Somatostatin 28 and coupling of human interdigestive intestinal motility and pancreatic secretion

GASTROENTEROLOGY

1992;103:974-981

Somatostatin 28 and Coupling of Human Interdigestive Intestinal Motility and Pancreatic Secretion MANFRED VON DER OHE, PETER LAYER, CHRISTOPH WOLLNY, JOHN W. ENSINCK, THEO L. PEETERS, CHRISTOPH BEGLINGER and HARALD GOEBELL Division of Gastroenterology, Department of Medicine, University of Essen, Essen, Germany; Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington; Division of Gastroenterology, Department of Medicine, University of Leuven, Leuven, Belgium; and Division of Gastroenterology, Department of Medicine, University of Basel, Basel, Switzerland

To determine the effects of small increases in somatostatin 28 plasma concentrations on human interdigestive gastrointestinal motility and pancreatic secretion, six fasting volunteers were intubated with gastroduodenal multilumen tubes and motility and pancreatic enzyme secretion were measured. Subjects received intravenous NaCl and somatostatin 28 at 11 and 44 pmol - kg-’ - h-’ for 120 minutes or at least one interdigestive cycle. The two doses increased plasma somatostatin 28 levels within the physiological or into the supraphysiological range, respectively. Somatostatin 28 at 11 and 44 pmol - kg-‘. h-’ decreased the length of the interdigestive motility cycle by 50% and 67% compared with controls, respectively (both P < 0.002). Propagation velocity of the migrating motor complex (P < 0.01)and plasma motilin were decreased (P < 0.01). The smaller and larger dose decreased pancreatic enzyme outputs by 50% and 65%, respectively (P < 0.005), but with the smaller dose, phase III-associated enzyme outputs were greater than phase I outputs. These findings suggest that small changes in somatostatin 28 plasma concentrations modulate human interdigestive motility and pancreatic enzyme output while coupling of motor and secretory events is preserved.

S

omatostatin is a potent inhibitor of several gastrointestinal secretory and motor functions when administered exogenously at pharmacological doses,‘*’ but its physiological role is not fully understood. Somatostatin 28 appears to be the major active circulating form of somatostatin; its release is increased in response to a meal, and it has been proposed to act as a coregulator of postprandial gastrointestinal function.3-g Whether endogenous release of somatostatin 28 is involved in the regulation of interdigestive gastroin-

testinal motor and secretory functions is unknown. Because its plasma disappearance half-time is only a few minutes,‘0-‘6 basal somatostatin 28 plasma concentrations indicate that there is substantial release even in the fasting state. It has been reported that fluctuations in somatostatin plasma concentrations occur in concert with interdigestive motor events, and it was postulated that somatostatin may participate in the regulation of the interdigestive motility cycle. 17,180n the other hand, intravenous administration of exogenous somatostatin 14, which induces constant elevations in plasma somatostatinlike immunoreactivity levels, decreases the length of the interdigestive cycle without disrupting its periodic pattern.‘.17 These observations suggest that fluctuating release of somatostatin may not be a prerequisite for modulation of the periodicity of the interdigestive cycle. To test this hypothesis, we aimed to determine if in healthy humans in the interdigestive state, small, constant elevations of somatostatin 28 plasma concentrations influence (1)periodicity and patterns of intestinal motility, (2) pancreatic enzyme output, and (3) coupling of motor and secretory events. We did not aim to simulate physiological interdigestive release of somatostatin 28. Materials and Methods Human Subjects The protocol was approved by the Institutional Ethical Committee. Having given informed written consent, six healthy male volunteers (aged 21-32 years] who were within 10% of ideal body weight participated in this study.

