Propulsive Contractions Research Articles

AB277. SPR-04 Myosalpinx contractions are essential for egg/embryo transport in the oviduct

ObjectiveOviducts or fallopian tubes are smooth muscle lined dynamic tubular organs that connect the ovaries to the uterus and facilitate several physiological processes including gamete transport, fertilization and early embryo development. Several stages of the reproductive process occur exclusively within the oviduct and are subject to physiological regulation. The four main functions of the oviduct include: (I) the transport of the ovum from the ovary to the site of fertilization; (II) the oviduct aids in transport of spermatozoa from the site of deposition to the site of fertilization within the ampulla; (III) the oviduct provides a suitable environment for the egg with secretions along the duct providing protection of the egg from mechanical damage and for maintenance of viability of the egg during its transport; (IV) transportation of the fertilized ovum (embryo) to the uterus where implantation and further development occurs. Given the complexities and the different physiological functions of the oviduct it is not surprising that it is functionally organized into different regions. Dogma in the literature suggests that egg or embryo transport depends mainly on the incessant beat of the ciliated epithelium towards the uterus. However, egg transport may also be dependent upon contractions of the smooth muscle lined wall or myosalpinx. In order to fully understand the physical mechanisms that contribute to the coordinated movement of the egg we investigated the role of the calcium-activated chloride conductance, Ano1 on the generation of pacemaker activity.MethodsVideo imaging and spatio-temporal mapping along with intracellular microelectrode recordings were performed to define the role of myosalpinx in egg/embryo transport. The Cre-recombinase LoxP technology was also utilized to determine the role of the calcium-activated chloride conductance, Ano1 in adult tissues.ResultsEgg transport is highly dependent upon phasic contractions of the smooth muscle lined wall or myosalpinx. The phasic and propulsive contractions of the myosalpinx depend upon specialized ICC, termed ICC-OVI. There is regional dependence on the role of Ano1 in pacemaker activity and that global reduction in Ano1 in mature female mice leads to reduced fertility.ConclusionsThese data further support the role of myosalpinx activity in egg/embryo transport in the oviduct and the importance of Ano1 in the generation of pacemaker activity within the oviduct. A critical role in Ano1 in egg/embryo transport and fertility is also demonstrated.Funding Source(s)NIH RO1 DK57236

Optical tracer size differences allow quantitation of active pumping rate versus Stokes-Einstein diffusion in lymphatic transport.

Lymphatic uptake of interstitially administered agents occurs by passive convective–diffusive inflow driven by interstitial concentration and pressure, while the downstream lymphatic transport is facilitated by active propulsive contractions of lymphatic vessel walls. Near-infrared fluorescence imaging in mice was used to measure these central components of lymphatic transport for the first time, using two different-sized molecules––methylene blue (MB) and fluorescence-labeled antibody immunoglobulin G (IgG)-IRDye 680RD. This work confirms the hypothesis that lymphatic passive inflow and active propulsion rates can be separated based upon the relative differences in Stokes–Einstein diffusion coefficient. This coefficient specifically affects the passive-diffusive uptake when the interstitial volume and pressure are constant. Parameters such as mean time-to-peak signal, overall fluorescence signal intensities, and number of active peristaltic pulses, were estimated from temporal imaging data. While the mean time to attain peak signal representative of diffusion-dominated flow in the lymph vessels was 0.6±0.2??min for MB and 8±6??min for IgG, showing a size dependence, the active propulsion rates were 3.4±0.8??pulses/min and 3.3±0.5??pulses/min, respectively, appearing size independent. The propulsion rates for both dyes decreased with clearance from the interstitial injection-site, indicating intrinsic control of the smooth muscles in response to interstitial pressure. This approach to size-comparative agent flow imaging of lymphatic function can enable noninvasive characterization of diseases related to uptake and flow in lymph networks.

Stimulation of dopamine D2-like receptors in the lumbosacral defaecation centre causes propulsive colorectal contractions in rats.

