Role of extrinsic innervation in modulating nitrergic transmission in the canine ileocolonic region

The human colon can dilate, often to life-threatening proportions. Our aim was to explore nitrergic mechanisms underlying colonic dilation in conscious dogs with enterically isolated ileocolonic loops either extrinsically innervated (n = 4) or extrinsically denervated (n = 4). We recorded phasic pressures in ileum and ileocolonic sphincter (ICS), colonic tone, compliance, and relaxation during ileal distension. By NADPH-diaphorase histochemistry, we assessed effects of extrinsic denervation and enteric isolation on nitrergic fibers. Extrinsic denervation increased phasic pressures in ileum, ICS, and colon and abolished ICS and colonic relaxation in response to ileal distension. The nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine (L-NNA) increased phasic pressures at all sites and ICS tone but did not abolish colonic relaxation during ileal distension in innervated loops. L-NNA reduced compliance and induced colonic high-amplitude propagated contractions in denervated loops. The NOS substrate donor L-arginine reversed effects of L-NNA. The number of NADPH-diaphorase fibers increased in both enterically isolated preparations. Nonnitrergic extrinsic nerve pathways mediate reflex colonic relaxation during ileal distension. Enteric isolation augments the number of NOS fibers, an effect not modified by extrinsic denervation.     

Modular and functionally-different descending recto-anal motor pathways in a rat model

We evaluated the motor responses in recto-anal preparations obtained from rats, in terms of the excitation displayed by modules of nerve networks and descending distally directed pathways, when subjected to the mechanographic on-line technique, a partitioned organ bath, electrical stimulation (EFS, 0.8 ms, 5 Hz) and distension. EFS elicited modular contractions, which increased in amplitude distally, in circular muscle rings isolated from the proximal, middle or distal rectum. The modular responses of the internal anal sphincter or anal canal were relaxation or contraction, respectively. The application of EFS to the distal rectum induced a descending contractile response in the anal canal (5.24±0.34 mN), while distension by balloon evoked a descending response consisting of contraction (1.72±0.20 mN) followed by relaxation (3.42±0.24 mN). The responses were sensitive to tetrodotoxin. Atropine considerably depressed the contractions in all preparations. Whether or not atropine was present, L-NNA increased the excitatory responses, while L-arginine decreased the contractions and extended the relaxation of internal anal sphincter and anal canal. The results suggest that excitatory neurotransmission(s) expressed in the distal rectum dominate modular nerve networks. Functionally-different descending pathways are involved in the motor activity of the anal canal. Stimulatory cholinergic pathways are dependent on the electrically-induced excitation, and inhibitory nitrergic pathways are sensitive to distension of rectal wall.     

Patterns of esophageal inhibition during swallowing,pharyngeal stimulation,and transient LES relaxation. Lower esophageal sphincter

Lower esophageal sphincter (LES) relaxation and esophageal body inhibition co-occur during esophageal peristalsis but not necessarily during pharyngeal stimulation or transient LES relaxation (tLESR). This study examined these relationships and the impact on reflux. Nine young volunteers were studied. An artificial high-pressure zone (HPZ) was established, and pH was recorded 8 and 5 cm proximal to the LES. Pharyngeal stimulation was by water injection and gastric distension with liquid or gas. Peristalsis, pharyngeal stimulation, and spontaneous events were recorded. Swallowing relaxed the LES in 100% of trials (the HPZ in 80%) and caused no reflux. Pharyngeal stimulation relaxed the LES in two-thirds of trials, had no effect on the HPZ, and caused no reflux. Gastric distension was associated with 117 tLESRs, 48% with acid reflux, and 32% with gas reflux; there was no effect on the HPZ. We conclude that LES relaxation is a necessary but not sufficient condition for reflux. LES relaxation and esophageal body inhibition are independent events that may be concurrent (swallowing) or dissociated (tLESR).     

