Pyloric Response Research Articles

Impact of gastric per-oral endoscopic myotomy on static and dynamic pyloric function in gastroparesis patients.

Functional Lumen Imaging Probe (EndoFLIP) tests typically measure static pyloric parameters, but the pylorus exhibits phasic variations on manometry. Dynamic changes in pyloric function have not been quantified using EndoFLIP, and the impact of Gastric Per-Oral Endoscopic Myotomy (G-POEM) on static and dynamic pyloric activity in gastroparesis is unknown. EndoFLIP balloon inflation to 30, 40, and 50mL was performed to measure mean, maximum, and minimum values and variability in pyloric diameter and distensibility before and after G-POEM in 20 patients with refractory gastroparesis. The impact of phasic contractions on these pyloric measures was compared. G-POEM increased mean (P<.0001) and maximum (P=.0002) pyloric diameters and mean (P=.02) and maximum (P=.02) pyloric distensibility on 50mL EndoFLIP inflation but not intraballoon pressures or minimum diameters or distensibility. Temporal variability of pyloric diameter (P=.02) and distensibility (P=.02) also increased after G-POEM. Phasic coupled contractions propagating from the antrum through the pylorus were observed in 37.5% of recordings; other phasic activity including isolated pyloric contractions were seen in 23.3%. Variability of pyloric diameter and distensibility tended to be higher during recordings with phasic activity. Some pyloric responses to G-POEM were influenced by age, gastroparesis etiology, gastric emptying, and prior botulinum toxin injection. Pyloric activity exhibits dynamic changes on EndoFLIP testing in gastroparesis. G-POEM increases maximal but not minimal diameter and distensibility with increased variations, suggesting this therapy enhances pyloric opening but may not impair pyloric closure. Phasic pyloric contractions contribute to variations in pyloric activity.

Exploring pyloric dynamics in stenting using a distensibility technique.

Perforated duodenal ulcers can be treated with a covered stent. Stent migration is a severe complication, sometimes requiring surgery. Pyloric physiology during stent treatment has not been studied and mechanisms for migration are unknown. The aim of this study was to investigate the pyloric response to distention, mimicking stent treatment, using the EndoFLIP. A nonsurvival study in five pigs was carried out, followed by a pilot study in one volunteer. Animals were gastroscoped during anaesthesia and the EndoFLIP was placed straddling the pylorus. Baseline distensibility readings were performed at stepwise balloon distentions to 20, 30, 40, and 50mL, measuring pyloric cross-sectional area and pressure. Measurements were repeated after administration of a prokinetic drug and after a liquid meal. In the human study, readings were performed in conscious sedation at baseline and after stimulation with metoclopramide. During baseline readings, the pylorus was shown to open more with increasing distention together with higher amplitude motility waves. Reaching maximum distention-volume (50mL), pyloric pressure increased significantly (P=0.016), and motility waves disappeared. After prokinetic stimulation, the pressure decreased and the motility waves increased in frequency and amplitude. After food stimulation, the pressure stayed low and the motility showed increase in amplitude. During both tests, the pylorus showed higher pressure and lack of motility waves at maximum probe distention. The pylorus seems to act as a sphincter at low distention but when further dilated starts acting as a pump. Fully distended the pyloric motility disappears and the pressure remains high, suggesting that a stent with high-radial force might show less migration.

Exploring pyloric dynamics in stenting – Using a distensibility technique

Perforated duodenal ulcers can be treated with a stent. Stent migration is a severe complication, sometimes requiring surgery. Pyloric physiology during stent-treatment has not been studied and mechanisms for migration are unknown. To investigate the pyloric response to distention, mimicking stent-treatment, using the EndoFLIP, a non-survival study in five pigs was carried out, followed by a pilot study in one volunteer. Animals were gastroscoped during anaesthesia and the EndoFLIP was placed straddling the pylorus. Baseline distensibility readings were performed at stepwise balloon distentions to 20 ml, 30 ml, 40 ml and 50 ml, measuring pyloric Cross Sectional Area and pressure. Measurements were repeated after administration of a pro-kinetic drug and after a liquid meal. In the human study readings were performed in conscious sedation at baseline and after stimulation with metoclopramide. During baseline readings the pylorus was shown to open more with increasing distention together with higher amplitude motility waves. Reaching maximum distention-volume (50 ml), pyloric pressure increased significantly (p = 0.016) and motility waves disappeared. After pro-kinetic stimulation the pressure decreased and the motility waves increased in frequency and amplitude. After food stimulation the pressure stayed low and the motility showed increase in amplitude. During both tests the pylorus showed higher pressure and lack of motility waves at maximum probe distention. The pylorus seems to acts as a sphincter at low distention but when further dilated starts acting as a pump. Fully distended the pyloric motility disappears and the pressure remains high, suggesting that a stent with high radial force might show less migration.