0 1992 by the American

Gastroenterological 0016-5085/92/$3.00

Association

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Tubes,

Motility

Recordings,

and Sampling

After an overnight fast, subjects were admitted to the Clinical Gastroenterology Research Laboratory at 7 AM and intubated with two polyvinyl multilumen tubes to aspirate duodenal and gastric contents and to record motility from antropyloric, duodenal, and upper jejunal sites. A nine-lumen orointestinal tube was placed with its tip 15 cm distal to the ligament of Treitz within the proximal jejunum (140 cm from front teeth line). With the tube in this position, pressure recording ports were located in the antrum (three sites, each z cm apart), duodenum (15 and 35 cm from the pylorus), and proximal jejunum (55 cm from the pylorus) and constantly perfused with deionized water at 0.1 mL/min. Additional ports for perfusion of polyethylene glycol (45 mg/min) and aspiration of duodenal juice were located in the proximal (15 cm from the pylorus) and distal duodenum (just proximal to the ligament of Treitz), respectively. A four-lumen gastric tube was placed in the antrum. The gastric tube had a distal aspiration port at its tip, a port for marker perfusion (phenolsulfonphthalein, 250 pg/mL, 1 mL/min; 15 cm proximal to tip of tube) to assess completeness of gastric aspiration, and two additional pressure recording sites (25 and 25.5 cm from tip of tube within lower esophageal sphincter) perfused with deionized water at 0.1 mL/min. Positions of gastric and intestinal tubes were checked fluoroscopically before and after experiments. To measure gastroduodenal motility, the perfusion catheters were connected to a lowcompliance perfusion system.‘g The voltage output of each calibrated pressure transducer was preamplified and continuously recorded by an eight-channel recorder (Sensormedics, Essen, Germany). Ten-minute gastric and duodenal samples were collected by continuous aspiration into vials that were immersed in ice. Blood samples were collected via a cannula placed into the left antecubital vein. A second cannula was inserted into the right antecubital vein for infusions of test substances. Then 5 mL of venous blood was sampled in ethylenediaminetetraacetic acid (EDTA) tubes at 20-minute intervals, centrifuged at 4’C at 5000 rpm, and stored at -2O’C with 0.25 mL 1N HC1/2 mL of plasma for somatostatin determination or with aprotinin (50 pL) for motilin measurements. Experimental

Protocol

After correct positioning of the gastric and duodenojejunal tubes, we started continuous perfusion of gastric and duodenal marker solutions and recording of antral and small intestinal motility. Each subject received four intravenous infusions (12 mL/h) in the following order: NaCl(l54 mmol/L), somatostatin 28 (11 pmol - kg-’ - h-l), NaCl (154 mmol/L), and somatostatin 28 (44 pmol. kg-’ * h-l). Hence, each somatostatin period had its own preceding control period. All NaCl and somatostatin infusions were started 10 minutes after identification of a duodenal phase III and administered for at least one or more complete interdigestive motility cycle(s), so that the duration of each infusion was at least 120 minutes. This protocol was chosen in view of the short plasma disappearance half-time of somatostatin 28

and its brief biological action.2~‘0~‘2~20 Synthetic somatostatin 28 was kindly provided by Prof. L. Moroder, Max Planck Institute, Martinsried, Munich, Germany. Vials (1 mL) of somatostatin 28 (30 nmol/mL) dissolved in NaCl (154 mmol/L) containing 0.1% of human serum albumin were prepared by the University of Base1 Hospital Pharmacy, Switzerland, and stored at -20°C. Isotonic (154 mmol/L) NaCl solution with 0.1% human serum albumin served as volume and carrier control. Chemical,

