic increase (8.6 +/- 0.6 mmHg) in basal ICS pressure (P less than 0.05) without an ileal effect, and tetrodotoxin alone induced phasic ileal and ICS contractions (delta ICS = 7.3 +/- 1.5 mmHg). These data suggest the action of at least two inhibitory neurons tonically at the ICS.

Characterization of opiate-mediated responses of the feline ileum and ileocecal sphincter.

Although opioid peptides have been demonstrated immunohistochemically in the feline intestine, the action of these peptides is unknown. The aims of this study were: (a) to determine the distal ileal and ileocecal sphincter (ICS) responses to morphine sulfate (MS), methionine enkephalin (ME) and leucine enkephalin (LE); (b) to determine the mechanism by which exogenous opiates mediate these responses; (c) to determine the type of receptor involved in mediating these responses and (d) to ascertain whether endogenous opiate-mediated responses may be vagally induced. The ICS responded to all three opiate agonists with tonic and phasic contractions, the latter being associated with increased spike activity. The ED(max) for ICS pressure response was 1 mug/kg for ME, 5 mug/kg for LE, and 150 mug/kg for MS. The distal ileum responded with increased spike activity and phasic contractions. The ED(max) for the ileal motility index response was 1.0 x 10(-1) mug/kg for ME, 1 mug/kg for LE, and 150 mug/kg for MS. Thus, both sites demonstrated similar dose-response relationships, both responding to at least 100 times lower doses of enkephalins than MS. The ICS contraction preceded ileal contractions. The ileal and ICS response was not antagonized by atropine, hexamethonium, phentolamine, propranolol, cinanserin, or tetrodotoxin. Naloxone, 600 mug/kg, antagonized the response to the enkephalins while 10 mug/kg antagonized the response to MS. Higher doses of the specific-receptor agonist SKF 10047 and kappa-receptor agonist ketocyclazocine were required before a contractile response was elicited. Electrical stimulation of the cervical vagus induced ICS contraction and a fall in blood pressure. The ICS contractile response but not the blood pressure response was inhibited by naloxone 1 mg/kg. These data indicate: (a) tonic and phasic ICS contraction followed by ileal contraction may be mediated through delta-type opiate receptors located in the muscle membrane and (b) opiate-mediated ICS contraction may be induced during vagal stimulation.

Effects of PGE1 and PGF2 alpha on the responses of gastrointestinal sphincters to field stimulation.

The study concerned the effects of PGE1 and PGF2 alpha on the spontaneous tone and the responses to field stimulation of isolated strips from: lower esophageal sphincter (LES), pyloric sphincter (PS) and ileocaecal sphincter (ICS) of cats. PGE1 and PGF2 alpha (0.3 microM) increased the LES tone and abolished the PS contractions. PGF2 alpha increased the tone of ICS while PGE1 had no effect at all. The effects of the prostaglandins (PG) were reduced when the preparations were pretreated with atropine, propranolol and phenoxybenzamine (1 microM). PGE1 and PGF2 alpha decreased the LES relaxation in response to field stimulation (0.5 msec, 2 Hz for 10 sec at supramaximal current). No responses of PS to field stimulation were observed after PG treatment. PGF2 alpha increased the amplitude of the relaxation response in the ICS to field stimulation. PGE1 did not change the effect of field stimulation in ICS. The effects of PGE1 and PGF2 alpha on the LES and ICS responses to field stimulation were not influenced by adrenergic and cholinergic blocking agents. The data suggest a PG effect on non-adrenergic, non-cholinergic (purinergic) transmission in the gastrointestinal sphincter smooth muscle on field stimulation. Due to the high concentration of PG used this effect was probably a pharmacological one.