The pathophysiological roles of the CNS in bowel dysfunction in patients with irritable bowel syndrome and Parkinson's disease remain obscure. In the present study, we demonstrate that dopamine in the lumbosacral defaecation centre causes strong propulsive motility of the colorectum. The effect of dopamine is a result of activation of sacral parasympathetic preganglionic neurons via D2-like dopamine receptors. Considering that dopamine is a neurotransmitter of descending pain inhibitory pathways, our results highlight the novel concept that descending pain inhibitory pathways control not only pain, but also the defaecation reflex. In addition, severe constipation in patients with Parkinson's disease can be explained by reduced parasympathetic outflow as a result of a loss of the effect of dopaminergic neurons. We have recently demonstrated that intrathecally injected noradrenaline caused propulsive contractions of the colorectum. We hypothesized that descending pain inhibitory pathways control not only pain, but also the defaecation reflex. Because dopamine is one of the major neurotransmitters of descending pain inhibitory pathways in the spinal cord, we examined the effects of the intrathecal application of dopamine to the spinal defaecation centre on colorectal motility. Colorectal intraluminal pressure and expelled volume were recorded in vivo in anaesthetized rats. Slice patch clamp and immunohistochemistry were used to confirm the existence of dopamine-sensitive neurons in the sacral parasympathetic nuclei. Intrathecal application of dopamine into the L6-S1 spinal cord, where the lumbosacral defaecation centre is located, caused propulsive contractions of the colorectum. Inactivation of spinal neurons using TTX blocked the effect of dopamine. Although thoracic spinal transection had no effect on the enhancement of colorectal motility by intrathecal dopamine, the severing of the pelvic nerves abolished the enhanced motility. Pharmacological experiments revealed that the effect of dopamine is mediated primarily by D2-like dopamine receptors. Neurons labelled with retrograde dye injected at the colorectum showed an inward current in response to dopamine in slice patch clamp recordings. Furthermore, immunohistochemical analysis revealed that neurons immunoreactive to choline acetyltransferase express D2-like dopamine receptors. Taken together, our findings demonstrate that dopamine activates sacral parasympathetic preganglionic neurons via D2-like dopamine receptors and causes propulsive motility of the colorectum in rats. The present study supports the hypothesis that descending pain inhibitory pathways regulate defaecation reflexes.

Oral ingestion of a 5-HT4 receptor agonist evokes a CNS-ENS mediated gastro-colonic reflex involving High Amplitude Propulsive Contractions (HAPCs) in the human colon within 5minutes

Oral ingestion of a 5-HT4 receptor agonist evokes a CNS-ENS mediated gastro-colonic reflex involving High Amplitude Propulsive Contractions (HAPCs) in the human colon within 5minutes

The ghrelin receptor agonist, HM01, activates the innervation of the colon to initiate coordinated propulsive contractions and bowel emptying

The ghrelin receptor agonist, HM01, activates the innervation of the colon to initiate coordinated propulsive contractions and bowel emptying

Site and mechanism of the colokinetic action of the ghrelin receptor agonist, HM01

It has been recently demonstrated that the ghrelin receptor agonist, HM01, caused defecation in rats that were treated to provide a model for the constipation of Parkinson's disease. HM01 significantly increased fecal output and increased Fos activity in neurons of the hypothalamus and hindbrain, but not in the spinal defecation center. Other ghrelin agonists act on the defecation center. Receptor pharmacology was examined in ghrelin receptor (GHSR1a) transfected cells. Anesthetized rats were used to investigate sites and mechanisms of action. HM01 activated rat GHSR1a at nanomolar concentrations and was antagonized by the GHSR1a antagonist, YIL781. HM01, intravenous, was potent to activate propulsive colorectal contractions. This was prevented by pelvic nerve section and by intravenous YIL781, but not by spinal cord section rostral to the defecation centers. Direct intrathecal application of HM01 to the defecation center at spinal level L6-S1 initiated propulsive contractions of the colorectum. HM01 stimulates GHSR1a receptors on neurons in the lumbosacral defecation centers to cause propulsive contractions and emptying of the colorectum. It has greater potency when given systemically, compared with other GHSR1a agonists.

