Effects of model bile infusion on fasting small bowel motility

A636 AGA ABSTRACTS

GASTROENTEROLOGY Vol. 118, No.4

3244 RELATION BETWEEN GASTRIC EMPTYING AND SMALL BOWEL TRANSIT IN NORMAL SUBJECTS STUDIED WITH BREATH TESTS.

naloxone in the distal one-half of gut (p < 0.01). Conclusion: Slowing of intestinal transit by PYY is abolished by luminal naloxone.

Benny Geypens, Anja Luypaerts, Yvo Ghoos, Paul Rutgeerts, KU Leuven, Leuven, Belgium.

IVAgent

For gastric emptying (GE) and orocecal transit *C breath tests have been developed. Combining labels allows to measure gastric half emptying time (t l12g) using [J4C]octanoic acid and orocecal transit time (OCTT) using lactose-[I3C]ureide. Applying deconvolution distills the small bowel half emptying time (tI/2sb)from these tests. The aim was to study the relation between gastric emptying and small bowel transit with these techniques. Methods: 65 healthy subjects performed a breath test using a meal of 440 kcal with the above described labels in an omelet. Breath samples for 14C and 13C were obtained before and every 15 minutes after eating the test meal during 4 and 10 hrs respectively. Calculations were done via deconvolution to obtain tl/ Zg' Further deconvolution of the percent dose recovery curve (PDR) in breath 13C02 with the PDR curve from breath 14C02 resulted in a curve representing entry of the BC label into the cecum, yielding tll2sb. Results: The median values in min were: t l l Zg : 95; OCTT: 300; tl/Z,b: 438, the P90 being 166, 420 and 743 minutes respectively. Correlation of tll2g and t1l2sb was significant at -0.25. This is illustrated in the figure, with P90 for both. The combination of slow GE with slow small bowel emptying never occurs. Conclusion: The significant negative correlation of t1l2sb and t1l2g is due to the lack of the combination of delay in both. This is an indication for a compensatory effect of small bowel emptying for slow gastric emptying. Rapid gastric emptying is not necessarily compensated by slow intestinal transit.

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300 0

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60

120

180

240

300

PYY PYY PYY

Luminal Agent

Cumulative % Marker Recovered

saline (Control) saline naloxone (proximal gut) naloxone (distal gut)

7385± 2.35 9.65 ± 2.591 6839± 193 29.25 + 1.05

3246 SLOWING OF INTESTINAL TRANSIT BY OLEATE IN THE RAT IS ABOLISHED BY LUMINAL ONDANSETRON, A 5-HT 3 RECEP· TOR ANTAGONIST. Henry C. Lin, Oscar L. Perdomo, Henry A. Fisher, Cedars-Sinai Med Ctr, Los Angeles, CA. Antagonists to 5-hydroxytryptamine 3 (5-HT3 ) receptors are proposed as a treatment for irritable bowel syndrome and other functional bowel diseases. Although fatty-meal related symptoms are common in this patient population, little is known about the effect of these antagonists on the intestinal response to fat. Aim: To test the hypothesis that the slowing of intestinal transit by fat may be blocked by luminal Ondansetron, a 5-HT3 receptor antagonist, we compared intestinal transit in response to oleate in a conscious rat model. Methods: Intestinal transit was measured in 4 SpragueDawley rats that were equipped with a duodenal and midgut perfusion catheter. 0.3 ml pH 7.0 buffer (control) or oleate was delivered as a bolus into the gut via the duodenal catheter. 2.4 mg/kg Ondansetron (Ond) or 0.15 M saline was mixed with buffer or oleate. 0.5 mllactulose was given through the duodenal catheter 15 min after the delivery of buffer or oleate. The lactulose breath hydrogen test was used to measure intestinal transit. Exhaled breath was collected every 15 min in a 3 L airtight collection chamber and measured for hydrogen concentration. After each gas sample was obtained, the air in the collection chamber was exchanged with ambient air. Intestinal transit was calculated as the time-to-rise of hydrogen concentration. The results were compared by paired t-test . Results: I . Intestinal transit was slowed by oleate (buffer control vs oleate; p < 0.005). 2. Intestinal transit of buffer was slowed by Ondansetron (buffer control vs buffer + Ond; p < 0.05). 3. Slowing of intestinal transit by oleate was abolished by Ondansetron (oleate vs oleate + Ond; p <0.005). Conclusion: Slowing of intestinal transit by fat in the rat is abolished by luminal Ondansetron. Supported in part by NIH DK 46459

t112g (min) Effect ofOleate and Ondansetron on Intestinal Transit

3245

Duodenal·caecum transit time (min) asmean ± SE Buffer Control Oleate Buffer + Ond

