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Pancreatic polypeptide is not involved in the regulation of the migrating motor complex in man
Regulatory Peptides, 3 (1982) 41-49 Elsevier Biomedical Press
41
Pancreatic polypeptide is not involved in the regulation of the migrating motor complex in man J. Janssens, J. Hellemans, T.E. Adrian, S.R. Bloom, T.L. Peeters, N. Christofides and G.R. Vantrappen Department of Medical Research, University Hospital St. Rafa~l, B-3000 Leuven, Belgium, and Department of Medicine, Hammersmith Hospital, London W12, United Kingdom (Received 12 May 1981 ; revised manuscrip~ received 18 August 1981 accepted for publication 25 August 1981 )
Summa~ The role of pancreatic polypeptide (PP) and motilin in the regulation of the migrating motor complex (MMC) was studied in normal subjects. Both plasma motilin and PP levels changed cyclically in the fasted state and were highest in the late phase II period preceding the activity front in the duodenum. A continental breakfast invariably disrupted the MMC and induced a fed pattern of motility. After the meal plasma motilin levels decreased whereas PP levels rose significantly. Infusion of pure porcine motilin during the fasted state induced an activity front and a rise in plasma PP levels. Infusion of bovine PP in doses producing plasma PP levels above the postprandial values neither induced an activity front nor prevented its occurrence. During PP infusion, however, plasma motilin levels were low, although the activity front was not inhibited. PP seems to have no clear role in the regulation of the motor component of the MMC of man. The role of motilin in the production of the activity front of the MMC is discussed. pancreatic polypeptide; motilin; migrating motor complex; small intestinal motility
Introduction The migrating motor complex (MMC) of man is the equivalent of the interdigestive myoelectric complex first identified in dogs by Szurszewski in 1969 [15]. The Address for correspondence: Prof. Dr. G. Vantrappen, Internal Medicine, Academisch Ziekenhuis St. Rafa~l, Capucijnenvoer 35, B-3000 Leuven, Belgium. Tel.: 016/23 79 21 ext. 2406. 0167-0 ! 15/82/0000-0000/$02.75 © 1982 Elsevier Biomedical Press.
42 MMC of man, like that of dogs [2] comprises 4 different phases: a rest period (phase 1), a period of irregular contractions (phase 2), a period of rythmic contractions occurring at maximal frequency (phase 3, also called the activity front) and a period of rapid decline in activity (phase 4). All phases progress aborally, and occur cyclically with a period of about 92 min in man [19]. As first described by us [18] and subsequently confirmed by others [3,6], the MMC not only comprises a cyclically recurring motor phenomenon but is accompanied by secretory phenomena as well. Gastric, pancreatic and biliary secretions fluctuate in accordance with the different phases of the complex with the highest secretion rate occurring at the time of the gastroduodenal activity front [10,16]. The regulation of the MMC is incompletely understood. Motilin has been implicated in the initiation of the MMC in the gastroduodenal area in man as well as in several animal species. Recently, Schwartz and coworkers [12] demonstrated in man that pancreatic polypeptide (PP) levels in plasma fluctuate cyclically in the interdigestive state and that the fluctuations are synchronous with the rate of gastric acid secretion. Keane et al. [6] demonstrated in dogs that the cyclic variations in plasma PP levels are correlated with the different phases of the MMC, the highest levels occurring just prior to the start of the activity front in the gastroduodenal area. The present study aimed at determining the role of PP in the regulation of the MMC of man.
