William Y. Chey

Study of Electromechanical Activity of the Stomach in Humans and in Dogs With Particular Attention to tachygastria

The relationship between electric and mechanical activities of the gastric antrum was investigated in both humans and dogs. In 2 patients, in whom platinum monopolar electrodes were implanted on the serosal surface of the antrum and a perfused manometric tube was placed in the stomach, the number of gastric contractions detected by manometry was only less than 50% of the pacesetter potentials accompanied by action potentials or second potentials. No contraction of the stomach was recorded by manometry when pacesetter potentials occurred without action potentials or second potentials. The relationship was further investigated in 11 anesthetized dogs prepared with implanted electrodes and sensitive ministrain gauges implanted on the serosal surface of the stomach and an intragastric manometric tube. In these dogs, phasic contractions were always recorded by the method using ministrain gauges although the electrical activity showed only PSPs without action potentials or second potentials. The manometry, however, could not recognize these phasic contractions. When the stomach was stimulated by bethanechol infusion through the splenic artery, as in the human stomach, the manometry detected less than 50% of gastric contractions detected by the strain gauge recording. The gastric dysrhythmia including tachygastria, tachyarrhythmia, and bradygastria was induced in 10 dogs by epinephrine, 100 micrograms X kg-1 X h-1, infused via the splenic artery. During the period of gastric dysrhythmia, the phasic contractions disappeared and no contraction associated with action potential could be observed. The phasic contractions reappeared as long as the PSPs occurred regularly in a frequency of 4-5 cycles/min during either the control period or during the period of epinephrine infusion. The epinephrine-induced gastric dysrhythmia was blocked or reversed to normal pacesetter potentials by intraarterial infusion of phentolamine. Our study suggests the following: (1) the pacesetter potentials not only pace and direct gastric contraction, but they may also play a role in the genesis of phasic contractions of the stomach, and (2) gastric contractions detected by sensitive strain gauges are not always recorded by the intraluminal manometry and, thus, gastric dysrhythmia may not be detected by the manometry in humans.

Gastric and Small Intestinal Myoelectric Dysrhythmia Associated with Chronic Intractable Nausea and Vomiting

We describe a patient with symptoms of severe nausea, vomiting, epigastric bloating and pain, and marked weight loss due to a gastrointestinal motility disturbance. Motility abnormalities were characterized by uncoordinated high pressure (as high as 300 mm Hg) contractions and uncoordinated interdigestive motor complexes in the duodenum and small intestine, and tachygastria often associated with tachyarrhythmia in the gastric myoelectric activity recordings. Uncoordinated interdigestive myoelectric complexes again were found in the duodenum and small intestine. These abnormal myoelectric activities observed in the in-vivo study were confirmed in the in-vitro study. After distal hemigastrectomy and gastrojejunostomy, the symptoms of nausea, vomiting, and epigastric pain decreased considerably. Thus, the motility abnormality found in the study appears to be responsible for the symptoms described. This is probably a new clinical entity. The importance of manometric and myoelectric study of a gastrointestinal motility for unexplained nausea and vomiting is emphasized.

Radioimmunoassay of motilin. Validation and studies on the relationship between plasma motilin and interdigestive myoelectric activity of the duodenum of dog.

A radioimmunoassay method of motilin was developed in our laboratory and was validated in dogs with a platinum monopolar electrode in the duodenum. We confirmed that a bolus infusion of 0.3 M tris-buffer solution or 0.1 N HCl solution in the duodenum produces a significant rise in plasma immunoreactive motilin (IRM) concentrations. This coincided with a marked increase in the percentage of spike potentials on slow waves of the duodenum, similar to phase III of interdigestive myoelectric-activity (MA). A possible relationship between plasma IRM and interdigestive MA of canine duodenum was studied. It was found that cyclic changes occurred in the fasting plasma IRM concentrations in dogs. While the peak motilin concentration was always observed in phase III, the lowest concentration of motilin was found in phase I of interdigestive MA in the duodenum. In dogs with the electrodes in the duodenum and jejunum, the peak IRM concentration did not correlate with phase III of interdigestive MA in the jejunum. A dose of synthetic porcine motilin, 0.06 μg/kg/hr, which produced the plasma IRM concentration comparable to the peak fasting motilin concentration, could induce an identical phase III in the duodenum. These observations indicate that there is a relationship between cyclic changes in plasma IRM concentrations and interdigestive MA of the duodenum. It is suggested further that motilin is a hormone which may play an important role in inducing phase III of interdigestive MA in the duodenum.

Effect of secretin and cholecystokinin on gastric emptying and gastric secretion in man.

