Oral prostaglandin E analogues induce intestinal migrating motor complexes after a meal in dogs. Evidence for a central mechanism

The effects of oral, intravenous, and intracerebroventricular administration of synthetic derivatives of prostaglandins E1 (misoprostol) and E2 (enprostil) on postprandial gastrointestinal motility were investigated in dogs chronically fitted with strain gauge transducers on the antrum and the proximal and middle jejunum. Synthetic prostaglandin E analogues administered orally at a dose of 20-50 micrograms/kg 15 min before the meal did not modify the postprandial pattern of gastric contractions but suppressed the spontaneous postprandial irregular activity on the jejunum and induced a cyclic pattern of migrating motor complexes for 4-6 h after the meal. These postprandial migrating motor complexes induced by prostaglandin E were propagated between the two recording sites and had a period similar to that observed in the fasted state. However, the duration of phase 2 was significantly increased and the amplitude of the phase 3 decreased. This jejunal cyclic motor pattern was reproduced by administration of synthetic prostaglandin E derivatives either intravenously (4-10 micrograms/kg) 15 min before the meal or intracerebroventricularly (50 ng/kg) 1 h after the meal. The intestinal migrating motor complex activity observed after oral administration of synthetic prostaglandin E derivatives was abolished by the previous intracerebroventricular (40 micrograms/kg) but not intravenous (200 micrograms/kg) administration of SC-19220, a receptor antagonist of prostaglandin E. These results suggest that oral administration of synthetic prostaglandin E1 (misoprostol) or prostaglandin E2 (enprostil) analogues before a meal induces postprandial migrating motor complexes on the jejunum in dogs through a mechanism involving central prostaglandin receptors.     

Mechanism of interdigestive migrating motor complex in conscious dogs

Background  

The migrating motor complex (MMC) is well characterized by the appearance of gastrointestinal contractions in the interdigestive state. This study was designed to clarify the mechanisms of gastric MMC (G-MMC) and intestinal MMC (I-MMC) in conscious dogs.     

Enterohepatic circulation of bile acids after cholecystectomy.

Bile acid metabolism was investigated in 10 patients after cholecystectomy, 10 gallstone patients, and 10 control subjects. Diurnal variations of serum levels of cholic and chenodeoxycholic acid conjugates were not abolished by cholecystectomy. Cholic acid pool size was significantly reduced in cholecystectomised patients and the fractional turnover rate and the rate of intestinal degradation of bile acid showed a significant increase. In cholecystectomised patients fasting bile was supersaturated in cholesterol, though less than in gallstone patients, but, in both, feeding resulted in improvement of cholesterol solubility in bile. These data suggest that after cholecystectomy the small intestine alone acts as a pump in regulating the dynamics of the enterohepatic circulation of bile acids and that the improvement of cholesterol solubility in bile is due to a more rapid circulation of the bile acid pool in fasting cholecystectomised patients.     

Characteristics of postprandial duodenal motor patterns in dogs

In this study special attention was paid to the characteristics of duodenal motility under the influence of various test meals. Closely spaced strain gauge transducers and a computerized method were used to analyze motor patterns of the duodenum and the adjacent jejunum. Compared with an acaloric meal, nutrients shortened the length of contraction spread in the duodenum from 5.2±1.0 to 3.8±0.5–2.8±0.6 cm and in the jejunum from 10.5±3.0 to 7.4±1.3–5.2±0.8 cm. Additionally, contraction frequency was reduced. Basic differences were found between duodenal and jejunal motility. They were most marked in absence of nutrients. The duodenal motor pattern was characterized by a lower contraction frequency (8.0±2.2 vs 11.1±1.8/min), a shorter length of contraction spread (5.2±1.0 vs 10.5±3.0 cm), and a higher incidence of stationary contractions (50% vs 34%). On the duodenal bulb 72% of contractions represented contraction waves, whereas in the mid-duodenum the predominant feature was stationary contractions (57%) promoting the mixing of chyme with secretions. The characteristic duodenal motor patterns might be related to special functions of the duodenum for transport and digestion.The study was supported by the Deutsche Forschungsgemeinschaft, grant Eh 64/2.     