Materials and Methods
Upper small intestinal motility was measured by means of three perfused manometric catheters (Clay Adams PE 205; Becton Dickinson and Co., Parsipanny, N J, U.S.A.) with recording orifices 25 cm apart. Under fluoroscopic control the most proximal orifice was positioned in the midportion of the descending duodenum. The methods of recording and of analysing the tracings have been published previously [17]. Four different experiments were performed. In a group of 13 normal volunteers pressure measurements were started after an overnight fast and blood samples were taken every 15 min. In most cases the study lasted until at least two activity fronts were recorded. Nine of these subjects continued the study for 2-3 h following a continental breakfast of 450 kcal (1882 k J). The breakfast was given 20 min after the recurrence of an MMC. In a group of 6 volunteers pure natural porcine motilin (kindly supplied by Professor J.C. Brown, Vancouver, Canada) was infused intravenously at rates of 1.75 and 3.50 pmol. kg - t . min -t (3 volunteers for both doses). The motilin infusion was started 1 or 2rain after the activity front of an MMC appeared at the level of the distal recording orifice. During the motilin infusion blood samples were taken every 5 rain, and every 15 min for an additional 30-60 min thereafter. To 4 other volunteers an intravenous infusion of bovine pancreatic polypeptide (kindly supplied by Dr. R.E. Chance, Eli Lilly, Indianapolis, U.S.A., Batch No. 615-D63-188-8) was given at a rate of 1 p m o l . k g - I . m i n -~. Blood samples were drawn every 15 min. Blood samples were analysed for motilin and pancreatic polypeptide. Motilin was measured by a radioimmunoassay developed to pure natural porcine motilin [l 1]. The radioimmunoassay of pancreatic
43
polypeptide used an antiserum raised to BPP and has been previously described in detail [1]. Statistical analysis of the data was performed by Student's t-test. The fluctuations of basal plasma motilin and pancreatic polypeptide levels in relation to the migrating motor complex were analysed by autocorrelation as described in a previous paper [11]. Informed consent was obtained from all volunteers before the start of each experiment.
Results
In the first experimental group of 13 volunteers 27 activity fronts were recorded. The characteristics of the activity fronts were not different from a control group published earlier [19]. Variations of plasma motilin and PP levels in relation to the occurrence of an activity front were analysed b~¢ normalizing the period length [11]. For 13 cycles of the MMC the time interval between two consecutive activity fronts was considered as 10 units and the motilin and PP values at 0.5, 1.5, 2.5, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 9.5 units were calculated by linear interpolation of the actually measured levels. The values were also transformed into normal variates (u = ( X .Y)/S). When the normal variates were averaged for corresponding units a sinusoidal curve was obtained for both motilin and PP (Fig. 1). Obviously the fluctuations of motilin and PP paralleled each other very closely. The data for both hormones were also arranged into a continuous string (the transformed data from the 13 cycles were put in one sequence) and analysed by autocovariance. For motilin as well as for pancreatic polypeptide (Fig. 2) the autocovariance fluctuated sinusoidally, reaching positive and negative peaks every 10 lags indicating that both hormone levels fluctuated in accordance with the different phases of the MMC. In view of these findings basal motilin and basal PP levels were always computed by averaging the
*0.6 A 0
÷O.Z,
n
o- +0.2 0 Z
o
-0.2 -0.~ -0.6 5.5 10 TIME units
Fig. 1. T r a n s f o r m e d m o t i l i n and PP values as a function of time units.
44
LU o +0.3 Z <
<
0
0 ¢J 0
5 -0.3
t
<
t
t
t
J
t
l
t
l
T
f
L
t
t
J
50
100 TIME LAGS
Fig. 2. Autocovariance of transformed PP values. Arrows indicate expected location of positive and negative peaks.
values over the time interval between two activity fronts. Plasma levels of motilin and of PP varied between different subjects. Interindividual variation of basal levels were within a range of 9-204 pM for motilin (57 -+ 61 pM, mean -+ S.D.) and 5-107 pM for PP (27 -+ 31 pM, mean -+ S.D.). A continental breakfast of 450 kcal (1882 kJ) invariably disrupted the MMC in all 9volunteers and changed the interdigestive pattern into a pattern of digestive motility. Concurrently plasma motilin levels tended to decrease after a short initial rise, but compared to the basal level only the value obtained 67.5 min after the start of the meal reached the P < 0.05 significance level. In contrast plasma PP levels rose significantly after the meal (Fig. 3). The mean
MEAL
160
£ i\
pM
I
t
11,0
ppp AF
120
AF
AF
\;
t
100 80
o
60 /,0 20 0
-'o, ~Y"
.~
"•0'•
'd
b.o.# 1
10 0.133.
l
J
11
12
I
1 p.m.
I
M°titin
I
I
I
3
/.