Activation-dependent descending reflex evacuation motority of anal canal in rat model

The evacuative motor responses of the anal canal and recto-anal reflexes during defecation were studied in an isolated rat recto-anal model preparation using (i) partitioned organ bath, (ii) electrical stimulation, (iii) balloon distension and (iv) morphological techniques. Electrical field stimulation applied to the anal canal or to the distal part of the rectum elicited tetrodotoxin (10(-7) M)-sensitive frequency-dependent local or descending contractions of the anal canal and the local responses were bigger in amplitude (14.9 ± 1.35 mN) than the descending contractions (5.3 ± 0.7 mN at frequency of 5 Hz, p < 0.05). The balloon-induced distension of the distal rectum evoked descending responses of the anal canal consisting of a short contraction (1.50 ± 0.18 mN) followed by deep relaxation (3.12 ± 0.34 mN). In the presence of atropine (3 x 10(-7) M) the electrically-elicited (5 Hz) local or descending contractions of the anal canal were suppressed and a relaxation revealed. The initial contraction component of the distension-induced response was decreased while the relaxation was not changed. During atropine treatment, spantide (10(-7) M) lowered even more the contractile component of the anal canal response. NG-nitro-L-arginine (5 x 10(-4) M) enhanced the contraction, prevented the atropine-dependent relaxation of the electrically-elicited response and inhibited the distension-induced relaxation. L-Arginine (5 x 10(-4) M) suppressed the contraction and extended the relaxation. ChAT-, substance P- and NADPH-diaphorase-positive perikarya and nerve fibers were observed in myenteric ganglia of the anal canal. The results suggest activation-dependent descending reflex motority of the anal canal involving electrical stimulation-displayed cholinergic and tachykininergic and distension manifested nitrergic neuro-muscular communications.     

Diminished nitroprusside-induced relaxation of inflamed colonic smooth muscle in mice.

The dextran sodium sulphate (DSS) induced colitis in mice was used as a experimental model to study the contractility of murine longitudinal colonic smooth muscle during inflammation. Smooth muscle segments of proximal, middle and distal colon were mounted in organ baths. Smooth muscle contraction was induced by carbachol showing an aboral increase in activity, whereas in the inflamed middle colonic segment a marked decrease in activity was observed. The dilatative effect of sodium-nitroprusside (SNP) as a nitric oxide donor was investigated after precontraction by carbachol. Both in normal and DSS segments administration of SNP to isolated mouse colonic smooth muscle preparations caused regional differences in relaxation, the highest relaxation seen in normal proximal colonic tissue. However, this relaxation was markedly reduced in inflamed proximal preparations, associated with a diminished cGMP contents.     

Functional coordination of motor activity in colonic smooth muscles in rat experimental model

Spontaneous and electrically-elicited motor activity was recorded by triple organ bath in rat segment-model preparation as display of excitation of local nerve networks and ascending or descending reflex pathways underlying contractile potency and functional coordination of colonic longitudinal and circular muscles. Spontaneous high-amplitude contractions, but not relaxations, appeared synchronously in both muscles. Electrical field stimulation applied to proximal or distal part of segments elicited both tetrodotoxin (0.1 microM)-sensitive local motor responses of the stimulated part and ascending or descending motor responses of the contralateral, nonstimulated part of the preparations. Contractions characterized the local response of longitudinal muscle. The circular muscle responded with relaxation followed by contraction. Synchronous ascending contractions and descending contraction of the longitudinal muscle and relaxation followed by contraction of the circular muscle were observed when the middle part of segments was stimulated, thus indicating that locally-induced nerve excitation propagated via intrinsic ascending or descending nerve pathways that could be synchronously coactivated by one and the same stimulus. The ascending motor responses were more pronounced and the motor responses of longitudinal muscle were expressed more than those of circular muscle suggesting an essential role of ascending reflex pathways and longitudinal muscle in the coordinated motor activity of colon.     