Motility,

and Statistical

Analyses

Amylase activity was determined according to Bernfeld.‘l Trypsin activity was measured by using Na-ptosyl+arginine methyl ester HCl and chymotrypsin activity by using n-benzoyl-L-tyrosin-ethyl ester as substrates.” Concentrations of polyethylene glycol and phenolsulfonphthalein were analyzed and used to calculate recovery and intraluminal volume flow rate per minute as described earlier.23~24 Peripheral plasma concentrations of somatostatin 28 and motilin were determined by specific radioimmunoassays as previously described.g.25 Phase I motor activity was defined as periods with less than two contractions within 5-minute segments. Migrating motor complexes (MMC, phase III activity) were defined as uninterrupted periods of regular contractions (IO-12/min) within the duodenum for at least 2 minutes with distal propagation and included transition of late phase II to phase III motor activity. Propagation velocity of intestinal activity fronts was determined by measuring the time elapsing between consecutive occurrence of an activity front at the proximal duodenal and the jejunal motility port, i.e., at sites 40 cm apart. For statistical analyses, paired t tests were used after testing for normal distribution with the KolmogoroffSmirnoff test; when 6 values did not show a normal distribution (amylase outputs), tests were performed after log transformation.26 First, values obtained during the first and second NaCl infusions were compared in each subject to exclude carryover effects between the first somatostatin period and the subsequent NaCl period. Next, the effects of each somatostatin infusion vs. NaCl were assessed separately by computing the differences between values obtained during each somatostatin dose and its preceding NaCl infusion. These 6 values were then used to compare the effects of the two somatostatin doses. In addition, within each NaCl and somatostatin infusion, we compared phase I- and phase III-associated enzyme outputs. In figures, control values are represented by data obtained during the first NaCl infusion. Data are expressed as mean values t SEM, unless indicated otherwise.

Results Plasma

Somatostatin

28

Mean basal concentration of somatostatin 28 was 33.3 rt 2.5 pg/mL and remained unaltered in response to both the first and second intravenous NaCl infusion (32.6 f 2.2 pg/mL and 33.1 -t 2.4 pg/ mL, respectively). Mean plasma somatostatin 28 concentrations were 32.5 + 2.7 pg/mL during phase I,

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34 + 2.1pg/mL duringphase II, and 31.8+ 2.6pg/mL during phase III. Somatostatin 28 plasma concentrations doubled within 20 minutes in response to infusion of somatostatin 28 at a dose of 11 pmol *kg-’ - h-’ and remained at a constant plateau thereafter (58.3 f 4.1pg/mL; P < 0.001 vs. NaCl). Somatostatin 28 infusion at a dose of 44 pmol - kg-’ - h-’ caused a fourfold increase in plasma somatostatin 28 to 118.9 f 10.9 pg/mL (P < 0.001; F igure 1). There was no fluctuation of somatostatin 28 plasma concentrations in association with motility phases, neither during NaCl nor during somatostatin infusion.

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Plasma Motilin Plasma concentrations of motilin were 169 f 30 and 167 f 39 pg/mL during the first and second NaCl infusion, respectively. Somatostatin 28 at a dose of 11 and 44 pmol . kg-’ - h-l decreased plasma motilin to 123 k 24 and 79 + 20 pg/mL, respectively (both P < 0.01 vs. NaCl). During somatostatin infusion, there were no motilin peaks associated with phase III motility. Intestinal

Motility

During the first NaCl infusion, the mean length of the interdigestive motility cycle was 130 + 36 minutes; phase I comprised 24 f 7 minutes, phase II 94 ? 9 minutes, and phase III 13 + 3 minutes (Fig-

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mlnutos Figure 1. Somatostatin 28 plasma concentrations before and during intravenous administration of graded doses of somatostatin 28 over 120 minutes. Results are expressed as mean values & SEM, n = 6. Both somatostatin doses significantly increased plasma somatostatin compared with their preceding saline controls (each *P < 0.001). The depicted control reflects data obtained during the first saline infusion. 0, Control: A, somatostatin 28 (11 pmol - kg-‘- h-l); Cl, somatostatin 28 (44 pmol . kg-’ - h-l).