5 TIME (hr) M.R.
Fig. 3. Motilin and PP levels in one volunteer (MR) after a continental breakfast of 450 kcal (1882 kJ) given 20 rain after the occurrence of an activity front (AF).
i.min
i)
33 21 32 29
mean
42
mean VH. V.G. C.F.
48 42 35
infusion (min)
Time to MMC from
C.J. D.F. V.R.
Volunteer
54
19 20 124
71
61 95 58
Basal a
245
180 196 360
222
220 292 208
Infusion pcak
Motilin (pM)
724
903 980 290
312
363 308 360
Peak in ~g of basal
aBasal levels are computed by averaging plasma levels over one period of the interdigestive complex.
3.50 3.50 3.50
1.75 1.75 1.75
Dose (pmol.kg
Motilin infusion experiments
TABLE I
22
26 14 25
23
13 47 10
Basal a
86
1O0 92 65
55
39 103 23
Infusion peak
446
4(X) 680 260
2(X)
3(X) 219 230
Peak in % of basal
Pancreatic polypeptide (pM)
46 TABLE II Effect of infusion of pancreatic polypeptide ( I pmol-kg Volunteer
I. min I) on plasma motilin levels
Pancreatic polypeptide plasma levels in pM
Motilin plasma levels in pM
Basal level a
Plateau level b
Basal level a
Plateau level ~
L.B, V.I. C.W. M.S.
5+2 24+4 18+6 25+3
158±10 180± l0 214± 16 250± 12
11± 4 23± 6 36+20 17 + 3
5+2 4±2 5+2 3~2
M e a n ± S.D.
18±9
200<40
22 + 10
4~ I
Basal levels are computed by averaging plasma levels over one period of the interdigestive complex. b Plateau levels are computed by averaging plasma levels over one hour, beginning 30 min after the start of the PP infusion. Computed by averaging the motilin levels in the same samples as those used to compute plateau PP levels.
PP level during the first postprandial hour was 72.8 -+ 39.1 pM (mean -+ S.E.M.) as compared to a fasting level of 15.5-+7.8 pM. All postprandial values differed significantly from the basal level. Infusion of pure porcine motilin (Table I) at a dose of 1,75 pmol. k g - I . min-] induced an activity front after 42 min and a rise in plasma motilin level to a peak value of 312% of the basal pre-infusion level. At a dose of 3.50 pmol. k g - I • min- ] the activity front appeared 29 min after the start of
180 PP (o1
i
MOTILIN
160
(•1 AF
AF
,0
AF
I /
120 100
\lJ
-
INFUSION
m,
.~-
" •
80
15
60
~ '
~
10
20
xx x
0
25
20
, -60
-30
-15
0
/
"e-
Q- _ -q"
¢
; 3
I 60
9~0 I 120 TIME (mln)
0
Fig. 4. Motilin and PP-levels in one volunteer (LB) during PP infusion (1 pmol-kg started at 0 rain. Activity fronts (AE) indicated by arrows.
l-rain
]) which
47 the infusion and the peak motilin level was 724% of the basal level. The motilin infusions produced a rise in plasma PP as well, which started some 15 min after that of motilin. Peak levels were 200 and 446% of the basal pre-infusion levels (Table I). In the last series of experiments bovine PP was infused intravenously in 4 volunteers at a rate of 1 p m o l . k g - I . m i n - ~ for 2h. Infusion of PP had no effect on the occurrence of the activity front which was neither induced nor abolished. Table II summarizes the plasma PP and motilin levels during the PP infusion. In contrast with the motilin-infusions, infusion of PP rapidly led to plateau levels within 30 min after the start of the infusion. Plasma motilin levels decreased dramatically during PP-infusion becoming almost undetectable in all four volunteers. An example of the results of one volunteer is given in Figure 4.