Enteric descending and afferent neural signaling stimulated by giant migrating contractions: essential contributing factors to visceral pain

We investigated whether strong compression of an intestinal segment by giant migrating contractions (GMCs) initiates pseudoaffective signals from the gut, similar to those initiated by its distension with a balloon. The experiments were performed on conscious dogs by using close intra-arterial infusions of test substances that affect the receptors only in the infused segment. The stimulation of GMCs by close intra-arterial infusion of CGRP or distension of an intestinal segment by balloon increased the heart rate; the increase in heart rate was greater when the balloon distension and GMCs occurred concurrently in separate intestinal segments. The suppression of contractility in the distended segment blocked the increase in heart rate. By contrast, the stimulation of rhythmic phasic contractions (RPCs) or their spontaneous occurrence did not increase the heart rate. The occurrence of GMCs as well as intestinal distension also produced descending inhibition. The descending inhibition was blocked by the inhibition of nitric oxide synthase, but it was unaffected by the inhibition of adenylyl cyclase, purinergic receptors P2X and P2Y, and muscarinic receptors M(1) and M(2). The synaptic transmission for descending inhibition was mediated primarily by nicotinic receptors and activation of nitric oxide synthase. It was unaffected by the inhibition of tachykinin receptors NK(1), NK(2), and NK(3); serotonin receptors 5-HT(1A), 5-HT(2)/5-HT(1C), 5-HT(3), and 5-HT(4); and muscarinic receptors. Our findings show that GMCs, but not RPCs, initiate pseudoaffective signals from the gut. In the presence of visceral hypersensitivity or impaired descending inhibition, the GMCs may become a noxious stimulus.     

Inhibition of nitric oxide synthesis blocks the inhibitory response to capsaicin in intestinal circular muscle preparations from different species

Moderate concentrations of the sensory stimulant drug capsaicin caused relaxation in human and animal intestinal circular muscle preparations (guinea-pig proximal, mouse distal colon, human small intestine and appendix) in vitro. With the exception of the guinea-pig colon, the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine (L-NOARG; 10(-4) M) strongly inhibited the relaxant effect of capsaicin. Tetrodotoxin, an inhibitor of voltage-sensitive Na+ channels failed to significantly reduce the inhibitory effect of capsaicin in the guinea-pig colon, human ileum and appendix; it caused an approximately 50% reduction in the mouse colon. The relaxant effect of capsaicin was strongly reduced in colonic preparations from transient receptor potential vanilloid type (TRPV1) receptor knockout mice as compared to their wildtype controls. It is concluded that nitric oxide, possibly of sensory origin, is involved in the relaxant action of capsaicin in the circular muscle of the mouse and human intestine.     

Effects of a cannabinoid receptor agonist on colonic motor and sensory functions in humans: a randomized, placebo-controlled study

Cannabinoid receptors (CBR) are located on cholinergic neurons in the brain stem, stomach, and colon. CBR stimulation inhibits motility in rodents. Effects in humans are unclear. Dronabinol (DRO), a nonselective CBR agonist, inhibits colonic motility and sensation. The aim of this study was to compare effects of DRO and placebo (PLA) on colonic motility and sensation in healthy volunteers. Fifty-two volunteers were randomly assigned (double-blind) to a single dose of 7.5 mg DRO or PLA postoperative with concealed allocation. A balloon-manometric assembly placed into the descending colon allowed assessment of colonic compliance, motility, tone, and sensation before and 1 h after oral ingestion of medication, and during fasting, and for 1 h after 1,000-kcal meal. There was an overall significant increase in colonic compliance (P = 0.045), a borderline effect of relaxation in fasting colonic tone (P = 0.096), inhibition of postprandial colonic tone (P = 0.048), and inhibition of fasting and postprandial phasic pressure (P = 0.008 and 0.030, respectively). While DRO did not significantly alter thresholds for first gas or pain sensation, there was an increase in sensory rating for pain during random phasic distensions at all pressures tested and in both genders (P = 0.024). In conclusion, in humans the nonselective CBR agonist, DRO, relaxes the colon and reduces postprandial colonic motility and tone. Increase in sensation ratings to distension in the presence of relaxation of the colon suggests central modulation of perception. The potential for CBR to modulate colonic motor function in diarrheal disease such as irritable bowel syndrome deserves further study.     