Pyloric motility and energy intake responses to intraduodenal fat in lean, overweight and obese humans

Pyloric motility and energy intake responses to intraduodenal fat in lean, overweight and obese humans

Pyloric motor response to central and peripheral nitric oxide in the ferret.

This study has investigated the relative importance of central nervous and peripheral nitroxidergic mechanisms in the control of pyloric motility. In 10 urethane-anaesthetized ferrets, drugs were administered directly to the CNS via a 0.5-mm-diameter cannula inserted into the 4th ventricle, approximately at the obex. Drugs were also given directly to the upper GI tract by close intra-arterial (i.a.) injection at the coeliac axis. Antropyloroduodenal pressures were recorded with a five-channel sleeve/sidehole micromanometric assembly (1.35 x 1.75 mm o.d.), which was introduced via the duodenum. Pyloric motility was stimulated throughout the main part of each study with a continuous i.v. infusion of CCK-8 (30 pmol min-1). This infusion produced an immediate and sustained increase in tonic and phasic pyloric activity, and sustained abolition of antral pressure waves. CCK-8 also induced a duodenal motor response, but this was short-lived (11.4 +/- 7.9 min). Coeliac axis injection of the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) decreased phasic pyloric activity (from 330 +/- 35 to 148 +/- 21 mmHg min-1 after SNAP 5 micrograms, P < 0.01). By comparison central SNAP administration over the same dose range had no effect on CCK-stimulated pyloric motlity. Inhibition of endogenous NO synthase with L-Nitro Arginine Methyl Ester (L-NAME, 100 mg kg-1 close i.a.) caused a marked increase of phase pyloric motor activity from 349 +/- 59 to 1044 +/- 140 mmHg min-1 (P < 0.01). In addition, SNAP caused marked stimulation of pyloric tone from 2.6 +/- 0.5 to 13.1 +/- 2.8 mmHg (P < 0.01). Central nervous administration of L-NAME caused modest enhancement of phasic pyloric activity (248 +/- 31 to 283 +/- 32 mmHg min-1 P < 0.05) and pyloric tone (2.6 +/- 0.5 to 3.7 +/- 0.7 mmHg, P < 0.05). Our data indicate that motor activity of the ferret pylorus is potently modulated by NO released within the upper gut. Additionally, there is potential for modulation of pyloric motility by central nervous system production of NO.

Stimulation of pyloric contractions by intraduodenal triglyceride is persistent and sensitive to atropine.

Intraduodenal lipid infusion stimulates phasic and tonic pyloric contractions and suppresses antral contractions. This study determined: (i) whether this response is sustained over 90 min; and (ii) the role of muscarinic mediation of this response. Antropyloroduodenal motility was recorded in 17 healthy volunteers with a sleeve/sidehole manometric assembly. Subjects received either a 90 min intraduodenal infusion of saline or triglyceride (20% Intralipid) at a rate of 1 mL/min; 30 min after the start of this infusion, the eight subjects who received triglyceride were given intravenous atropine 15 micrograms/kg over 30 s, followed by a maintenance infusion of 4 micrograms/kg/h until the study was completed. Intraduodenal triglyceride infusion stimulated isolated pyloric pressure waves consistently, producing a median rate of 2.4 per min after 30 min of triglyceride infusion, compared with a median rate of 0 per min pre-infusion. In intravenous saline studies, there was a reduction (P < 0.05) in the median rate of isolated pyloric pressure waves to 1.3 per min at 90 min, when compared with pyloric pressure waves at 30 min. Atropine reduced isolated pyloric pressure waves to a median rate of 0 per min, significantly different from preatropine (P < 0.01) and from intravenous saline studies (P < 0.0001). These results indicate that the phasic pyloric response to intraduodenal lipid persists during 90 min stimulation, albeit with significant attenuation. In humans, muscarinic cholinergic blockade prevents the occurrence of triglyceride stimulated localized pyloric contractions.