Discussion Many investigators have attempted during the past ten years to elucidate the nature of the control system that regulates the initiation and distal progression of the MMC and its disruption by feeding. It has become clear that hormonal factors are very important for the initiation of the complex in the upper part of the tract [14,15]. A circulating hormone cannot be a candidate for this control function if its plasma level does not change cyclically in accordance with the different phases of the MMC, and if it is not able to induce an MMC when it is exogenously administered in physiological doses or endogenously released. Several previous studies and the present study indicate that both these requirements are fulfilled for motilin [4,5,7,9,14,19]. The present study also confirms the previous observationthat plasma motilin levels are low after feeding when the MMC is disrupted. Apart from motilin, PP is the only gastrointestinal hormone which is known to change cyclically during fasting [8]. It has also been demonstrated that cyclic fluctuations of PP levels parallel the cyclic changes in acid secretion in man [12] and that a peak in plasma PP precedes the onset of the activity front of the MMC in the duodenum of dogs [6]. Our data confirm these observations in man. In the fasting state plasma PP levels fluctuate cyclically in accordance with the different phases of the human MMC and are highest in the late phase II period preceding the onset of the activity front in the gastroduodenal area. However, the second prerequisite for PP to be a good candidate for the initiation of the MMC has not been fulfilled: infusion of bovine PP, even in doses that produce very high plasma PP levels, neither induced an activity front nor prevented its occurrence. The fact that plasma PP levels are high after a meal while the MMC is disrupted further argues against PP as a candidate for the initiation of the MMC. One could even speculate that the high postprandial PP levels have a role in the disruption of the MMC. Our data, however, clearly indicate that exogenous infusion of PP in doses that produce plasma PP levels above the postprandial values, do not disrupt the MMC. The most intriguing finding of this study was that exogenous infusion of PP induced a fall in plasma motilin level without inhibiting the activity front of the MMC. Clearly, a rise in plasma motilin level is not an absolute prerequisite for the
48
activity front of the MMC to occur in the small intestine of man. One, therefore, is tempted to conclude that the plasma motilin fluctuations that occur in the interdigestive state are nothing more than epiphenomenon; the same could be true for the PP fluctuations. In fact, plasma fluctuations of these two hormones could be related to the secretory component of the MMC [16] by being either part of it or by being involved in its regulation. Whatever the interpretation of the relation between hormone fluctuations and the activity front of the MMC, it remains true that motilin infusion is able to trigger the development of an activity front. In our experiments intravenous infusion of porcine motilin induced a rise in plasma PP. It is quite possible that motilin infusion induces still other effects which account for the induction of an activity front. It should be remembered that in the fasting state motilin and PP levels are increased several minutes before the activity front. Motilin could be involved in a chain of events leading towards the activity front, triggered at the motilin point during motilin infusion. That MMC's occur under PP infusion and at low motilin levels, could be due either to the fact that this pathway is bypassed, or that different pathways exist.
References 1 Adrian, T.E., Bloom, S.R., Bryant, M.G., Polak, J.M., Heitz, P. and Barnes, A.J., Distribution and release of human pancreatic polypeptide, Gut, 17 (1976) 940-944. 2 Code, C.H.F. and Marlett, J.A., The interdigestive myoelectric complex of the stomach and small bowel of dogs, J. Physiol. (London), 246 (1975) 289-309. 3 Di Magno, E.P., Hendricks, J.C., Go, V.L.W. and Dozois, R.R., Relationships among canine fasting pancreatic and biliary secretions, pancreatic duct pressure, and duodenal phase III motor activity-Boldyreff revisited, Dig. Dis. Sci., 24 (1979) 689-693. 4 Itoh, Z., Honda, R., Hiwatashi, K., Takeuchi, S., Aizawa, I., Takayanagi, R. and Couch, E.F., Motilin-induced mechanical activity in the canine alimentary tract, Scand. J. Gastroenterol., I1 (Suppl. 39) (1976) 93-110. 5 Itoh, Z., Takeuchi, S., Aizawa, I., Mori, K., Taminato, T., Seino, Y., Imura, H. and Yanaihara, H., Changes in plasma motilin concentration and gastrointestinal contractile activity in conscious dogs, Dig. Dis. 23 (1978) 929-935. 6 Keane, F.B., Di Magno, E.P., Dozois, R.R. and Go, V.L.W., Relationships among canine interdigestive exocrine pancreatic and biliary flow, duodenal motor activity, plasma pancreatic polypeptide, and motilin. Gastroenterology, 78 (1978) 310-316. 7 Lee, K.Y., Chey, W.Y., Tai, H.H., Wagner, D. and Yajima, H., Cyclic changes in plasma motilin levels and interdigestive myoelectric activity of canine antrum and duodenum, Gastroenterology, 72 (1977) 1162.