Crural diaphragm inhibition during esophageal distension correlates with contraction of the esophageal longitudinal muscle in cats

Esophageal distension causes simultaneous relaxation of the lower esophageal sphincter (LES) and crural diaphragm. The mechanism of crural diaphragm relaxation during esophageal distension is not well understood. We studied the motion of crural and costal diaphragm along with the motion of the distal esophagus during esophageal distension-induced relaxation of the LES and crural diaphragm. Wire electrodes were surgically implanted into the crural and costal diaphragm in five cats. In two additional cats, radiopaque markers were also sutured into the outer wall of the distal esophagus to monitor esophageal shortening. Under light anesthesia, animals were placed on an X-ray fluoroscope to monitor the motion of the diaphragm and the distal esophagus by tracking the radiopaque markers. Crural and costal diaphragm electromyograms (EMGs) were recorded along with the esophageal, LES, and gastric pressures. A 2-cm balloon placed 5 cm above the LES was used for esophageal distension. Effects of baclofen, a GABA(B) agonist, were also studied. Esophageal distension induced LES relaxation and selective inhibition of the crural diaphragm EMG. The crural diaphragm moved in a craniocaudal direction with expiration and inspiration, respectively. Esophageal distension-induced inhibition of the crural EMG was associated with sustained cranial motion of the crural diaphragm and esophagus. Baclofen blocked distension-induced LES relaxation and crural diaphragm EMG inhibition along with the cranial motion of the crural diaphragm and the distal esophagus. There is a close temporal correlation between esophageal distension-mediated LES relaxation and crural diaphragm inhibition with the sustained cranial motion of the crural diaphragm. Stretch caused by the longitudinal muscle contraction of the esophagus during distension of the esophagus may be important in causing LES relaxation and crural diaphragm inhibition.     

Exercise training improves endothelium-mediated vasorelaxation after chronic coronary occlusion.

The present study evaluated combined effects of chronic coronary occlusion and exercise training on endothelial function. Gradual occlusion was produced by placement of an ameroid constrictor around the proximal left circumflex (LCX) coronary artery of female swine. Two months after placement of the ameroid, animals were restricted to their pens or exercise trained for 16 wk. Epicardial arteries (>500 microm ID) were isolated from the collateral-dependent LCX coronary artery distal to the occlusion and the nonoccluded left anterior descending (LAD) coronary artery. Bradykinin- and ADP-mediated relaxation of LCX and LAD coronary arteries was enhanced after exercise training. Inhibition of nitric oxide synthase with N(G)-nitro-L-arginine methyl ester decreased bradykinin- and ADP-mediated relaxation in LCX and LAD myocardial regions. Importantly, combined inhibition of effects of endothelium-derived hyperpolarizing factor with increased extracellular K(+) (20-30 mM) and nitric oxide synthase completely abolished coronary LAD and LCX relaxation to bradykinin. Our data indicate that exercise training improves endothelium-mediated relaxation of arteries isolated after chronic coronary artery occlusion, likely as a result of enhanced production of nitric oxide and endothelium-derived hyperpolarizing factor.     

Synaptic transmission in simple motility reflex pathways excited by distension in guinea pig distal colon

We examined specific receptor/transmitter combinations used at functionally identified synapses in ascending and descending reflex pathways of guinea pig distal colon. Excitatory (EJPs) or inhibitory junction potentials (IJPs) were recorded intracellularly from nicardipine-paralyzed circular smooth muscle in either the oral or anal recording chamber of a three-chambered organ bath, respectively. Blockade of synaptic transmission in the central chamber with a 0.25 mM Ca2+/12 mM Mg2+ solution abolished EJPs evoked by distension applied either in the central or the far (anal) chamber. IJPs evoked by distension in the central or the far (oral) chamber were depressed to approximately 50% of control. Hexamethonium (nicotinic receptor antagonist, 200 microM) in the central chamber reduced IJPs evoked by far or central distension to 50%, whereas EJPs evoked by far distension were abolished and EJPs evoked by central distension were reduced to 70% of control. Hexamethonium in the recording chambers reduced both IJPs and EJPs evoked by central distension to approximately 50%. EJPs in the ascending pathway were unaffected by blockade of muscarinic receptors in the central chamber or blockade of neurokinin 3 tachykinin receptors in this or the recording chamber. In the descending pathway, blockade of P2 receptors in the same chambers had only a minor effect on distension-evoked IJPs. Thus some intrinsic sensory neurons of guinea pig colon have long descending projections (>30 mm), but ascending projections of <15 mm. In contrast to the ileum, transmission between ascending or descending interneurons and from sensory neurons to descending interneurons is predominantly via nicotinic receptors; but transmission to inhibitory or excitatory motoneurons and from sensory neurons to ascending interneurons involves nicotinic and other unidentified receptors.     