Colokinetic effect of noradrenaline in the spinal defecation center: implication for motility disorders

Chronic abdominal pain in irritable bowel syndrome (IBS) usually appears in combination with disturbed bowel habits, but the etiological relationship between these symptoms remains unclear. Noradrenaline is a major neurotransmitter controlling pain sensation in the spinal cord. To test the hypothesis that the descending noradrenergic pathway from the brain stem moderates gut motility, we examined effects of intrathecal application of noradrenaline to the spinal defecation center on colorectal motility. Colorectal intraluminal pressure and expelled volume were recorded in vivo in anesthetized rats. Intrathecal application of noradrenaline into the L6-S1 spinal cord, where the lumbosacral defecation center is located, caused propulsive contractions of the colorectum. Inactivation of spinal neurons by tetrodotoxin blocked the effect of noradrenaline. Pharmacological experiments showed that the effect of noradrenaline is mediated primarily by alpha-1 adrenoceptors. The enhancement of colorectal motility by intrathecal noradrenaline was abolished by severing of the pelvic nerves. Our results demonstrate that noradrenaline acting on sacral parasympathetic preganglionic neurons through alpha-1 adrenoceptors causes propulsive motility of the colorectum in rats. Considering that visceral pain activates the descending inhibitory pathways including noradrenergic neurons, our results provide a rational explanation of the concurrent appearance of chronic abdominal pain and colonic motility disorders in IBS patients.

Can colonic migrating motor complexes occur in mice lacking the endothelin-3 gene?

In mammals, colonic migrating motor complexes (CMMC) are a major propulsive contraction responsible for the expulsion of faecal content. Mice with a mutation of the endothelin-3 gene raised on a 129SL background strain have ~70% colonic aganglionosis, lack CMMC, and are lethal within 12 days postpartum. In contrast, endothelin-3 mutant mice raised and maintained on a C57BL6 background strain (lethal-spotted (ls/ls) mice) can live for much longer, but it is unclear whether CMMC generation is preserved in these mice also lacking the endothelin-3 gene. The aim of this study was to determine whether CMMC exist in ls/ls mouse colon and, if so, whether their existence and frequency are related to the length of aganglionosis. Spatiotemporal mapping and mechanical recordings of colonic wall movements were made from isolated whole colons obtained from wild-type and ls/ls mice. Although ls/ls mice had a megacolon, they still generated CMMC in the ganglionic segment, which on some occasions could propagate short distances into the aganglionic region. There was large variability in aganglionosis length, which showed a weak correlation with the existence or frequency of CMMC. Interestingly, CMMC propagation velocity was slower in ls/ls mice when evoked by intraluminal fluid. A myogenic motor pattern was identified in the aganglionic region that was maintained under tonic inhibition. We show that despite megacolon, ls/ls mice still generate CMMC in the ganglionic region. These offspring have sufficient propulsive motility in the ganglionic segment to live a normal murine lifespan and rarely die of bowel obstruction.

A ghrelin receptor agonist is an effective colokinetic in rats with diet-induced constipation.

Despite constipation being a common problem, the treatments that are available have side effects and are only partly effective. Recent studies show that centrally penetrant ghrelin receptor agonists cause defecation in humans and other species. Here, we describe some features of a rat model of low fiber-induced constipation, and investigate the effectiveness of the ghrelin agonist, capromorelin. Rats were given low-fiber diets for 5 weeks. Their colorectal responsiveness to distension and to a behavioral test, water avoidance and colon histology were compared to those of rats on a standard diet. After the low-fiber diet, distension of the colon produced fewer propulsive contractions, behaviorally induced defecation was reduced, and the lining of the colorectum was inflamed. However, capromorelin was similarly effective in causing defecation in constipated and non-constipated rats. Low-fiber diet in rats produces a constipation phenotype, characterized by reduced responsiveness of the colorectum to distension and to a behavioral stimulus of defecation, water avoidance. The effectiveness of capromorelin suggests that centrally penetrant ghrelin receptor stimulants may be effective in treating constipation.