Nitric oxide as a putative nonadrenergic noncholinergic inhibitory transmitter in the canine pylorus in vivo.

Antropyloroduodenal motility was recorded in seven anesthetized dogs to assess the role of nitric oxide and L-arginine metabolites in nonadrenergic noncholinergic (NANC) mediation of pyloric relaxation. Pyloric activity induced by duodenal field stimulation was inhibited by antral field stimulation and electrical vagal stimulation. Intra-arterial NG-L-arginine-methyl-ester (L-NAME) reduced the inhibition from antral or vagal stimulation (P less than 0.05). Intravenous infusion of L-NAME also blocked the inhibitory effect of vagal and antral stimulation but left the tetrodotoxin-insensitive action of intra-arterial vasoactive intestinal peptide (VIP) and sodium nitroprusside unchanged. L-Arginine reversed the effect of L-NAME whereas D-arginine did not. L-NAME enhanced pyloric contractions to intra-arterial acetylcholine. The NANC inhibition of the substance P-stimulated pyloric response in vitro was blocked by L-NAME and reversed by addition of L-arginine. Sodium nitroprusside was effective as a relaxant in vitro but VIP was not. These data suggest that metabolites of L-arginine mediate neural inhibition of canine pyloric motor activity.

Diameter and Wall Thickness Recording of Canine Pylorus with Implantable Miniature Ultrasonic Transducers

Outer diameter and thickness of the muscular wall of canine pylorus were measured simultaneously by determining the distance between pairs of implanted ultrasonic transducers, evaluating the sonic transit time with a digital sonometer. For the study of the motility in the gastroduodenal transit zone, the ultrasonically determined pyloric responses were compared with signals from conventional strain-gauge transducers sutured to the neighboring duodenum and gastric antrum. After stimulation of the gastrointestinal motility by an intravenous bolus injection of cholecystokinin octapeptide, pyloric contractions with a frequency of 5.2 min-1 could be recorded for some minutes; those contractions were independent of the more rapid antral and duodenal motility. Together with the observed tonic constriction of the pyloric ring, which could be inhibited by intravenous injection of adrenaline, an autonomous role of the gastroduodenal junction as a true sphincter is supported.

Medullary raphe: a new site for vagally mediated stimulation of gastric motility in cats

Thyrotropin-releasing hormone (TRH) is clearly implicated in the control of gastric function via interactions in the dorsal motor nucleus of the vagus (DMV) of the cat. The source of the TRH innervation of the DMV is important to determine because this region could be of importance in control of gastric function. TRH-immunoreactive (ir) neurons are located in the raphe obscurus (Ro), raphe pallidus (Rp), and raphe magnus (Rm). Retrograde tracer applied to the DMV resulted in the most numerous labeled neurons in the caudal Ro and Rp in the same region where TRH-ir neurons are located. To address the question whether DMV-projecting neurons in the raphe subnuclei play a role in control of gastric motility, the following experiments were performed in alpha-chloralose-anesthetized cats while recording pyloric motility and blood pressure. Microinjection of a cell body excitant L-glutamate (44-200 nl, 0.5 M) into the caudal Ro and Rp in 15 experiments produced significant increases in pyloric minute motility index (MMI) of 4.9 +/- 1.5 (from 1.6 +/- 0.7 preinjection to 6.5 +/- 1.8 postinjection, P less than 0.05). Mean blood pressure (MBP) decreased significantly in these animals by 12 +/- 7 mmHg (from 100 +/- 6 to 88 +/- 8 mmHg, P less than 0.05). Saline microinjection in the same sites in seven cases resulted in no significant change in pyloric MMI (-1.0 +/- 0.8) or MBP (-4 +/- 11 mmHg). In five of these experiments, a second microinjection of L-glutamate (132-240 nl) was performed into the caudal Ro and Rp after spinal cord transection. This resulted in a significant increase in pyloric MMI of 3.3 +/- 0.9 (from 1.0 +/- 0.5 preinjection to 4.3 +/- 1.1 postinjection, P less than 0.05) but no change in MBP (+1 +/- 1 mmHg). Bilateral vagotomy resulted in the abrupt cessation of the pyloric response to caudal Ro and Rp stimulation. Microinjection of L-glutamate into the rostral Rp and caudal Rm in nine experiments resulted in no significant changes in pyloric MMI (-0.4 +/- 0.8) or MBP (-10 +/- 11 mmHg). These data indicate that a population of neurons in the caudal raphe nuclei, which may contain TRH, project to the DMV. In addition, excitation of these neurons causes an increase in gastric motility that is not caused by inhibition of sympathetic outflow to the gut but rather by excitation of vagal neurons in the DMV.