S-28 [llpmol/kglh]

0B

control

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[Emimin]

Figure 2. (A) Effect of somatostatin 28 on the length of duodenal interdigestive motility cycle (total bar) and proportion of motility phases within cycle compared with controls (represented by the first saline infusion). Results are expressed as mean values + SEM, n = 6. Each dose was compared with the preceding saline control. Note that the significant decrease in cycle lengths (each *P < 0.002 vs. controls) was mainly caused by a decrease in phase II duration. (B)Propagation velocity of MMC in duodenum and proximal jejunum during graded doses of somatostatin 28 for 120 minutes. Results are expressed as mean values + SEM, n = 6; *P i 0.01 vs. preceding saline control. Depicted control values reflect data obtained during the first saline infusion.

ure 2A). Similar values were obtained during the second NaCl infusion (mean cycle length, 124 +- 29 minutes). Somatostatin 28 at 11 pmol - kg-’ - h-’ significantly shortened the length of the entire cycle to 67 & 10 minutes (P < 0.002 vs. NaCl). The decrease in cycle length was mainly caused by a decrease in phase II duration to 23 + 6 minutes (P < 0.001 vs. NaCl), whereas absolute durations of phase I (30 + 7 minutes) and III (9 + 1 minutes) remained unchanged (Figure 2A). Somatostatin 28 at 44 pmol *kg-’ - h-’ decreased the cycle length to 43 + 6 minutes (P < 0.001vs.NaCl) and the duration of phase II to 9 f 1 minutes (P < 0.001 vs. NaCl); again, the durations of phases I (27 f 3 minutes) and III (9 f 1 minutes) were not altered significantly (Figure 2A). Thus, somatostatin 28 induced a dose-dependent decrease in the interdigestive cycle length by shortening the duration of phase II.

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Somatostatin 28 reduced the propagation velocity of the MMC compared with controls (Figure 2B). Under control conditions mean interdigestive MMC propagation velocity was 6.7 k 0.5 cm/min. Somatostatin 28 at 11 and 44 pmol . kg-’ - h-’ decreased propagation velocity to 4.7 k 0.5 and 4.2+ 0.4cm/min, respectively (both P < 0.01 vs. NaCl; Figure 2B). In 83% of control experiments, MMCs originated in 28 at 11 pmol. kg-’ - h-’ the antrum. Somatostatin did not affect this predominant initiation site (75%) of activity fronts. During administration of somatostatin 28 at 44 pmol *kg-’ - h-‘, inconsistent changes were observed: there was no difference in two volunteers, whereas in four others antral MMCs were reduced or absent. There were no significant differences in the distances of distal propagation among control and somatostatin experiments. Similarly, frequency (lo-12/min) and amplitude of contractions were similar in control and test studies (Figure 3). Pancreatic

Enzymes

During the first NaCl infusion, mean chymotrypsin output during the overall interdigestive cycle was 36.9 + 4.9 U/min, trypsin output 47.3+ 7.1U/ min, and amylase output 312 + 76 U/min. Similar values were obtained during the second NaCl infusion (32.8 + 4.5 U/min, 43.0 + 6.2 U/min, and 338 + 81 U/min, respectively). Somatostatin 28 at 11 pmol +kg-’ - h-’ significantly decreased overall outputs of chymotrypsin (20.5+ 3.2 U/min), trypsin (22.6 + 3.6 U/min), and amylase (167 f 45 U/min) (all P < 0.005 vs. NaCl). Somatostatin 28 at 44 pmol . kg-’ - h-’ caused a further decrease (chymotrypsin, 138 f 2.2 U/min; trypsin, 12.1 f 1.8 U/min; amylase, 148 + 46 U/min; all P < 0.002 vs. NaCl). During NaCl infusions, duodenal motility phases I, II, and III were associated with the expected significant (P < 0.02) fluctuations in duodenal outputs of chymotrypsin (Figure 4), trypsin, and amylase (not shown). Somatostatin 28 at 11 pmol- kg-’ -h-l reduced outputs during each phase by about 50%; consequently, at this dose, phase III-associated chymotrypsin outputs were significantly greater than phase I-associated outputs (P < 0.02). Thus, phase-associated fluctuations in duodenal enzyme outputs were preserved during the lower somatostatin dose (Figure 4). 28 at 44 pmolBy contrast, with somatostatin kg-’ - h-l, phase III-associated chymotrypsin output did not differ significantly from phase I-associated output (P > 0.1) because of a relatively greater reduction in phase III-associated outputs compared with phase I-associated output (Figure 4). Thus, with the