Oleate + Ond

270.0 ± 30.0

165.0 ± 16.2

SLOWING OF INTESTINAL TRANSIT BY PEPTIDE YY IS ABOLISHED BY LUMINAL NALOXONE.

168.8 ± 9.4

2850±6.1

Henry C. Lin, Susan Hum, Jin Hai Chen, Cedars-Sinai Med Ctr, Los Angeles, CA. Slowing of intestinal transit by fat in the distal gut (ileal brake) is abolished by immunoneutralization of peptide YY (PYY) (Gastro 110:1491, 1996) or by naloxone delivered luminally into the efferent limb of the response (proximal gut) (Gastro 11O:A787, 1996). It is unknown, however, whether the slowing of intestinal transit by PYY depends on a naloxone-sensitive opioid pathway. Aim: To test the hypothesis that the slowing of intestinal transit by PYY depends on a naloxone-sensitive opioid pathway, intestinal transit of buffer was compared during iv PYY in the presence or absence of naloxone delivered into the proximal or distal one-half of gut. Methods: 4 dogs were equipped with duodenal (10 em from pylorus) and midgut (160 em from pylorus) fistulas. Using occluding Foley catheters, the small intestine was compartmentalized into the proximal (between fistulas) and distal (beyond midgut fistula) one-half of gut. Buffer (pH 7.0) was perfused into both proximal and distal gut at 2 mllmin . PYY was delivered intravenously at 0.8 p.gIkglh. Naloxone (6 mg) was mixed with buffer and delivered into either the proximal or distal one-half of gut. Intestinal transit was measured by delivering 20 p.Ci of 99m- Tc-DTPA as a bolus at the start of the transit measurement and then counting the radioactivity in the output of the midgut fistula during the last 30 min of the 90-min experiment. Intestinal transit (mean ± SE)represented by the cumulative % marker recovered was compared using l-way repeated measures ANOV A. Additional comparisons were made using paired t-tests. Results: I. Intestinal transit depended on the treatment (p< 0.001). 2. PYY slowed intestinal transit (p < 0.0005). 3. Slowing of intestinal transit by PYY was abolished by naloxone in the proximal (p<0.0005) and reduced but not abolished by

3247 EFFECTS OF MODEL BILE INFUSION ON FASTING SMALL BOWEL MOTILITY. Nancy Am Ooteghem, Antonio Moschetta, Jens F. Rehfeld, Melvin Samsom, Louis M. Akkermans, Karel 1. Erpecum, Gerard P. Berge-Henegouwen, Gastrointestinal Research Unit, Univ Med Ctr, Utrecht, Netherlands; Semeiotica Medical, Univ Hosp, Bari, Italy; Dept of Clin Biochemistry, Rigshospitalet, Copenhagen, Denmark. In the fasting state gallbladder emptying is related to phase III of the Migrating Motor Complex (MMC), but it is unknown whether the exposition of the duodenal mucosa to bile initiates phase III activity, or whether the MMC cycle is the regulating factor for gallbladder emptying (CCK release). The aim of our study was to investigate the effect of bile infusion on fasting small bowel motility in a cholestyramine induced bile salt depleted state. Methods: antroduodenal motility was studied in 7 healthy volunteers ( age 29 ys, range 23-37, 4 males) after cholestyramine (12 g day), using a water-perfused catheter (4 antral sideholes at I ern intervals and 4 duodenal sideholes at 10 cm intervals). Antral and duodenal TMPD measurement was used to mantain correct position. DI was positioned 2.5 cm from the mid pyloric region. D2 was used as infusion port. Starting 30 min after phase III a 15 ml sham infusion of saline was administered in 15 min, 30 min after the second phase III, 15 ml of model bile (total lipid concentration 7 g/dl, cholesterol saturation 70 %, taurocholate (TC)/ egg yolk phosphatidylcholine (EYPC)+TC ratio =0.3) was infused. The motility parameters of 15 min before and after infusion were compared. Blood samples for CCK were drawn every 10 min. Data are presented as mean (SEM). Results: No effect of model bile infusion on the total duration of