Properties of the feline pyloric sphincter in vitro

The purpose of this study was to determine the intrinsic functions of the feline pylorus in vitro. The myoelectric and pressure characteristics of the intact pylorus, antrum, and duodenum, free of extrinsic hormonal or neural influences, were studied in an in vitro bath that allowed separation of the bathing medium surrounding the different bowel segments. Basal recordings revealed a zone of tonic high pressure of 28.4 ± 3.5 mmHg (mean ± SEM) at the pylorus. The basal slow wave frequencies in the pylorus and duodenum were 2.8 ± 1.4 and 12.6 ± 0.6 cycles/min, respectively. Spontaneous action potential-associated phasic contractions of the pylorus were noted in 38% of preparations. Enteric nerve stimulation with direct electric current (10 Hz, 1 ms, 10–50 V) applied proximal to the pylorus gave relaxation of the pylorus at the lower voltages and rebound excitation at higher voltages. Electrical stimulation distal to the pylorus yielded phasic contractile pyloric response during the entire stimulus. The duodenal instillation of 0.5 N HCl produced action potential-associated phasic contractions of the pylorus and duodenum but not the antrum. Pyloric responses to electrical stimulation or acidification were abolished by tetrodotoxin (10−5 M). Bethanechol (10−6 M) or substance P (10−7 M) produced a contractile response at the site of stimulation but this response was not transmitted to include adjacent bowel segments. These studies suggest that the pyloric sphincter with its intrinsic reflex properties can be studied in vitro.

Opiate nerves mediate feline pyloric response to intraduodenal amino acids.

Intraluminal pressures and myoelectric activity were recorded from the feline antrum, pylorus, and duodenum in response to intraduodenal amino acid solutions. Mixed amino acids (0.02 mg/ml, 3.0 ml) increased the amplitude of pyloric contractions (59.7 +/- 7.9 mmHg) and pyloric spike activity (73.7 +/- 6.8% of slow waves with spike activity) compared with a saline control (P less than 0.001). The selectivity of these responses was determined with specific amino acids. L-Tryptophan (10 or 40 mM) produced a response similar to the mixed amino acid response, while L-phenylalanine or L-glycine (10 or 40 mM) had no effect. Intra-arterial tetrodotoxin, intraluminal ethyl aminobenzoate, or intravenous naloxone (1.0 mg/kg) abolished the pyloric responses to amino acids (P less than 0.02). Bilateral cervical vagotomy had no effect. Cholecystokinin octapeptide (CCK-OP) produced dose-dependent increases in the amplitude of pyloric contractions and in pyloric spike activity. The ED50 dose of CCK-OP (1.0 microgram/kg iv) gave an increase in pyloric pressure of 155.6 +/- 49.9 mmHg and in spike activity of 77.7 +/- 9.4%, similar to mixed amino acids or tryptophan. These effects of CCK-OP were not antagonized, however, by a dose of naloxone (1.0 mg/kg) that blocked the maximal pyloric response to leucine-enkephalin. We concluded intraduodenal mixed amino acids or tryptophan increase phasic, spike-dependent pyloric contractions in the cat via nonvagal, naloxone-sensitive neural pathways, phenylalanine, a structurally similar essential amino acid, had no effect on the feline gastroduodenal junction, and the pyloric responses to exogenous CCK-OP are mediated by pathways distinct from the responses to tryptophan or mixed amino acids.