Characterization of ghrelin-sensitive neurons in the lumbosacral defecation center in rats.

Ghrelin is involved in the regulation of somatic growth, feeding behavior and energy homeostasis. Ghrelin stimulates neuropeptide Y (NPY) neurons and activates intracellular AMP-activated protein kinase (AMPK) in the hypothalamus. These NPY neurons also express the leptin receptor and leptin inhibits ghrelin-induced activation of NPY neurons. In the spinal cord, we have demonstrated colokinetic action of ghrelin. However, the precise characteristics of the ghrelin-sensitive neurons remain to be clarified. The aim of this study was firstly to confirm that the action of ghrelin is mediated via a neurogenic pathway in the spinal cord, and secondly to characterize the ghrelin-sensitive neurons by comparing with hypothalamic ghrelin-sensitive neurons. Rats were anesthetised with alpha-chloralose and ketamine, and colorectal intraluminal pressure and expelled volume were recorded in vivo. Drugs were applied intrathecally. Ghrelin caused enhancement of propulsive contractions. Tetrodotoxin completely blocked the colokinetic effect of ghrelin. An AMPK activator, aminoimidazole carboxamide ribonucleotide, failed to mimic the ghrelin effect. Leptin had no effect on the spontaneous contractions and did not exert a suppressive effect on the ghrelin-enhanced colorectal motility. An NPY Y1 receptor antagonist did not affect the action of ghrelin. NPY had no effect on the colorectal motility. This study showed that intrathecal injection of ghrelin stimulates colorectal motility by acting on ghrelin-sensitive neurons in the lumbosacral defecation center. The characteristics of ghrelin-sensitive neurons in the spinal cord are quite different from those of ghrelin-sensitive neurons in the hypothalamus.

Colonic migrating motor complexes, high amplitude propagating contractions, neural reflexes and the importance of neuronal and mucosal serotonin.

The colonic migrating motor complex (CMMC) is a critical neurally mediated rhythmic propulsive contraction observed in the large intestine of many mammals. It seems to be equivalent to the high amplitude propagating contractions (HAPCs) in humans. This review focuses on the probable neural mechanisms involved in producing the CMMC or HAPC, their likely dependence on mucosal and neuronal serotonin and pacemaker insterstitial cells of Cajal networks and how intrinsic neural reflexes affect them. Discussed is the possibility that myenteric 5-hydroxytryptamine (5-HT) neurons are not only involved in tonic inhibition of the colon, but are also involved in generating the CMMC and modulation of the entire enteric nervous system, including coupling motility to secretion and blood flow. Mucosal 5-HT appears to be important for the initiation and effective propagation of CMMCs, although this mechanism is a longstanding controversy since the 1950s, which we will address. We argue that the slow apparent propagation of the CMMC/HAPC down the colon is unlikely to result from a slowly conducting wave front of neural activity, but more likely because of an interaction between ascending excitatory and descending (serotonergic) inhibitory neural pathways interacting both within the myenteric plexus and at the level of the muscle. That is, CMMC/HAPC propagation appears to be similar to esophageal peristalsis. The suppression of inhibitory (neuronal nitric oxide synthase) motor neurons and mucosal 5-HT release by an upregulation of prostaglandins has important implications in a number of gastrointestinal disorders, especially slow transit constipation.

Both exogenous 5-HT and endogenous 5-HT, released by fluoxetine, enhance distension evoked propulsion in guinea-pig ileum in vitro.