Enteric mechanisms of initiation of migrating myoelectric complexes in dogs

The enteric mechanisms governing initiation of migrating myoelectric complexes were studied in 6 conscious dogs, each implanted with a set of 12 bipolar electrodes on the small intestine. The small intestine was transected and reanastomosed at three sites to give four isolated segments of equal length. Each segment had three implanted electrodes. All four isolated segments generated migrating myoelectric complexes which were, initially, totally independent of each other in time. The most proximal segment had the longest mean migrating myoelectric complex time period (106.2 +/- 10.1 SEM min) and the second segment had the shortest mean migrating myoelectric complex time period (66.8 +/- 6.7 SEM min). Distal to the second segment, the mean migrating myoelectric complex time period increased progressively (83.1 +/- 11.2 SEM min and 95.8 +/- 7.6 SEM min, respectively). Isolation of the small intestine into segments did not significantly change migrating myoelectric complex propagation characteristics such as velocity and direction of propagation within each segment. The mean duration of phase 3 activity was not affected in the first segment but increased significantly in the distal three segments (p less than 0.05). The propagation of migrating myoelectric complexes across the sites of transection and reanastomosis started recovering 45-60 days after surgery and recovered fully by 98-108 days. The study findings show that enteric mechanisms control the initiation of migrating myoelectric complexes. Each small segment of the small intestine is capable of initiating migrating myoelectric complexes of its own and behaves as a relaxation oscillator. In the intact small intestine, regional migrating myoelectric complex oscillators are coupled by the intrinsic neurons so that the proximal oscillators drive the distal oscillators. Recovery of migrating myoelectric complex propagation across sites of transection and reanastomosis suggest that intrinsic nerves regenerate after transection.     

Effects of oral laxatives on colonic motor complexes in dogs.

The effect of oral laxatives on the organisation of colonic motor complexes was investigated in four conscious dogs. Six strain gauge transducers were implanted on the colon of each dog. After a control period of two to three hours, dogs were orally dosed with 1, 2, or 4 ml/kg of castor oil, or 0.5 g/kg magnesium citrate. Oral olive oil, 4 ml/kg, was used as control. The recording was continued for another 10 hours or until defecation occurred. Each dog showed spontaneous cyclic bursts of contractions (contractile states) at all recording sites during the control period. Contractile states migrating orad or caudad over at least half the length of the colon were called colonic migrating motor complexes (CMMC). Castor oil and magnesium citrate significantly increased the period of colonic motor complexes, but olive oil had no significant effect. None of the above substances changed the percentage of orad migrating motor complexes, as compared with the control values. Periods in which colonic motor activity was completely absent for at least 60 min over at least three consecutive recording sites occurred more frequently after all of the substances. The occurrence of these periods of inhibition, however, was not a consistent feature and there seemed to be no relationship between the occurrence of inhibitory periods and defecation during the recording period. The dogs defecated within 10 hours after administration of magnesium citrate, 1, 2, and 4 ml/kg of castor oil in 12.5, 25, 37.5, and 88.8% of experiments respectively, but never with olive oil. Defecation was generally accompanied by giant migrating contractions in the colon. We conclude that oral laxatives, magnesium citrate and castor oil have a profound effect on colonic motor complexes and colonic motor activity. The period of CMMC is significantly prolonged after their oral administration because of an increased number of non-migrating motor complexes or periods of inhibition of motor activity.     

Effect of total sympathectomy and of decentralization on migrating complexes in dogs

The effect of total sympathectomy and of decentralization on interdigestive myoelectric activity of the stomach and small intestine and on cycling levels of plasma motilin were studied in conscious dogs. In controls, 98.3% +/- 7.9% of the migrating myoelectric complexes (mean +/- SD) originated in the stomach. In sympathectomized dogs, 38.17% +/- 16.7% originated in the stomach, 35.8% +/- 12.3% in the duodenum, and 26.3% +/- 4.3% in the jejunum. In decentralized dogs, 5.3% +/- 1.4% of the migrating myoelectric complexes originated in the stomach, 71.0% +/- 16.5% in the duodenum, and 23.9% +/- 17.4% in the jejunum. Cycling of plasma motilin was not affected by long-term sympathectomy but coordination of peak levels of plasma motilin and initiation of gastric migrating myoelectric complexes was disrupted in decentralized dogs. These data suggest that central nervous input is required for initiation of migrating myoelectric complexes in the stomach and that central vagal but not central sympathectic input is essential for cycling of plasma motilin.     