The effects of secretin and cholecystokinin on gastric emptying and gastric secretion of acid were studied in man. The intravenous administration of secretin in a dose of 1 U per kg of body weight caused a significant decrease in gastric emptying measured 15 min after the intragastric instillation of 500 ml of normal saline solution in 10 subjects. The mean percentage of gastric emptying following the administration of secretin was 40.7% as compared with a control value of 85.2%. A decrease in gastric emptying of similar magnitude was observed in 9 subjects following the intravenous administration of cholecystokinin in a dose of 0.5 Ivy dog unit per kg. Gastric secretion of acid was stimulated by a continuous intravenous infusion of pentagastrin or histamine acid phosphate and both gastric and duodenal contents were collected simultaneously. The intravenous administration of secretin in a dose of 1 U per kg resulted in marked inhibition of acid secretion stimulated by either pentagastrin in a dose of 0.12 μg per kg per hr or histamine acid phosphate in a dose of 0.02 mg per kg per hr in 10 subjects. Secretin appeared to have a greater inhibitory effect on acid secretion stimulated by pentagastrin than on histamine-stimulated secretion. Inhibition of acid secretion similar in magnitude to that produced by secretin was observed following the administration of cholecystokinin in a dose of 1 U per kg. Gastric secretion of acid stimulated by pentagastrin in a dose of 6 μg per kg per hr or histamine acid phosphate in a dose of 0.04 mg per kg per hr, however, was not influenced by the same dose of secretin in a dose similar to that which inhibited smaller doses of these stimuli.

Neural Hormonal Regulation of Exocrine Pancreatic Secretion

Exocrine pancreatic secretion is regulated by hormone-hormonal and neural-hormonal interactions involving several regulatory peptides and neurotransmitter from the gut, the pancreas and the vagus nerve. The roles of the gastrointestinal peptides including secretin, CCK, neurotensin, motilin, PYY and pancreatic islet hormones including insulin, pancreatic polypeptide and somatostatin have been established. Interactions among secretin, CCK and neurotensin produce synergistic stimulatory effect. Motilin modulates the cyclic pattern of pancreatic secretion while local insulin provides a permissive role for the action of secretin and CCK at physiological concentration. Somatostatin, PYY and pancreatic polypeptide are inhibitory regulators, acting either on the release of secretin and CCK or on the action of the two stimulatory hormones. The vagal afferent-efferent pathway mediates the actions of many of these regulatory peptides, particularly of secretin and CCK. Acetylcholine and nitric oxide are the neurotransmitters known to mediate the actions of secretin and CCK. Serotonin (5-HT) released from enterochromaffin cells in the intestinal mucosa and nerve terminals of the enteric nervous system and intrapancreatic nerves may be involved in both stimulatory and inhibitory mechanism through its various receptor subtypes. 5-HT also mediates the action of secretin and CCK. The regulatory roles of neuropeptides, PACP and GRP, are now established, whereas those of others are being uncovered. Pancreatic juice provides both positive and negative feedback regulation of pancreatic secretion through mediation of both secretin- and CCK-releasing peptides. Three CCK-releasing peptides have been purified: monitor peptide from pancreatic juice, diazepam-binding inhibitor from porcine intestine, and luminal CCK-releasing factor from rat intestinal secretion. All have been shown to stimulate CCK release and pancreatic enzyme secretion. Pancreatic phospholipase A2 from pancreatic juice and intestinal secretion appears to function as a secretin-releasing peptide. However, the detailed map of neurohormonal regulatory pathways of exocrine pancreatic secretion is yet to be constructed.

Radioimmunoassay of cholecystokinin

A highly sensitive and specific radioimmunoassay for cholecystokinin (CCK) has been developed. Fully immunoreactive [125I]CCK33 was prepared by chloramine T-catalyzed iodination followed by purification by gel filtration and ion exchange chromatography. A high titer of antiserum was obtained by multiple immunizations of rabbits with 15% pure porcine CCK without conjugation. The antiserum was highly specific for CCK33 and CCK39, with 40% of the binding sites recognizing CCK8 at high affinity, but reacted weakly with gastrin. Plasma interference was eliminated by an XAD-2 resin column extraction technique with high recovery of CCK. The overall assay sensitivity was 3.3 pM with intra-and interassay coefficients of variation determined with a plasma of 11.2 pM at 9.6 and 20.8%, respectively. The assay was capable of detecting linear increments of both CCK33 and CCK8 added into plasma and intravenous infusion of CCK8 as low as 0.03 μg/kg/hr in dogs. The assay was validated by its ability to monitor increase of plasma CCK immunoreactivity after ingestion of a meat meal in both humans and dogs, as well as following intragastric infusion of liver extract meal and intraduodenal infusion of phenylalanine in dogs. When the CCK8 and gastrin binding sites of the antiserum were removed by immunoadsorption, the treated antiserum remained capable of measuring a postprandial change in plasma CCK concentration, indicating that CCK33-like immunoreactivity was present in the plasma.

A phase 1/2A trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohn's disease.