The roles of 5-HT3 and 5-HT4 receptors in the modulation of intestinal propulsion by luminal application of 5-HT and augmentation of endogenous 5-HT effects were studied in segments of guinea-pig ileum in vitro. Persistent propulsive contractions evoked by saline distension were examined using a modified Trendelenburg method. When 5-HT (30 nM), fluoxetine (selective serotonin reuptake inhibitor; 1 nM), 2-methyl-5-HT (5-HT3 receptor agonist; 1 mM), or RS 67506 (5-HT4 receptor agonist, 1 μM) was infused into the lumen, the pressure needed to initiate persistent propulsive activity fell significantly. A specific 5-HT4 receptor antagonist, SB 207266 (10 nM in lumen), abolished the effects of 5-HT, fluoxetine, and RS 67506, but not those of 2-methyl-5-HT. Granisetron (5-HT3 receptor antagonist; 1 μM in lumen) abolished the effect of 5-HT, fluoxetine, RS 67506, and 2-methyl-5-HT. The NK3 receptor antagonist SR 142801 (100 nM in lumen) blocked the effects of 5-HT, fluoxetine, and 2-methyl-5-HT. SB 207266, granisetron, and SR 142801 had no effect by themselves. Higher concentrations of fluoxetine (100 and 300 nM) and RS 67506 (3 and 10 μM) had no effect on the distension threshold for propulsive contractions. These results indicate that luminal application of exogenous 5-HT, or increased release of endogenous mucosal 5-HT above basal levels, acts to lower the threshold for propulsive contractions in the guinea-pig ileum via activation of 5-HT3 and 5-HT4 receptors and the release of tachykinins. The results further indicate that basal release of 5-HT is insufficient to alter the threshold for propulsive motor activity.

Interplay between myogenic pacemakers and enteric neurons determine distinct motor patterns in the rat colon.

Waxing and waning of slow waves amplitude has been recently associated with a segmentation motor pattern in the murine small intestine. The 'wax and wane' phenomenon in this area of the gastrointestinal tract seems to be the result of modulation of slow waves by a second pacemaker of a lower frequency displayed by the interstitial cells of Cajal near the deep muscular plexus (ICC-DMP). In the rat colon, smooth muscle cyclic depolarizations causing low-frequency (LF) contractions (0.9±0.1cpm) occur together with slow wave activity associated to high-frequency (HF) contractions (14±0.3cpm; ripples). In the present manuscript, we demonstrate the presence of 'wax and wane' in rat colonic slow waves. Depolarization from the 'wax' to the 'wane' was 7.6±1.2mV, i.e., smooth muscle cells went from a resting membrane potential (RMP) of -50.0mV to a RMP of -42.4mV. The amplitude of the slow wave decreased from 14.0±2.2mV to 3.4±0.7mV. The wax and wane phenomenon occurred at 0.9±0.1cpm, coinciding with the frequency of cyclic depolarizations. Therefore, we hypothesized that the 'wax and wane' of slow waves in the rat colon could be the result of their interaction with the LF pacemaker. We describe three different myogenic motor patterns that depend on the level of smooth muscle and ICC excitation: (i) LF propulsive contractions, (ii) regular slow waves causing ripples, and (iii) a wax and wane pattern that may lead to segmentation. Different intra- and extra-luminal inputs probably determine the dominating motor pattern in each area through the enteric nervous system.

Sa2008 Efficacy and Safety of Linaclotide in Chronic Idiopathic Constipation Patients With Abdominal Bloating: Phase 3b Trial Results