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PANCREAS

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higher somatostatin 28 dose, motility-associated fluctuations of pancreatic enzyme outputs were not preserved. There were no significant differences among the aspirated amounts of polyethylene glycol during phases I, II, and III or during different test infusions. Discussion The main findings of the present study can be summarized as follows, Intravenous infusion of somatostatin 28 at a rate of 11 pmol - kg-’ - h-l (a) increased somatostatin 28 plasma concentrations above the normal interdigestive but below the postprandial range; (b) shortened the length of the interdigestive motility cycle as a result of a reduction of the duration of phase II; (c) decreased propagation velocity of intestinal MMCs; (d) decreased overall interdigestive pancreatic enzyme outputs but; and (e) preserved coupling between cyclical interdigestive pancreatic enzyme secretion and motility phases. Motility Intravenous administration of somatostatin 28 at 11 and 44 pmol - kg-’ - h-’ dose-dependently decreased the duration of the interdigestive cycle by approximately 50% and 67%, respectively. This reduction was a result of a dose-dependent decrease in phase II duration, whereas phase I and phase III durations remained unaffected. These findings correspond to effects described for somatostatin 14 at dosages that increased plasma SLI concentrations within the physiologica117~27 or pharmacological range. ‘* Because effects were blocked by atropine, a cholinergic mechanism was suggested.2* In the postprandial state, low infusion rates of somatostatin 14 had no effect on human duodenal motility and gallbladder volume, but higher, presumably pharmacological doses interrupted the fed pattern and induced phase III-like activity; somatostatin plasma concentrations were not measured.” In our study, both doses of somatostatin 28 reduced propagation velocity of the MMC by approximately 30%. Previous studies did not report any differences between somatostatin-induced activity fronts and spontaneous MMCS.“~~*-~~We did not observe effects of low dose somatostatin 28 on other parameters of the MMC, such as site of origination, distance of distal propagation, and frequency and amplitude of contractions. In a recent study, pharmacological doses of the somatostatin analogue octreotide induced premature MMCs in normal volunteers that were propagated at normal velocity3’; the difference may be attributable to the different form of somatostatin used.

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GASTROENTEROLOGY Vol. 103, No. 3

proximal

distal 4

duodenum

duodenum

Ab

pruximal

duudenum .

distal

@mm

Hg

Compared with humans, there are marked species differences with regard to motor responses to exogenous somatostatin administration. Thus, in pigs, only highly pharmacological doses of somatostatin 14, but not lower doses, affected motor events with inhibition of gastroduodenal spiking activity, disruption of MMC pattern, and inhibition of distal propagation of MMCs into the jejunoileum.32 In dogs, pharmacological doses of somatostatin 14 doubled the frequency of activity fronts in the upper small intestine and very high doses even interrupted fed motor pattern by inducing activity fronts that resembled the MMC in the fasting state and were propagated distally.32,33 How somatostatin affects human gastrointestinal motility is unclear. There is evidence that somatostatin interacts with cholinergic control mechanisms of intestinal motility.34-3s Exogenous somatostatin has also been suggested to influence release and/or

duudenum

Figure3. Manometricmotility recordings of the antropyloric region (top two tracings), proximal and distal duodenum, and proximal jejunum during continuous infusion of NaCl (0.9%) (A) and somatostatin 28 (B).

action of motilin, which may play a role in the regulation of interdigestive motility.‘7*1a~z5However, similar to what has been described for somatostatin 14,17 we found a suppression of motilin release by somatostatin 28 rather than a stimulation. These findings suggest that if mechanical activity causes motilin release, this mechanism is blocked by somatostatin. Moreover, in contrast to a previous study in which somatostatin l&induced activity fronts entirely lacked a gastric component,17 we now report that the antrum may participate in somatostatin 28-induced motor complexes. Because plasma motilin concentration was decreased, this observation may reflect a different mediation compared with spontaneous antral phase III activity that may be associated with, and possibly require, increased plasma motilin concentrations.