Background: Intestinal inflammation associated with Crohns disease is characterized by a type 1 helper T cell response and elevated levels of interleukin (IL)‐12. We report our clinical experience with a novel oral IL‐12/IL‐23 inhibitor (STA 5326) for the treatment of active Crohns disease. Materials and Methods: We conducted an open‐label, dose‐escalating trial of the orally delivered small molecule immunomodulator STA 5326 in 73 patients with active Crohns disease (Crohns disease activity index [CDAI] 220‐450, inclusive). Five cohorts of patients were treated for up to 4 weeks with 14 mg twice a day (bid), 35 mg daily (qd), 28 mg bid, 35 mg bid, or 70 mg qd. The endpoints of the study included safety and improvement in clinical activity measured by the CDAI and the Crohns disease endoscopic index of severity. Results: STA 5326 was well tolerated. Reported adverse events were similar across dose cohorts. The most common (>15%) drug‐related adverse events observed were dizziness, nausea, headache, and fatigue. Clinical activity at day 28/29 was observed at qd doses of 28 mg and above for the clinical endpoints of response and remission: 70 points or greater decrease in CDAI (range 42%‐82% of patients); 100 points or greater decrease in CDAI (range 38%−64% of patients), and CDAI <150 (range 15%−36%). Conclusions: Oral qd dosing of STA 5326 for 4 weeks was well tolerated in doses up to 70 mg qd in patients with active moderate to severe Crohns disease. Clinical activity was observed at qd doses of 28 mg and above.

Secretin, 100 years later.

One hundred years have elapsed since the discovery of secretin by Bayliss and Starling in 1902. In the past century, the research of secretin has gone by many milestones including isolation, purification and structural determination, chemical synthesis, establishment of its hormonal status by radioimmunoassay and immunoneutralization, identification of the specific receptor, cloning of secretin and its receptor, and identification of a secretin-releasing peptide. It has become clear that secretin is a hormone-regulating pancreatic exocrine secretion of fluid and bicarbonate, gastric acid secretion, and gastric motility. The release and actions of secretin is regulated by hormone–hormonal and neurohormonal interactions. The vagus nerve, particularly its afferent pathway, plays an essential role in the physiological actions of secretin. Substantial information about the property of the secretin receptor has been accumulated, but a potent secretin receptor-specific antagonist remains to be formulated. The neural regulatory mechanisms of the release and action of secretin await further elucidation. The physiological role of secretin in intestinal secretions and motility and extragastrointestinal organs remains to be defined. The presence of secretin and its receptor in the central nervous system is well documented, but its function as a neuropeptide has been recognized gradually and requires extensive study in the future.

A physiological role of peptide YY on exocrine pancreatic secretion in rats.

BACKGROUND Peptide YY (PYY) given intravenously was shown to inhibit pancreatic exocrine secretion both in the dog and the rat. However, a possible physiological role of PYY on the pancreatic secretion has not been clarified. The present study was undertaken to investigate its physiological role on the exocrine pancreas. METHODS In conscious rats, plasma PYY was determined in response to oral ingestion of a 6-mL meal and intravenous infusion of PYY; small intestinal transit time was measured by phenol red as a nonabsorbable marker, and pancreatic secretory studies were performed in rats with pancreatic fistulas and jugular vein catheters. RESULTS Oral ingestion of the meal (containing phenol red, 1.6 mg/100 mL) significantly increased plasma PYY within 30 minutes. During this period, most (97%) of the phenol red was detected in the proximal two-thirds of the small intestine. Intravenous infusion of PYY in 25, 50, and 100 pmol.kg-1 x h-1 produced a dose-dependent increase in plasma PYY. The dose of PYY that simulated the peak postprandial level was 50 pmol.kg-1 x h-1, and this dose of PYY significantly inhibited the pancreatic secretion stimulated by physiological doses of secretin and cholecystokinin-8 (CCK-8). After the meal, pancreatic secretion of bicarbonate and protein significantly increased in rats pretreated with normal rabbit serum, whereas this increase was significantly augmented in rats pretreated with an anti-PYY serum because the postprandial increase in plasma PYY was abolished. CONCLUSIONS PYY plays a regulatory role in the postprandial pancreatic exocrine secretion in rats.

Plasma secretin concentrations in fasting and postprandial state in man

Plasma immunoreactive secretin concentrations were determined in both healthy subjects and patients with duodenal ulcer. The modified radioimmunoassay method could detect significant increases in the plasma secretin concentrations when 0.05 N HCl was infused intraduodenally at a rate of 1.1 and 2.2 ml/min. The mean fasting plasma secretin concentration of 13 normal healthy subjects was 4.4±0.38 pg/ml which was significantly less (P<0.01) than that of 13 duodenal ulcer patients, 6.9±0.64 pg/ml. In both groups ingestion of a meat-containing meal resulted in significant increase in the plasma secretin concentrations. Recording of pH from proximal duodenum indicated that pH fell periodically below 4.5 during the postprandial period, indicating that only a short segment of proximal duodenum was exposed to acid after meal. The postprandial rise in plasma secretin levels was abolished when antral pH was raised above 5.5 by intragastric infusion of 0.3 N NaHCO3 solution. These observations indicate that although fasting plasma secretin levels are low, the plasma secretin levels increase significantly after ingestion of a meal. This increase appears to be attributable to an increased amount of acid delivered to the proximal duodenum, and patients with duodenal ulcer were found to release more secretin during the postprandial period than normal subjects.