Colonic motor patterns, which might become biomarkers of colonic dysmotility in constipation, are still poorly defined in humans but have been clarified including the role of myogenic, neurogenic and interstitial cells of Cajal (ICC) control systems in the rat, mouse and guinea pig. The purpose of this study was to explore the characteristics of colonic motor patterns in 8 healthy volunteers and 22 patients with chronic constipation by high-resolutionmanometry (HRM). A 36-channel Unisensor solid-state probe, 1 cm spaced, was fixed at the transversedistal colon by colonoscopy for 6-8 hours manometry recording with Medkinetic acquisition software. After 60 min baseline recording, a yogurt meal (460 g, 1400 kJ) was given to observe the gastro-colonic reflex for 90 min, thereafter 2 mg prucalopride was given to evaluate short-term effects. Results: 1) Unique to HRM recordings were the clearly definable, distinguishable and quantifiable simultaneous and propulsive contractions which all had superimposed haustral contractions; distinct from any animal model. 2) In healthy volunteers, common motor patterns included simultaneous contractions (duration of 1-3 s, 40 100 mmHg, frequency 0.5-1.7 cpm), propulsive contractions including high amplitude propulsive contractions (HAPCs; 100-250 mmHg; figure), and stationary haustral contractions (30150 mmHg) that were often rhythmic at the ICC pacemaker frequency (3 cpm). The yogurt meal and 2 mg prucalopride promoted propulsive contractions, and decreased simultaneous contractions from 7 to 2 per 30 min recording. Eight HAPCs were observed in 3 cases, with propagating distances of 8-36 cm, amplitudes of 100-220 mmHg, velocity of 53 mm/s, several HAPCs were repetitive with intervals of 60-150 sec. HAPCs usually occurred without other patterns although it happened once in between 2 simultaneous contractions. 3) In patients with chronic constipation, simultaneous and retrograde-propagating contractions of low amplitude were the main patterns, no HAPCs were observed. Simultaneous contractions (duration 1-3 s, 30 mm Hg, frequency 0.4 -1.1 cpm) were significantly promoted by yogurt (from 5 to 16 episodes / 30 min). Retrograde contractions were increased after yogurt and prucalopride, with propagating distances of 8-21 cm, 10-60 mmHg, velocity of 61 mm/s and intervals of 60-150 sec. This did not occur in healthy volunteers. 4) Flatulence was associated with simultaneous contractions; yogurt increased the episodes of flatulence in both patients and healthy volunteers. In conclusion, rhythmic low amplitude simultaneous contractions and retrograde contractions, abundance of low amplitude rhythmic haustral contractions and failure to induce HAPCs characterized chronic constipation, suggestive of enhancement of local myogenic activity and dysfunctional neurogenic control systems of propulsion.

Sa2007 Colonic Motor Patterns in Patients With Chronic Constipation Assessed by High Resolution Manometry

Colonic motor patterns, which might become biomarkers of colonic dysmotility in constipation, are still poorly defined in humans but have been clarified including the role of myogenic, neurogenic and interstitial cells of Cajal (ICC) control systems in the rat, mouse and guinea pig. The purpose of this study was to explore the characteristics of colonic motor patterns in 8 healthy volunteers and 22 patients with chronic constipation by high-resolutionmanometry (HRM). A 36-channel Unisensor solid-state probe, 1 cm spaced, was fixed at the transversedistal colon by colonoscopy for 6-8 hours manometry recording with Medkinetic acquisition software. After 60 min baseline recording, a yogurt meal (460 g, 1400 kJ) was given to observe the gastro-colonic reflex for 90 min, thereafter 2 mg prucalopride was given to evaluate short-term effects. Results: 1) Unique to HRM recordings were the clearly definable, distinguishable and quantifiable simultaneous and propulsive contractions which all had superimposed haustral contractions; distinct from any animal model. 2) In healthy volunteers, common motor patterns included simultaneous contractions (duration of 1-3 s, 40 100 mmHg, frequency 0.5-1.7 cpm), propulsive contractions including high amplitude propulsive contractions (HAPCs; 100-250 mmHg; figure), and stationary haustral contractions (30150 mmHg) that were often rhythmic at the ICC pacemaker frequency (3 cpm). The yogurt meal and 2 mg prucalopride promoted propulsive contractions, and decreased simultaneous contractions from 7 to 2 per 30 min recording. Eight HAPCs were observed in 3 cases, with propagating distances of 8-36 cm, amplitudes of 100-220 mmHg, velocity of 53 mm/s, several HAPCs were repetitive with intervals of 60-150 sec. HAPCs usually occurred without other patterns although it happened once in between 2 simultaneous contractions. 3) In patients with chronic constipation, simultaneous and retrograde-propagating contractions of low amplitude were the main patterns, no HAPCs were observed. Simultaneous contractions (duration 1-3 s, 30 mm Hg, frequency 0.4 -1.1 cpm) were significantly promoted by yogurt (from 5 to 16 episodes / 30 min). Retrograde contractions were increased after yogurt and prucalopride, with propagating distances of 8-21 cm, 10-60 mmHg, velocity of 61 mm/s and intervals of 60-150 sec. This did not occur in healthy volunteers. 4) Flatulence was associated with simultaneous contractions; yogurt increased the episodes of flatulence in both patients and healthy volunteers. In conclusion, rhythmic low amplitude simultaneous contractions and retrograde contractions, abundance of low amplitude rhythmic haustral contractions and failure to induce HAPCs characterized chronic constipation, suggestive of enhancement of local myogenic activity and dysfunctional neurogenic control systems of propulsion.