Evidence for an opiate-mediated pyloric sphincter reflex.

The purpose of this study was to determine the mechanism by which the feline pylorus contracts in response to duodenal acidification. Simultaneous intraluminal pressures and serosal electrical activity were recorded from the antrum, pylorus, and duodenum of the anesthetized cat. The pylorus demonstrated a narrow zone of tonically increased pressure. Duodenal but not antral acidification increased the frequency and amplitude of phasic spike-associated pyloric contractions (P less than 0.001). This response was antagonized by tetrodotoxin, intraluminal (ethyl aminobenzoate), or naloxone. Bilateral cervical vagotomy, atropine, phentolamine, propranolol, cinanserine, diphenhydramine, or cimetidine had no effect on the pyloric response to duodenal acidification. Duodenal spike activity was also increased by duodenal acidification but was antagonized by atropine and not by naloxone. Leucine- or methionine-enkephalin intra-arterially produced dose-dependent increases in phasic pyloric contractions. The EDmax for leucin-enkephalin was 1.0 microgram/kg. The enkephalins inhibited duodenal spike activity in a dose-dependent fashion. These studies suggest that the pyloric spike-associated, high-amplitude phasic contractions in response to duodenal acidification involve local neural pathways that may be mediated through an opioid peptide. The pyloric response to duodenal acidification is distinguished from that of the duodenum, which is cholinergic.

Hormonal effects on the pylorus.

The control mechanisms of pyloric pressure responses have not been elucidated clearly. The purposes of this study were twofold: 1) to determine the dose-related pressure responses of the pylorus to exogenous glucagon, secretin, and cholecystokinin, and 2) to correlate changes in pyloric pressure with serum concentrations of these hormones. Pyloric pressures were measured by infusion manometry, and the serum concentrations of glucagon and secretin were quantitated using radioimmunoassays. Each of the hormones tested, glucagon, secretin, and cholecystokinin, increased the pyloric pressure significantly. The lowest active dosages tested for each of these peptide hormones were 2 micrograms.kg-1.h-1, 2 U.kg-1.h-1, and 1 U.kg-1.h-1, respectively. The maximal pyloric pressure responses recorded were 8.7 +/- 1.1 (P less than 0.05), 12.6 +/- 2.1 (P less than 0.02), and 14.8 +/- 1.7 (P less than 0.02) mmHg, respectively. The pyloric pressure responses to insulin hypoglycemia, duodenal acidification, and intraduodenal olive oil were 11.3 +/- 1.5, 13.4 +/- 1.4, and 11.3 +/- 1.4 mmHg, respectively. The serum concentrations of immunoreactive glucagon during infusion of the lowest active dosage of glucagon and insulin hypoglycemia were 801 +/- 55 and 322 +/- 12 pg/ml, respectively. The serum concentrations of immunoreactive secretin during infusion of the lowest active dosage of secretin and during duodenal acidification were 980 +/- 60 and 110 +/- 7.0 pg/ml, respectively. Although pyloric contraction can be induced by administration of exogenous glucagon, secretin, and cholecystokinin, these studies suggest that these effects may have no physiological relevance.