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that, in the presence of marked overall inhibition of enzyme outputs, coupling between pancreatic secretion and small intestinal motor events was preserved in response to the lower dose of somatostatin 28, similar to what we observed for low-dose somatostatin 14.27

0

11

Somatostatin-28

44

[pmollkgh]

Figure 4. Effect of graded doses of somatostatin 28 on interdigestive motility phase-associated duodenal chymotrypsin outputs. Results are expressed as mean values f SEM, n = 6. Note that similar to control studies (represented by the first saline infusion), during the lower somatostatin dose phase III-associated chymotrypsin outputs were significantly greater compared with phase I-associated outputs (*P < 0.02). By contrast, with the higher somatostatin dose the difference between phase III- and phase I-associated outputs was not significant.

The higher dose of somatostatin 28 caused a further decrease in phase III-associated enzyme outputs, whereas phase I- and phase II-associated outputs were not significantly altered compared with the lower somatostatin dose. Consequently, in contrast to the lower dose, the pharmacological dose of somatostatin abolished the coupling of motility and pancreatic secretion. We speculate that, compared with phase I- and II-associated secretion, phase IIIassociated enzyme secretion may be controlled by different mechanisms that possibly are more responsive to supraphysiological plasma concentrations of somatostatin. Plasma Somatostatin

In control studies, constant basal somatostatin were measured in all subjects. In view of the short plasma dissappearance half-time of 4 minutes,‘0-‘6 these concentrations suggest continuous endogenous release of somatostatin 28 in the interdigestive state. Somatostatin 28 at a dose of 11 pmol - kg-’ - h-’ produced a plateau concentration exceeding those normally measured under fasting conditions but lower than levels obtained after a mea1.3vgSomatostatin 28 at a dose of 44 pmol ekg-’ - h-’ caused an increase in somatostatin 28 plasma concentrations into a supraphysiological range.3*g There are conflicting data regarding whether somatostatin participates in the regulation of interdigestive gastrointestinal motility and secretion or whether fluctuations of somatostatin plasma concentrations occur in concert with interdigestive motor and secretory events. Somatostatin-like immunoreactive plasma concentrations have been reported to increase in association with the MMC.2,‘7*‘8In the present study we failed to document such changes in fasting somatostatin plasma concentrations, possibly because of the differences in somatostatin molecular forms. On the other hand, periodic release of somatostatin may not be necessary to induce cyclic responses, because our data suggest that constant elevations of somatostatin plasma concentrations may dose-dependently modulate the periodicity of motor and secretory activities while motor-secretory coupling is preserved. Thus, these findings are compatible with the concept that continuous interdigestive release of somatostatin may participate in the control 28 plasma concentrations

Pancreatic

Secretion

Recent findings suggest that somatostatin 28 may be a hormonal regulator of postprandial exocrine pancreatic function in humans.3~8~gWhereas an inhibitory effect of exogenous somatostatin 14 or somatostatin analogues at pharmacological doses on both stimulated and unstimulated exocrine pancreatic secretion has been well established,2*384” the present study suggests that small elevations of somatostatin 28 plasma concentration within the physiological range cause a dose-dependent decrease in interdigestive human pancreatic enzyme secretion. In fasting humans, several secretory functions within the proximal gastrointestinal tract including pancreatic secretion are linked to gastrointestinal motility2428*47,48. We therefore correlated interdigestive motor events with pancreatic secretion in response to graded doses of somatostatin 28. During administration of the lower dose the decrease in enzyme outputs was similar for each motility phase; i.e., phase III-associated outputs remained greater than phase I-associated outputs. Theoretically, such changes may have been caused by pooling artifacts during somatostatin-induced motor quiescence and subsequently increased delivery of duodenal contents to the aspiration site during activity fronts. However, the amounts of nonabsorbable marker aspirated duodenally were not significantly influenced by somatostatin 28 compared with controls or by different motor phases. Therefore, our findings suggest