Enterohepatic circulation rates of cholic acid and chenodeoxycholic acid in man.

The rate of enterohepatic cycling of cholic acid and chenodeoxycholic acid was determined in five male subjects. Pool sizes were measured by isotope dilution technique after intraduodenal administration of 14C-labelled cholic and chenodeoxycholic acid. The hourly hepatic secretion rate of bile acids was determined by an intestinal perfusion technique. From these data the cycling frequency was calculated. Chenodeoxycholic acid circulated on an average 1.34 (range, 1.13--1.57) times faster than cholic acid, probably because chenodeoxycholic acid to a larger extent than cholic acid is absorbed from the proximal small intestine and thus partly bypasses the hepaticoileal circuit. This difference in cycling rate may have methodological as well as physiological implications.     

Enterohepatic cycling of bilirubin: a putative mechanism for pigment gallstone formation in ileal Crohn's disease.

BACKGROUND & AIMS: Patients with ileal disease, bypass, or resection are at increased risk for developing gallstones. In ileectomized rats, bilirubin secretion rates into bile are elevated, most likely caused by increased colonic bile salt levels, which solubilize unconjugated bilirubin, prevent calcium complexing, and promote its absorption and enterohepatic cycling. The hypothesis that ileal disease or resection engenders the same pathophysiology in humans was tested. METHODS: Sterile gallbladder bile samples were obtained intraoperatively from 29 patients with Crohn's disease and 19 patients with ulcerative colitis. Bilirubin, total calcium, biliary lipids, beta-glucuronidase activities, and cholesterol saturation indices in bile were measured, and markers of hemolysis and ineffective erythropoiesis in blood were assessed. RESULTS: Bilirubin conjugates, unconjugated bilirubin, and total calcium levels were increased 3-10-fold in bile of patients with ileal disease and/or resection compared with patients with Crohn's colitis or ulcerative colitis. Biliary bilirubin concentrations correlated positively with the anatomic length and duration of ileal disease. Endogenous biliary beta-glucuronidase activities were comparable in all groups, and both the hemogram and serum vitamin B12 levels were normal. CONCLUSIONS: This study establishes that increased bilirubin levels in bile of patients with Crohn's disease are caused by lack of functional ileum, supporting the hypothesis that enterohepatic cycling of bilirubin occurs.     

Inhibition of nocturnal acidity is important but not essential for duodenal ulcer healing.

We have determined the relative importance of day and night time gastric acid inhibition for duodenal ulcer healing by comparing the anti-ulcer efficacy of a single morning with that of a single bedtime dose of ranitidine. One hundred and thirty patients with active duodenal ulcer were randomly assigned to a double-blind therapy with ranitidine 300 mg at 8 am or the same dose at 10 pm for up to eight weeks. The antisecretory effects of these regimens were also assessed by 24 h intragastric pH monitoring in 18 of these patients. At four weeks ulcers had healed in 41/61 (67%) of patients taking the morning dose and in 47/63 (75%) of those receiving the nocturnal dose (95% CI for the difference -0.09 +0.25; p ns). At eight weeks, the corresponding healing rates were 82% and 85.5%, respectively (95% CI for the difference -0.11 +0.17; p ns). Both treatments were significantly superior to placebo in raising 24 h intragastric pH, although the effects of the morning dose were of shorter duration than those of the nocturnal dose. These findings suggest that suppression of nocturnal acidity is important but not essential to promote healing of duodenal ulcers; a prolonged period of acid inhibition during the day (as obtained with a single large morning dose of H2-blockers) may be equally effective.     