Noncholinergic nonadrenergic inhibitory innervation of the canine pylorus

Vagal nerve stimulation in atropine-treated dogs leads to an inhibitory motor response at the pylorus. The roles played by the cholinergic and the adrenergic nervous systems in this response were investigated in pentobarbital-anesthetized dogs. Force transducers were sutured to the gastric antrum, pylorus, and duodenum. Electrical vagal stimulation of the distal cut ends of the thoracic vagi was performed for 1-min periods. Minute motility indices were obtained for prestimulatory, stimulatory, and poststimulatory motor activity before and after each drug administration. Atropine sulfate (0.1–1.0 mg/kg i.v.) was administered to all animals. After atropine administration, 12 dogs received hexamethonium bromide as a bolus intravenous injection (30 mg/kg) and seven dogs received hexamethonium by infusion (60 mg/kg/hr i.v.). A second group of six dogs received the infusion of hexamethonium first, followed by atropine injection. A third group of 11 dogs received atropine followed by phenoxybenzamine, phentolamine, and propranolol (each at 4 mg/kg i.v.). Guanethidine sulfate (4 mg/kg i.v.) was administered either after the adrenergic receptor antagonists and atropine (eight dogs) or after atropine alone (four dogs). Following atropine injection, spontaneous contractile activity was observed only in the pylorus. Vagal stimulation produced significant inhibition of this activity and, in a majority of the animals, a concomitant relaxation of the pyloric tone. Hexamethonium infusion, but not bolus injection, blocked the pyloric inhibition, relaxation response. Vagal stimulation during the infusion of hexamethonium without atropine produced an excitatory response in the antrum and pylorus. None of the drugs affecting the adrenergic nervous system prevented the vagally mediated inhibitory response. The inhibition, relaxation response of the canine pylorus to vagal stimulation is noncholinergic and nonadrenergic and is mediated through nicotinic and possibly muscarinic ganglionic receptors. The nervous pathways for the vagally mediated excitatory pyloric responses utilize both nicotinic and muscarinic synaptic transmission. The canine pylorus appears to be a physiologically unique zone.

Gastrin inhibition of the pyloric sphincter.

Pyloric sphincter responses to intraduodenal stimuli were measured on 10 normal subjects before and during pentagastrin administration, and after endogenous gastrin was released from the antral mucosa. Normally, intraduodenal hydrochloric acid, sodium oleate, and hypertonic amino acids each significantly increased the pyloric sphincter pressure. Both the intravenous administration of pentagastrin and endogenous gastrin released from the antral mucosa inhibited the pyloric responses to intraduodenal stimuli.

Reversibility of Pyloric Sphincter Dysfunction in Gastric Ulcer

To investigate both the cause and reversibility of pyloric sphincter dysfunction in patients with gastric ulcer, pyloric sphincter pressures were measured in 10 normal subjects and 13 patients with gastric ulcer before and during gastric acidification. Fasting serum gastrin concentration was significantly higher in patients with gastric ulcer than in normal subjects. Compared to normals, patients with gastric ulcer had significantly lower pyloric pressures in response to intraduodenal amino acids and sodium oleate. However, during gastric acidification, these same patients demonstrated normal pyloric responses to these stimuli. Serum gastrin concentrations did not change during gastric acidification. These studies show that: (1) in patients with gastric ulcer the pyloric sphincter does not respond normally to intraduodenal stimulation; (2) fasting serum gastrin concentration is elevated in patients with gastric ulcer; and (3) in these patients, pyloric sphincter dysfunction can be reversed by gastric acidification. The mechanism of pyloric dysfunction in patients with gastric ulcer remains unknown.

The hormonal regulation of pyloric sphincter function.

The purpose of this study was to evaluate the hormonal control of pyloric sphincter function. Studies were performed on both pyloric circular muscle, in vitro, and the human pylorus, in vivo. Full dose-response curves to gastrin I, cholecystokinin, and secretin were constructed for the pyloric muscle of the opossum studied at its length of optimal tension development, Lo. Both cholecystokinin and secretin were potent agonists on the muscle but gastrin I gave no increase in muscle tension. The combination of cholecystokinin and secretin was additive at submaximal concentrations but potentiation of the maximal responses was not observed. Gastrin I produced a surmountable, competitive-like antagonism to the effect of cholecystokinin on the pyloric muscle. The octapeptide of cholecystokinin was a more potent agonist than the whole molecule of cholecystokinin on the pyloric muscle. In man, the pyloric pressure rose significantly during intravenous infusion of either cholecystokinin or secretin. The combination of maximal doses of both hormones did not show significant potentiation. Gastrin I did not significantly increase pyloric pressure but did antagonize the pyloric response to duodenal acidification. These studies suggest that: (a) Both secretin and cholecystokinin augment pyloric sphincter pressure while gastrin I is an antagonist inhibiting their effects. (b) The hormonal responses of pyloric sphincter circular muscle, in vitro, can be correlated with human sphincter function, in vivo.