Reciprocal activity of longitudinal and circular muscle during intestinal peristaltic reflex

A two-compartment, flat-sheet preparation of rat colon was devised, which enabled exclusive measurement of longitudinal muscle activity during the ascending and descending phases of the peristaltic reflex. A previous study using longitudinal muscle strips revealed the operation of an integrated neuronal circuit consisting of somatostatin, opioid, and VIP/pituitary adenylate cyclase-activating peptide (PACAP)/nitric oxide synthase (NOS) interneurons coupled to cholinergic/tachykinin motor neurons innervating longitudinal muscle strips that could lead to descending contraction and ascending relaxation of this muscle layer. Previous studies in peristaltic preparations have also shown that an increase in somatostatin release during the descending phase causes a decrease in Met-enkephalin release and suppression of the inhibitory effect of Met-enkephalin on VIP/PACAP/NOS motor neurons innervating circular muscle and a distinct set of VIP/PACAP/NOS interneurons. The present study showed that in contrast to circular muscle, longitudinal muscle contracted during the descending phase and relaxed during the ascending phase. Somatostatin antiserum inhibited descending contraction and augmented ascending relaxation of longitudinal muscle, whereas naloxone had the opposite effect. VIP and PACAP antagonists inhibited descending contraction of longitudinal muscle and augmented ascending relaxation. Atropine and tachykinin antagonists inhibited descending contraction of longitudinal muscle. As shown in earlier studies, the same antagonists and antisera produced opposite effects on circular muscle. We conclude that longitudinal muscle contracts and relaxes in reverse fashion to circular muscle during the peristaltic reflex. Longitudinal muscle activity is regulated by excitatory VIP/PACAP/NOS interneurons coupled to cholinergic/tachykinin motor neurons innervating longitudinal muscle.     

Expression and motor effects of secretin in small and large intestine of the rat

Immunocytochemistry and in situ hybridization revealed abundant secretin expressing cells on duodenal villi with a gradual decrease throughout the small intestines of the rat. They were absent in pancreas, stomach and colon. Secretin caused relaxation of rat intestinal longitudinal muscle in vitro. Studies on colon revealed that the secretin-evoked response was unaffected by apamin, tetrodotoxin, L-NAME, VIP or PACAP pretreatment; secretin itself caused desensitization. Addition of VIP or PACAP when the secretin-evoked relaxation was maximal evoked a further relaxation suggesting the presence of distinct receptors. Secretin causes relaxation via activation of secretin receptors located on the smooth muscle and not via any of the related VIP/PACAP receptors.     

Impaired gastrocolonic response and peristaltic reflex in slow-transit constipation: role of 5-HT(3) pathways

Colonic motility is modulated by the 5-hydroxytryptamine (5-HT)(3)-dependent gastrocolonic response and 5-HT(3)-independent peristaltic reflex. We compared descending colon tone responses to antral distension, duodenal lipid perfusion, and colonic distension after double-blind placebo or granisetron in 13 healthy volunteers and nine slow-transit constipated patients. Antral distension (100-300 ml) and duodenal lipids (3 kcal/min) evoked increases in colon tone in volunteers, which were blunted in constipated patients (P < 0.05). Granisetron (10 microg/kg) reduced responses to antral distension and lipids in volunteers and to lipids in constipated patients (P < 0.05). The ascending contraction of the peristaltic reflex was blunted in constipated patients (P < 0.05), whereas descending responses were similar. Granisetron did not modify the peristaltic reflex. Colonic responses to bethanechol were similar in patients and volunteers. In conclusion, antral distension- and duodenal lipid-activated gastrocolonic responses and ascending contractions of the peristaltic reflex are impaired with slow-transit constipation with loss of both 5-HT(3)-dependent and -independent function. Thus abnormalities of neural reflex modulation of colonic motor function may play pathophysiological roles in slow-transit constipation.     