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of human periodic motor and secretory activities. Indeed, recent data obtained in animal experiments using immunoneutralization with a specific monoclonal somatostatin antibody suggest that in rats, somatostatin exerts a tonic inhibitory influence on pancreatic exocrine secretion4’ In humans such direct evidence of a regulatory role of somatostatin could only be obtained by using selective somatostatin receptor antagonists that to date are not available. References 1. Arnold R, Lankisch PG. Somatostatin

and the gastrointestinal tract. Clin Gastroenterol 1980;9:733-753. 2. Layer P, Ohe M, Mtiller MK, Beglinger C. Effects of somatostatin on the exocrine pancreas. Stand J Gastroenterol 1991;26:129-136. 3. Ensinck JW, Laschansky EC, Vogel RE, Simonowitz D, Roos B, Francis BH. Circulating pro-somatostatin-derived peptides: differential responses to food ingestion. J Clin Invest 1989;83:1580-1589. 4. Schusdziarra V, Rouiller D, Petri A, Harris V, Zyznar E, Conlon JM, Unger RH. Pancreatic and gastric release of somatostatin-like immunoreactivity during the intestinal phase of a meal. Am J Physiol 1979;6:E555-E560. 5. Chayvialle JA, Miyata M, Rayford PL, Thompson JC. Effects of test meal, intragastric nutrients, intraduodenal bile on plasma concentrations of immunoreactive somatostatin and vasoactive intestinal peptide in dogs. Gastroenterology 1980;79:844852. 6. Wass JAH, Penman E, Dryburgh JR, Tsiolakis D, Goldberg TL, Dawson AM, Besser GM, Rees LH. Circulating somatostatin after food and glucose in man. Clin Endocrinol 1980;12:569574. 7. Tsuda K, Sakurai H, Seino Y, Seino S, Tanigawa K, Kuzuya H, Imura H. Somatostatin-like immunoreactivity in human peripheral plasma measured by radioimmunoassay following affinity chromatography. Diabetes 1981;30:471-474. 8. Polonsky KS, Shoelson SE, Docherty HM. Plasma somatostatinincreases in response to feeding in man. J Clin Invest 1983;71:1514-1518. 9. Ensinck JW, Vogel RE, Laschansky EC, Francis BH. Effect of ingested carbohydrate, fat, and protein on the release of somatostatin-28 in humans. Gastroenterology 1990;98:633-638. 10. Vaysse N, Chayvialle A, Pradayrol L, E&eve JP, Susini C, Lapuelle J, Descos F, Ribet A. Somatostatin 28: comparison with somatostatin 14 for plasma kinetics and low-dose effects on the exocrine pancreas in dogs. Gastroenterology 1981;81:700706. 11. Hilsted L, Holst JJ. On the accuracy of radioimmunological determination of somatostatin in plasma. Regul Pept 1982;4:13-31. 12.Sheppard M, Shapiro B, Pimstone B, Kronbeim S, Berelowitz M, Gregory M. Metabolic clearance and plasma half-disappearance time of exogenous somatostatin in man. J Clin Endocrinol Metab 1979;48:50-53. 13. Polonsky K, Jaspan I, Berelowitz M, Pugh W, Moossa A, Ling N. The in vivo metabolism of somatostatin 28: possible relationship between diminished metabolism and enhanced biological action. Endocrinology 1982;111:1698-1702. 14. Seal A, Yamada T, Debas H, Hollinshead J, Osadchey B, Aponte G, Walsh J. Somatostatin-14 and -28; clearance and potency on gastric function in dogs. Am J Physiol 1982;283:G97-G102.