Pain associated with phase III of the duodenal migrating motor complex in patients with postcholecystectomy biliary dyskinesia

BACKGROUND: Correlation between various gastrointestinal events and particular aspects of the migrating motor complex has been reported. This study correlates postcholecystectomy pain to variations in biliary pressure associated with the duodenal motor cycle. METHODS: In 18 patients with postcholecystectomy pain and 10 control subjects, biliary and duodenal pressures were recorded simultaneously with microtransducers. After recording a spontaneous cycle, morphine was administered to induce a premature phase III and spasm of the sphincter of Oddi, and then cerulein was administered to stop the spasm. RESULTS: Transient but significant elevations of biliary pressure occurred at duodenal phase III in both groups, but a greater percentage of the patients developed pain during phase III (89% vs. 20%, p<0.01). Morphine produced premature phase III and biliary pressure elevation, which were accompanied by pain more frequently in the patients than in the control subjects (78% vs. 30%, p<0.05). Biliary pressure dropped after the cerulein injection, relieving the pain in 13 of 14 patients and in 2 of 3 control subjects who had morphine-induced pain. The phase III-related pain was relieved by endoscopic sphincterotomy in 14 of 15 patients. CONCLUSIONS: The cyclic elevation of biliary pressure in coordination with phase III of the duodenal motor cycle may contribute to the development of pain in patients with postcholecystectomy biliary dyskinesia.     

Mechanical characteristics of phase II and phase III of the interdigestive migrating motor complex in dogs

In conscious dogs certain parameters of the jejunal interdigestive phase II and phase III activity were studied by means of closely spaced strain gauges and videofluoroscopy. During phase III the frequency, force, and rise time of contractions and the contraction spread were increased, whereas the intercontractile intervals and the propagation velocity of contractions were diminished in comparison to phase II. The contraction waves of phase III were variable with regard to their length of spread and their rate of caudad migration. These two parameters adjusted the duration, the propagation velocity, and the length of the activity front. Propagation of contractions was sometimes interrupted by periods of uncoupling. Propagation velocities within contraction waves varied according to the pattern slow-fast-slow-fast, producing the videofluoroscopically observed roller coaster movements of the luminal contents. It is concluded that phase II and phase III are characterized not only by the occurrence of irregular and regular activity but by a significant change of a number of contraction parameters.     

Variability of migrating motor complex in humans

Fasting gastrointestinal motility in the human is characterized by the regular cycling activity of the migrating motor complex (MMC). Our purpose was to define the variability of the MMC within and between a group of six healthy subjects studied for 6–9 hr over six separate days with a perfused catheter system. A total of 88 phase III events was observed during 255 hr of recording in this group. The mean MMC cycling time varied significantly between subjects (range 113–230 min,P<0.001), and variation within subjects also was wide (sd range 58–70 min). Seventy-one percent of phase III events commenced in the gastric antrum, 18% in the proximal duodenum, 10% in the distal duodenum, and 1% in the proximal jejunum. For each subject, the velocity of propagation of phase III decreased significantly (P<0.001), and phase III duration increased significantly (P<0.001), with increasing distance from the os. In the antrum, phase I was predominant, and significant (P<0.006) variation between subjects was noted for percentage of MMC cycle occupied by phase I (overall mean ±sd 55±23%). Phase II was predominant in both duodenum and jejunum (mean range 70–80%), and no significant variation was noted between subjects for percentage of MMC occupied by phase II. We conclude that human MMC activity varies widely between individuals and within the same individual when studied on separate days.Presented, in part, at the American Gastroenterological Association meeting, Washington, D.C., May 1989, and published in abstract form in Gastroenterology (96:A127, 1989).     

Micturition is associated with phase III of the interdigestive migrating motor complex in man

OBJECTIVES: In previous manometric studies, we observed that micturition was associated with phase III of the migrating motor complex. The present study aimed to objectify this possible relationship and to examine whether modulation of micturition frequency influences migrating motor complex phase III incidence. METHODS: In a retrospective study, ambulatory antroduodenal manometry and micturition data of 27 subjects were analyzed. In a prospective study, antroduodenal motility and micturition patterns were studied in five subjects who were subjected to an oral water load. Volunteers were either allowed to micturate ad libitum or instructed to postpone micturition. RESULTS: In the retrospective part of the study, a statistically significant association was found between phase III and micturition. Of all micturitions, 50% took place during or within 10 min from phase III. Also, in the prospective part of the study, phase III and micturition, as well as micturition urge, showed a significant association (p < 0.05). CONCLUSION: Micturition and phase III of the migrating motor complex are associated in time.     