Altered temporal characteristics of the rectoanal inhibitory reflex in patients with abdominal distension

The rectoanal inhibitory reflex (RAIR) is important in gas and stool evacuation. We examined RAIR features in patients with chronic constipation who exhibited bloating with and without abdominal distension, to determine whether alterations in RAIR may be a factor in the pathogenesis of abdominal distension. Seventy-five female patients with chronic constipation with or without abdominal distension were included in the study. The presence or absence of abdominal distension was assessed according to the Rome II questionnaire. All patients underwent both RAIR and rectal sensitivity testing, and specific RAIR parameters were analyzed. Patients were divided into two groups: abdominal bloating with distension (D, n = 55) and abdominal bloating without distension (ND, n = 20). D had a longer time to the onset of anal sphincter inhibition (latency of inhibition) (P = 0.03) compared with ND. In logistic regression analysis, a combination of age, latency of inhibition and the time measured from onset of inhibition to the point of maximum inhibition predicted abdominal distension (P = 0.002). There were no differences between groups for the time from point of maximum inhibition to recovery and for the percentage of internal anal sphincter relaxation. This is the first study to examine the role of RAIR in patients with abdominal distension. Female patients with constipation and abdominal distension exhibited differences in the temporal characteristics of, but not in the degree of, anal sphincter relaxation compared with patients without distension. Since this study was uncontrolled, further studies are necessary to determine the contribution of altered anorectal reflexes to abdominal distension.     

Baclofen blocks LES relaxation and crural diaphragm inhibition by esophageal and gastric distension in cats

Esophageal distension and transient lower esophageal sphincter (LES) relaxation (TLESR) are accompanied by simultaneous relaxation of the LES and inhibition of crural diaphragm. Recent studies indicate that baclofen decreases the frequency of TLESR; however, its effect on the crural diaphragm is not known. We evaluated the effects of baclofen on LES relaxation and crural diaphragm inhibition induced by gastric distension and esophageal distension in cats. Five adult cats underwent surgical implantation of wire electrodes into the crural and costal diaphragm for measurement of their EMG activity, respectively. One week after the surgery, animals were lightly sedated and recordings were performed using a manometry catheter equipped with a 2.5-cm balloon. The effects of baclofen (10 micromol/kg iv) on the graded esophageal distension and gastric distension-induced LES and crural diaphragm responses were studied. Distension of the esophagus and stomach induces relaxation of the LES and inhibition of the crural diaphragm, simultaneously. Baclofen blocks both the esophageal and the gastric distension-induced relaxation of the LES and inhibition of the crural diaphragm. The magnitude of response to baclofen was significantly larger for the crural diaphragm inhibition than for the LES relaxation. Baclofen, a GABA(B) receptor agonist, blocks the reflex inhibitory pathway to the LES and crural diaphragm. The reflex inhibitory pathway to the crural diaphragm is more sensitive to blockade by baclofen than the reflex LES inhibitory pathway.     