8 Lux, G., Femppel, J., Lederer, P., Rrsch, W., Bloom, S.R. and Domschke, W., Pancreatic polypeptide, motilin and somatostatin levels during interdigestive motility in man, Gastroenterology, 78 (1980) 1212. 9 Lux, G.. Lederer, P., Femppel, J., Rrsch, W. and Domschke, W., Spontaneous and 13-nle-motilininduced interdigestive motor activity of esophagus, stomach and small intestine in man. In J. Christensen (ed.), Proceedings of the 7th. International Symposium on Gastrointestinal Motility, Iowa, U.S.A., September 11-14, 1979, Raven Press, New York, 1980, pp. 269-277. 10 Peeters, T.L., Vantrappen, G. and Janssens, J., Bile acid output and the interdigestive migrating motor complex in normals and in cholecystectomized patients, Gastroenterology, 79 (1980) 678-681. 11 Peeters, T.L., Vantrappen, G. and Janssens, J., Fasting plasma motilin levels are related to the interdigestive motor complex, Gastroenterology, 79 (1980) 716-719.
49 12 Schwartz, T.W., Stanquist, B., Olbe, L. and Stadil, F., Synchronous oscillations in the basal secretion of pancreatic polypeptide and gastric acid, Gastroenterology, 76 (1979) 14-19. 13 Szurszewski, J.H., A migrating electric complex of the canine small intestine, Am. J. Physiol., 217 (1969) 1757-1763. 14 Thomas, P.A. and Kelly, K.A., Hormonal control of interdigestive motor cycles of canine proximal stomach, Am. J. Physiol. 237 (1979) E192-EI97. 15 Thomas, P.A., Kelly, K.A. and Go, V.L.W., Does motilin regulate canine interdigestive gastric motility?, Dig. Dis., 24 (1979) 577-582. 16 Vantrappen, G., Peeters, T.L. and Janssens, J., The secretory component of the interdigestive migrating motor complex in man, Scand. J. Gastroenterol., 14 (1979) 663-667. 17 Vantrappen, G., Janssens, J., Hellemans, J. and Ghoos, Y., The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine, J. Clin. Invest., 59 (1977) 1158-1166.
18 Vantrappen, G., Janssens, J., Peeters, T., Bloom, S.R., Christofides, N. and Hellemans, J., Intraduodenal pH, motilin and interdigestive migrating motor complex in man, Scand. J. Gastroenterol., 13 (Suppl. 49) (1978) 190. 19 Vantrappen, G., Janssens, J., Peeters, T.L., Bloom, S.R., Christofides, N.D. and Hellemans, J., Motilin and the interdigestive migrating motor complex in man, Am. J. Dig. Dis., 24 (1979) 497-500.
41
Pancreatic polypeptide is not involved in the regulation of the migrating motor complex in man J. Janssens, J. Hellemans, T.E. Adrian, S.R. Bloom, T.L. Peeters, N. Christofides and G.R. Vantrappen Department of Medical Research, University Hospital St. Rafa~l, B-3000 Leuven, Belgium, and Department of Medicine, Hammersmith Hospital, London W12, United Kingdom (Received 12 May 1981 ; revised manuscrip~ received 18 August 1981 accepted for publication 25 August 1981 )
Summa~ The role of pancreatic polypeptide (PP) and motilin in the regulation of the migrating motor complex (MMC) was studied in normal subjects. Both plasma motilin and PP levels changed cyclically in the fasted state and were highest in the late phase II period preceding the activity front in the duodenum. A continental breakfast invariably disrupted the MMC and induced a fed pattern of motility. After the meal plasma motilin levels decreased whereas PP levels rose significantly. Infusion of pure porcine motilin during the fasted state induced an activity front and a rise in plasma PP levels. Infusion of bovine PP in doses producing plasma PP levels above the postprandial values neither induced an activity front nor prevented its occurrence. During PP infusion, however, plasma motilin levels were low, although the activity front was not inhibited. PP seems to have no clear role in the regulation of the motor component of the MMC of man. The role of motilin in the production of the activity front of the MMC is discussed. pancreatic polypeptide; motilin; migrating motor complex; small intestinal motility
Introduction The migrating motor complex (MMC) of man is the equivalent of the interdigestive myoelectric complex first identified in dogs by Szurszewski in 1969 [15]. The Address for correspondence: Prof. Dr. G. Vantrappen, Internal Medicine, Academisch Ziekenhuis St. Rafa~l, Capucijnenvoer 35, B-3000 Leuven, Belgium. Tel.: 016/23 79 21 ext. 2406. 0167-0 ! 15/82/0000-0000/$02.75 © 1982 Elsevier Biomedical Press.