Postprandial disruption of migrating myoelectric complex in dogs

Our aim was to determine the mechanism whereby the jejunoileum regulates postprandial gastroduodenal motility. Five dogs were prepared with a proximal jejunal infusion catheter and with gastric manometry catheters and serosal intestinal electrodes for recording gastric and intestinal motility. After two weeks, fasted dogs were studied during jejunal infusion of either isosmolar NaCl (154 mM) or isosmolar mixed nutrient solution (50% Meritene) on four separate days each. After completion of these baseline studies, the dogs underwent a model of autotransplantation of the entire jejunoileum (extrinsic denervation, disruption of intrinsic neural continuity with proximal duodenum). Two weeks later, identical studies as before were repeated with the now autotransplanted jejunoileum. Before transplantation, infusion of NaCl did not interrupt the characteristic interdigestive migrating motor complex either in the gastroduodenum or in the jejunoileum. However, infusion of nutrients interrupted the migrating motor complex both in the gastroduodenum and jejunoileum for the duration of the infusion (5 hr). After autotransplantation of the jejunoileum, the migrating motor complex continued to occur in the gastroduodenum and in the jejunoileum during infusion of NaCl, but the migrating motor complex cycled independently in each region without any temporal coordination. Jejunal infusion of nutrients interrupted the MMC in both regions for the duration of infusion (5 hr). Because inhibition of the gastroduodenal and jejunoileal migrating motor complex continued to occur during infusion of nutrients into the transplanted jejunum, we concluded that jejunoileal regulation of postprandial inhibition of interdigestive motility in the stomach and duodenum is mediated by hormonal factors and does not require intrinsic neural continuity.Supported in part by the USPHS NIH Digestive Disease Core Center (DK-34988), the Mayo Foundation, and the International College of Surgeons.Parts of the work were presented at the American Gastroenterological Association on May 18, 1987, in New Orleans. An abstract was published inGastroenterology, 94:A167, 1988.     

The secretory component of the interdigestive migrating motor complex in man.

Intraduodenal pH, bicarbonate and amylase secretion, and gastric acid and pepsin output were studied in relation to the migrating motor complex in man. The occurrence of a motor complex in the duodenum was preceded by an increase in gastric acid and pepsin output and followed by a peak in bicarbonate and amylase secretion. It is concluded that the interdigestive phase in man is characterized by periodic activity complexes comprising both motor and secretory components. These observations may have important implications for the interpretation of currently used functional tests of gastrointestinal secretion.     

Insulin action and hepatic glucose cycling in essential hypertension.

Peripheral insulin resistance is a feature of essential hypertension, but there is little information about hepatic insulin sensitivity. To investigate peripheral and hepatic insulin sensitivity and activity of the hepatic glucose/glucose 6-phosphate (G/G6P) substrate cycle in essential hypertension, euglycemic glucose clamps were performed in eight untreated patients and eight matched controls at insulin infusion rates of 0.2 and 1.0 mU.kg-1.min-1. A simultaneous infusion of (2(3)H)- and (6(3)H)glucose, combined with a selective detritiation procedure, was used to determine glucose turnover, the difference being G/G6P cycle activity. Endogenous hepatic glucose production (EGP) determined with (6(3)H)glucose was similar in hypertensive and control groups in the postabsorptive state (11.0 +/- 0.3 v 10.9 +/- 0.3 mumol.kg-1.min-1) and with the 0.2 mU insulin infusion (4.9 +/- 0.5 v 4.0 +/- 0.8 mumol.kg-1.min-1). With the 1.0 mU insulin infusion, glucose disappearance determined with (6(3)H)glucose was lower in the hypertensive group (21.8 +/- 2.4 v 29.9 +/- 2.4 mumol.kg-1.min-1, P less than .001). G/G6P cycle activity was similar both in the postabsorptive state (2.2 +/- 0.4 v 2.7 +/- 0.4 mumol.kg-1.min-1) and during insulin infusion (0.2 mU, 2.5 +/- 0.3 v 2.9 +/- 0.4; 1.0 mU, 4.7 +/- 0.3 v 5.3 +/- 1.1 mumol.kg-1.min-1 for hypertensive and control groups, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)