The role of the superior laryngeal nerve in esophageal reflexes

The aim of this study was to determine the role of the superior laryngeal nerve (SLN) in the following esophageal reflexes: esophago-upper esophageal sphincter (UES) contractile reflex (EUCR), esophago-lower esophageal sphincter (LES) relaxation reflex (ELIR), secondary peristalsis, pharyngeal swallowing, and belch. Cats (N = 43) were decerebrated and instrumented to record EMG of the cricopharyngeus, thyrohyoideus, geniohyoideus, and cricothyroideus; esophageal pressure; and motility of LES. Reflexes were activated by stimulation of the esophagus via slow balloon or rapid air distension at 1 to 16 cm distal to the UES. Slow balloon distension consistently activated EUCR and ELIR from all areas of the esophagus, but the distal esophagus was more sensitive than the proximal esophagus. Transection of SLN or proximal recurrent laryngeal nerves (RLN) blocked EUCR and ELIR generated from the cervical esophagus. Distal RLN transection blocked EUCR from the distal cervical esophagus. Slow distension of all areas of the esophagus except the most proximal few centimeters activated secondary peristalsis, and SLN transection had no effect on secondary peristalsis. Slow distension of all areas of the esophagus inconsistently activated pharyngeal swallows, and SLN transection blocked generation of pharyngeal swallows from all levels of the esophagus. Slow distension of the esophagus inconsistently activated belching, but rapid air distension consistently activated belching from all areas of the esophagus. SLN transection did not block initiation of belch but blocked one aspect of belch, i.e., inhibition of cricopharyngeus EMG. Vagotomy blocked all aspects of belch generated from all areas of esophagus and blocked all responses of all reflexes not blocked by SLN or RLN transection. In conclusion, the SLN mediates all aspects of the pharyngeal swallow, no portion of the secondary peristalsis, and the EUCR and ELIR generated from the proximal esophagus. Considering that SLN is not a motor nerve for any of these reflexes, the role of the SLN in control of these reflexes is sensory in nature only.     

Gastrin-releasing peptide is a modulatory neurotransmitter of the descending phase of the peristaltic reflex

The physiological role of gastrin-releasing peptide (GRP) and of its cognate receptors in regulating the intestinal peristaltic reflex was examined in a three-compartment flat-sheet preparation of rat colon. Mucosal stimulation applied to the central compartment at high, but not low levels of intensity, induced GRP release in the caudad compartment where descending relaxation was measured, but not into the ascending compartment where ascending contraction was measured or into the central compartment where the stimuli were applied. The selective GRP (BB(2)) receptor antagonist, [D-Phe(6),des-Met(14)]bombesin(6-14), inhibited descending relaxation and VIP release in the caudad compartment induced by high but not by low levels of stimulation applied to the mucosa in the central compartment. The selective neuromedin B (BB(1)) receptor antagonist, BIM-23127, had no effect on descending relaxation or VIP release. Neither the BB(1) nor the BB(2) antagonist had any effect on ascending contraction or substance P release in the orad compartment. Consistent with the effects of the antagonists on the peristaltic reflex, the BB(2) antagonist but not the BB(1) antagonist decreased the velocity of propulsion of artificial fecal pellets through isolated segments of guinea pig distal colon. The results indicate that GRP is selectively released from myenteric neurons in descending pathways during the peristaltic reflex and that it acts via BB(2) receptors to augment the descending phase of the peristaltic reflex and propulsion.     

Modulatory influences on antegrade and retrograde tonic reflexes in the colon and rectum

Tonic reflexes in the colon and rectum are likely to be important in health and in disorders of gastrointestinal function. The aim of this study was to evaluate the fasting and postprandial "colorectal" and "rectocolic" reflexes in response to 2-min isobaric distensions of the colon and rectum, accounting for enteric sensation, compliance, and distending balloon volume. In 14 healthy fasting subjects, a dual barostat assembly was positioned (descending colon and rectum). A 2-min phasic distension was performed in the colon and rectum in random order while the opposing balloon volume was recorded. Sensation (phasic distension) and compliance (ramp distension) were also determined. The experiment was repeated postprandially. Colonic distension resulted in significant rectal tonic contraction in the fasting (rectal volume change: -35.4 +/- 8.4 ml, P < 0.01) and postprandial (-22.2 +/- 8.4 ml, P < 0.01) states. After adjustment for colonic sensitivity, for compliance, and for distending balloon volume, the rectal volume change remained significant; the extent of the tonic response, however, correlated significantly with increasing pain score (P < 0.01). In contrast, rectal distension did not produce a significant tonic response in the colon (fasting: -6.5 +/- 7.3 ml; postprandial: 2.7 +/- 7.3 ml), either unadjusted or adjusted for rectal sensitivity, compliance, and distending balloon volume. In conclusion, the colorectal reflex, but not the rectocolic reflex, can be readily demonstrated both before and after a meal in response to a 2-min isobaric distension in the colon and rectum, respectively. Although the presence of the colorectal reflex does not depend on colonic sensitivity or the volume of the distending colonic balloon, these factors modulate the reflex, especially in the fasting state.