April 2000

AGAA637

the MMC cycle (first MMC 104.11 (6.9) min, second MMC 114.7 (8.6)min) was observed. Nor did bile infusion have an effect on the start of the next phase III (90.9 (8.6) min vs 75.7 (6.8) min, p=ns). Bile infusion did not affect the origin of the phase III (antral:duodenaI4:3 after bile, 5:2 after saline). 10 cm distal to the infusion port (03) a significant higher frequency of contractions (1.1 (0.7) vs 0.5 (0.8), p=O.012) and a higher motility index (6.8 (l) vs 4.4 (1.3), p=0.OO7) was observed after bile infusion. This effect was not present at 20 cm (04). No increase in motor activity was observed after saline infusion. There was no significant variation in CCK plasma levels before vs after bile infusion (0.25 (0.24) vs 0.62 (0.5) pmol/l). Conclusion: The increase in motor activity observed after infusion seems to be a local effect of exposition to bile of the duodenal wall. Infusion of bile did not affect the timing of the MMC. It is therefore unlikely that intraduodenal bile plays a mayor role in the initiation of phase III of the MMC.

3248 ACCELERATED ORO-CECAL TRANSIT TIME IS A DETERMINING FACTOR FOR THE DEVELOPMENT OF DIARRHEA IN LACTOSE MALABSORBERS. Ines Schwetz, Heinz F. Hammer, Johann Hammer, Dept of Gastroenterology, KF-University, Graz, Austria; Dept of Gastroenterology, Univ, Vienna, Austria. Background: Diarrhea in lactose malabsorbers has been considered to be a typical example of carbohydrate induced diarrhea. This osmotic diarrhea occurrs only if at least 45 g of carbohydrates are malabsorbed, but patients with diarrhea often consume considerably lower amounts of lactose. Therefore other factors contributing to the pathogenesis of diarrhea have to be considered. Aim of the study was to assess the amount of malabsorbed lactose and oro-cecal transit time in lactose malabsorbers with or without diarrhea. Methods: In 43 consecutive patients (26 female, 17 male; mean age: 49 yrs., range: 31-82 yrs.) in whom lactose malabsorption was confirmed by lactose hydrogen breath test, the amount of malabsorbed lactose was assessed by comparing the area under the breath hydogen curves obtained for a four hour period after ingestion of 50 g of lactose and, on a separate day, 25 g of lactulose (ratio AUC LlAUC LL). Oro-cecal transit time was assessed as the time intervall between ingestion of lactose and the increase of breath hydrogen concentration of at least 15 ppm over baseline. Patients noted the occurrence of diarrhea after ingestion of lactose. Data were analyzed using nonparametric statistics. Results: As shown in the table patients with or without diarrhea had no significant differences in their ratio AUC LlAUC LL. In contrast, patients with diarrhea had a significantly faster oro-cecal transit time of the ingested lactose as compared to patients without diarrhea. In addition, in patients with diarrhea there was a significant negative correlation (r = - 0,41, p
Diarrhea

yes no

Patlants

AUCUAUCll

o-e Transit(min)

14 29

1.07+/-0.57 1.08+/-0.76

42.9+/-33.7 82.5+/-64.5')

mean +/-SO, X) p<0.05, O-C..orocecal

3249 NEONATAL MATERNAL SEPARATION RESULTS IN STRESSINDUCED VISCERAL HYPERALGESIA IN ADULT RATS: A NEW MODEL FOR ms. Santosh V. Coutinho, Marciano R. Sablad, Jerry C. Miller, Huping Zhou, Alan Lam, Alfred I. Bayati, Paul M. Plotsky, Emeran A. Mayer, Ucla/Cure, Los Angeles, CA; AstraZeneca, Molndal, Sweden; Emory Univ, Atlanta. GA. Visceral hyperalgesia and allodynia, somatic normolhypoalgesia, and autonomic dysregulation of the gut are the hallmarks of irritable bowel syndrome (lBS). The pathophysiology of IBS remains unclear, due in large part to the lack of an analogous animal model. However, it has been