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15. Hirst BH, Conlon MJ, Coy DH, Holland J, Shaw B. Comparison of gastric exocrine inhibitory activities and plasma kinetics of somatostatin-28 and somatostatin-14 in cats. Regul Pept 1982;4:227-237. 16. Pate1 YC, Wheatley T. In vivo and in vitro plasma disappearance of somatostatin-28 and somatostatin-14 in the rat. Endocrinology 1983;12:220-225. 17. Peeters TL, Janssens J, Vantrappen GR. Somatostatin and the interdigestive migrating motor complex in man. Regul Pept 1983;5:209-217. 18. Aizawa I, Itoh Z, Harris V, Unger R. Plasma somatostatin-like immunoreactivity during interdigestive period in the dog. J Clin Invest 1981;68:206-213. 19. Arndorfer RC, Stef JJ, Dodds WJ, Linehan JH, Hogan WJ. Improved infusion system for intraluminal esophageal manometry. Gastroenterology 1977;73:23-27. 20. Susini C, Esteve JP, Vaysse N, Pradayrol L, Ribet A. Somatostatin 28: effects on exocrine pancreatic secretion in conscious dogs. Gastroenterology 1980;79:720-724. 21. Bernfeld P. Alpha-amylases. Methods Enzymol 1955;1:149158. 22. Hummel BC. A modified spectrophotometric determination of chymotrypsin, trypsin and thrombin. Can J Biochem 1955;37:1393-1397. 23. Go VLW, Hofmann AF, Summerskill WHJ. Simultaneous measurements of total pancreatic, biliary and gastric outputs in man using a perfusion technique. Gastroenterology 1970; 58:321-328. 24. Layer P, Chan ATH, Go VLW, DiMagno EP. Human pancreatic secretion during phase II antral motility of the interdigestive cycle. Am J Physiol 1988;254:G249-G253. 25. Peeters TL, Vantrappen GR, Janssens J. Fasting plasma motilin levels are related to the interdigestive motor complex. Gastroenterology 1981;79:716-719. 26. Box GEP, Hunter WS, Hunter JS. Statistics for experimenters. New York: Wiley, 1978:306-342. 27. Layer P, Boekstegers A, Miiller MK, Lotte A, Goebell H. Cyclical interdigestive pancreatic secretion in response to physiologic doses of somatostatin-14 in humans. Gastroenterology 1987;92:1495. 28. Lux G, Femppel J, Lederer P, Rosch W, Domschke W. Somatostatin induces interdigestive intestinal motor and secretory complex-like activity in man. Gastroenterology 1980;78:1212. 29. Neri M, Cuccurullo F, Marzio L. Effect of somatostatin on gallbladder volume and small intestinal motor activity in humans. Gastroenterology 1990;98:316-321. 30. Ormsbee HS, Koehler SL, Telford GL. Somatostatin inhibits motilin-induced interdigestive contractile activity in the dog. Dig Dis 1978;23:781-788. 31. Soudah HC, Hasler WL, Owyang C. Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma. N Engl J Med 1991;325:1461-1467. 32. Bueno L, Fioramonti J, Rayner V, Ruckebusch Y. Effects of motilin, somatostatin, and pancreatic polypeptide on the migrating myoelectric complex in pig and dog. Gastroenterology 1982;82:1395-1402. 33. Thor P, Krol R, Konturek SJ, Cox DH, Schally AV. Effect of somatostatin on myoelectrical activity of small bowel. Am J Physiol 1978;235:E249-E254. 34. Guillemin R. Somatostatin inhibits the release of acetylcholine-induced electrically in the myenteric plexus. Endocrinology 1976;99:1653-1654. 35. Teitelbaum D, O’Dorisio T, Perkins W, Gaginella T. Somatostatin modulation of peptide-induced acetylcholine release in guinea pig ileum. Am J Physiol 1984;246:G509-G514. 36. Hall KE, El-Sharkawy TY, Diamant NE. Vagal control of ca-

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Received June 6,1991. Accepted February 25, 1992. Address requests for reprints to: Peter Layer, M.D., Medizinische Klinik, Universitatsklinikum, HufelandstraBe 55, D-(W)4300 Essen 1, Germany. Supported by Deutsche Forschungsgemeinschaft grant La 483,’ 2-4 and 5-1. The authors thank L. Cherian for expert technical assistance.