Neural mechanisms of peristalsis in the isolated rabbit distal colon: a neuromechanical loop hypothesis.

Propulsive contractions of circular muscle are largely responsible for the movements of content along the digestive tract. Mechanical and electrophysiological recordings of isolated colonic circular muscle have demonstrated that localized distension activates ascending and descending interneuronal pathways, evoking contraction orally and relaxation anally. These polarized enteric reflex pathways can theoretically be sequentially activated by the mechanical stimulation of the advancing contents. Here, we test the hypothesis that initiation and propagation of peristaltic contractions involves a neuromechanical loop; that is an initial gut distension activates local and oral reflex contraction and anal reflex relaxation, the subsequent movement of content then acts as new mechanical stimulus triggering sequentially reflex contractions/relaxations at each point of the gut resulting in a propulsive peristaltic contraction. In fluid filled isolated rabbit distal colon, we combined spatiotemporal mapping of gut diameter and intraluminal pressure with a new analytical method, allowing us to identify when and where active (neurally-driven) contraction or relaxation occurs. Our data indicate that gut dilation is associated with propagating peristaltic contractions, and that the associated level of dilation is greater than that preceding non-propagating contractions (2.7 ± 1.4 mm vs. 1.6 ± 1.2 mm; P < 0.0001). These propagating contractions lead to the formation of boluses that are propelled by oral active neurally driven contractions. The propelled boluses also activate neurally driven anal relaxations, in a diameter dependent manner. These data support the hypothesis that neural peristalsis is the consequence of the activation of a functional loop involving mechanical dilation which activates polarized enteric circuits. These produce propulsion of the bolus which activates further anally, polarized enteric circuits by distension, thus closing the neuromechanical loop.

Butyrate increases and propionate decreases the frequency of propulsive contractions in guinea pig proximal colon (1110.7)

INTRODUCTION: Colonic bacteria produce short‐chain fatty acids (SCFAs) by fermentation of dietary carbohydrates and fiber. The production of SCFAs is greatest in proximal colon where propulsion is likely to be highly dependent on chemical/nutrient stimuli. AIM: To determine the effect of individual SCFAs on propulsive contractions in guinea pig proximal colon. METHODS: Proximal colon was excised, cannulated and placed in Kreb’s buffer in an organ bath. After equilibration, the colon was distended with 1 ml of Krebs’s buffer alone or containing sodium salts of acetate, butyrate, or propionate at 10‐100 mM. Motility was videorecorded, spatiotemporal maps generated, and the number of full‐length propulsive contractions during a 5 min period determined. RESULTS: The basal rate of propulsive contractions in Kreb’s buffer was 2.9±0.7 per 5 min. Butyrate and propionate had concentration‐dependent and opposing effects on propulsive contractions; acetate had no effect. Butyrate significantly increased propulsive contractions (maximal increase of 207% (p&lt;0.05) at 30 mM) whereas propionate abolished propulsive contractions (91‐100% inhibition at 10‐30 mM). Control Kreb’s buffer containing 10‐100 mM NaCl had no effect. CONCLUSION: SCFAs have differential effects on propulsive contractions in guinea pig proximal colon with butyrate being excitatory and propionate being inhibitory.Grant Funding Source: Supported by DK34153

Impairment of secondary peristalsis in Barrett’s esophagus by transnasal endoscopy-based testing