postulated that early life events, and the subsequent long-lasting alterations in stress-responsiveness are important predisposing factors. In rodents, neonatal maternal separation results in an enhanced responsiveness to psychological stress in adult life. AIM: To investigate the combined effect of neonatal maternal separation and psychological stress in adult life on responses to visceral and somatic stimuli in the rat. METHODS: Long Evans dams and their male pups were randomly assigned to one of the following rearing conditions: (l) NH: no handling or separation (2) MS180: 180 min daily maternal separation from post-natal day 2-14. Experiments were performed on adult animals (3 mos). The visceromotor response (VMR) to colorectal distension (CRD) was quantified by recording electromyographic (EMG) activity from the external oblique musculature. Cutaneous pain sensitivity was assessed using the nociceptive tail-flick reflex. RESULTS: Baseline responses to graded intensities of phasic CRD (10-80 mmHg, 20 s, 4 min interstimulus interval) were similar in both groups. Following acute water avoidance stress (WA, 1 hour), there was a significant increase in the magnitude of the VMR at all intensities of CRD in MS180, but not in NH rats. This stress-induced visceral hypersensitivity was more pronounced following repeated WA (2 consecutive days). Both groups exhibited similar baseline tail-flick latencies an~ a significant somatic analgesia (60 min) following WA. MS180 rats exhibited a significant somatic analgesia following second exposure to WA (next day), and a slow adaptation following repeated WA. In contrast, NH rats exhibited a near complete lack of analgesia following a second exposure to WA. Additionally, MS180 rats also had increased fecal pellet output following WA. CONCLUSIONS: Early life events in rat pups result in permanent alterations in their stress responsiveness and predispose the adult animals to the development of visceral hyperalgesia and somatic hypoalgesia in response to psychological stress. Additionally, colonic motor function in response to stress is also altered in maternally separated animals. Thus, we have developed an animal model that mimics the key features of IBS.

3250 EFFECT OF PSYCHOLOGICALLY INDUCED STRESS ON SYMPTOM PERCEPTION & AUTONOMIC NERVOUS SYSTEM RESPONSE OF PATIENTS (PTS.) WITH EROSIVE ESOPHAGITIS (EE) AND NON-EROSIVE REFLUX DISEASE (NERD). Ronnie Fass, Isaac Malagon, Bruce D. Naliboff, Gloria Pulliam, Nitzan Peleg, Emeran A. Mayer, Southern Arizona VA Health Care System, Tucson, AZ; Univ of Arizona, Tucson, AZ; CURElUCLA Neuroenteric Disease Program, Los Angeles, CA. Most pts. with gastroesophageal reflux disease (GERD) report stress exacerbates symptoms yet the underlying mechanisms remain unknown. Aims: Determine the effect of laboratory induced psychological stress on stimulus and autonomic nervous system response to intraesophageal acid in pts. with EE and NERD. Methods: 26 pts. with heartburn (at least Ix week) underwent upper endoscopy and if negative, 24-hour pH testing. SCL 90-R provided psychological profiles and MMPI-2 personality assessment. Stimulus response (SR) functions to intraesophageal acid (time to initial perception, intensity rating and acid perfusion sensitivity score-APSS) were determined. On day-I baseline acid perfusion was performed and after a 30min-washout period, randomization to stress (dichotic listening) or control condition (nature music) was performed and acid perfusion was repeated. Pts. crossed to the other arm on day-2. Autonomic measurements [heart rate, respiratory rate, skin conductance and subjective stress ratings (SSR)] were obtained at different study phases. Results: We enrolled 14 NERD (lOM, mean age 41.5:!:3.2, range 19-57) and 12 EE (lOM, mean age 38.3:!:4.1, range 19-56) (l1-grade 2, I-grade 4, Hetzel-Dent). SCL90R (T) scores for all psychological dimensions were similar between groups. Both groups scored higher on SSR scales of stress, anxiety and anger during stress compared to baseline (p