To investigate dysfunctions in esophageal peristalsis and sensation in patients with Barrett's esophagus following acid infusion using endoscopy-based testing. First, physiological saline was infused into the esophagus of five healthy subjects, at a rate of 10 mL/min for 10 min, followed by infusion of HCl. Esophageal contractions were analyzed to determine whether the contractions observed by endoscopy and ultrasonography corresponded to the esophageal peristaltic waves diagnosed by manometry. Next, using nasal endoscopy, esophageal sensations and contractions were investigated in patients with, as well as controls without, Barrett's esophagus using the same infusion protocol. All except one of the propulsive contractions identified endoscopically were recorded as secondary peristaltic waves by manometry. Patients with long segment Barrett's esophagus (LSBE) tended to have a shorter lag time than the control group, although the difference did not reach statistical significance (88 ± 54 s vs 162 ± 150 s respectively, P = 0.14). Furthermore, patients with LSBE had significantly fewer secondary contractions following the infusion of both saline and HCl than did either the control group or patients with short segment Barrett's esophagus (4.1 ± 1.2 vs 8.0 ± 2.8, P < 0.001 and 7.3 ± 3.2, P < 0.01, respectively, following saline infusion; 5.3 ± 1.2 vs 8.4 ± 2.4 and 8.1 ± 2.9 respectively, P < 0.01 for both, following infusion of HCl). Using nasal endoscopy and a simple acid-perfusion study, we were able to demonstrate disorders in secondary peristalsis in patients with LSBE.

Motility changes induced by intraluminal FeSO4in guinea pig jejunum

Dietary iron supplementation is associated with gastrointestinal (GI) side effects including vomiting, nausea, and diarrhea. Although inorganic iron in high concentrations may be damaging to the intestinal mucosa, we hypothesize that there are physiological effects on the GI tract that occur at concentrations achieved by supplementation. Thus, our aim was to investigate the effect of intraluminal ferrous sulfate (FeSO4 ) on jejunal motility. Segments of guinea pig jejunum were cannulated and the intraluminal pressure recorded with a transducer, while movements were recorded with a video camera. Peristaltic threshold was the oral pressure that evoked four consecutive propulsive contractions. The nutrients decanoic acid (1 mM), l-phenylalanine (50 mM), or the micronutrient FeSO4 (1 mM) were infused intraluminally. We also tested the effect of FeSO4 on electrochemically detected serotonin (5-HT, 5-hydroxytryptamine) released from in vitro tissues, both at rest and following mechanical stimulation. The jejuna peristaltic threshold was significantly decreased by all three nutrients: FeSO4 : 31 ± 2-23 ± 3 mmH2 O; decanoic acid: 27 ± 2-14 ± 2 mmH2 O; and l-phenylalanine: 30 ± 3-14 ± 3mmH2 O. Of the three, only decanoic acid induced segmentation, while FeSO4 inhibited decanoic acid-induced segmentation. Resting 5-HT release was increased by FeSO4 (128% of control), but mechanically evoked 5-HT release was reduced (70% of control). These data suggest that some luminal effects of inorganic iron on jejunal motility could be mediated through a pathway involving altered release of 5-HT. A better understanding of the interaction between luminal iron and 5-HT containing enterochromaffin cells could improve iron supplementation strategies, thus reducing side effects.

The mechanism of enhanced defecation caused by the ghrelin receptor agonist, ulimorelin

Discovery of adequate pharmacological treatments for constipation has proven elusive. Increased numbers of bowel movements were reported as a side-effect of ulimorelin treatment of gastroparesis, but there has been no investigation of the site of action. Anesthetized rats were used to investigate sites and mechanisms of action of ulimorelin. Intravenous ulimorelin (1-5 mg/kg) caused a substantial and prolonged (~1 h) increase in colorectal propulsive activity and expulsion of colonic contents. This was prevented by cutting the nerves emerging from the lumbosacral cord, by the nicotinic receptor antagonist hexamethonium and by antagonists of the ghrelin receptor. The effect of intravenous ulimorelin was mimicked by direct application of ulimorelin (5 μg) to the lumbosacral spinal cord. Ulimorelin is a potent prokinetic that causes propulsive contractions of the colorectum by activating ghrelin receptors of the lumbosacral defecation centers. Its effects are long-lasting, in contrast with other colokinetics that target ghrelin receptors.