42 MMC of man, like that of dogs [2] comprises 4 different phases: a rest period (phase 1), a period of irregular contractions (phase 2), a period of rythmic contractions occurring at maximal frequency (phase 3, also called the activity front) and a period of rapid decline in activity (phase 4). All phases progress aborally, and occur cyclically with a period of about 92 min in man [19]. As first described by us [18] and subsequently confirmed by others [3,6], the MMC not only comprises a cyclically recurring motor phenomenon but is accompanied by secretory phenomena as well. Gastric, pancreatic and biliary secretions fluctuate in accordance with the different phases of the complex with the highest secretion rate occurring at the time of the gastroduodenal activity front [10,16]. The regulation of the MMC is incompletely understood. Motilin has been implicated in the initiation of the MMC in the gastroduodenal area in man as well as in several animal species. Recently, Schwartz and coworkers [12] demonstrated in man that pancreatic polypeptide (PP) levels in plasma fluctuate cyclically in the interdigestive state and that the fluctuations are synchronous with the rate of gastric acid secretion. Keane et al. [6] demonstrated in dogs that the cyclic variations in plasma PP levels are correlated with the different phases of the MMC, the highest levels occurring just prior to the start of the activity front in the gastroduodenal area. The present study aimed at determining the role of PP in the regulation of the MMC of man.
Materials and Methods
Upper small intestinal motility was measured by means of three perfused manometric catheters (Clay Adams PE 205; Becton Dickinson and Co., Parsipanny, N J, U.S.A.) with recording orifices 25 cm apart. Under fluoroscopic control the most proximal orifice was positioned in the midportion of the descending duodenum. The methods of recording and of analysing the tracings have been published previously [17]. Four different experiments were performed. In a group of 13 normal volunteers pressure measurements were started after an overnight fast and blood samples were taken every 15 min. In most cases the study lasted until at least two activity fronts were recorded. Nine of these subjects continued the study for 2-3 h following a continental breakfast of 450 kcal (1882 k J). The breakfast was given 20 min after the recurrence of an MMC. In a group of 6 volunteers pure natural porcine motilin (kindly supplied by Professor J.C. Brown, Vancouver, Canada) was infused intravenously at rates of 1.75 and 3.50 pmol. kg - t . min -t (3 volunteers for both doses). The motilin infusion was started 1 or 2rain after the activity front of an MMC appeared at the level of the distal recording orifice. During the motilin infusion blood samples were taken every 5 rain, and every 15 min for an additional 30-60 min thereafter. To 4 other volunteers an intravenous infusion of bovine pancreatic polypeptide (kindly supplied by Dr. R.E. Chance, Eli Lilly, Indianapolis, U.S.A., Batch No. 615-D63-188-8) was given at a rate of 1 p m o l . k g - I . m i n -~. Blood samples were drawn every 15 min. Blood samples were analysed for motilin and pancreatic polypeptide. Motilin was measured by a radioimmunoassay developed to pure natural porcine motilin [l 1]. The radioimmunoassay of pancreatic
43
polypeptide used an antiserum raised to BPP and has been previously described in detail [1]. Statistical analysis of the data was performed by Student's t-test. The fluctuations of basal plasma motilin and pancreatic polypeptide levels in relation to the migrating motor complex were analysed by autocorrelation as described in a previous paper [11]. Informed consent was obtained from all volunteers before the start of each experiment.
Results
In the first experimental group of 13 volunteers 27 activity fronts were recorded. The characteristics of the activity fronts were not different from a control group published earlier [19]. Variations of plasma motilin and PP levels in relation to the occurrence of an activity front were analysed b~¢ normalizing the period length [11]. For 13 cycles of the MMC the time interval between two consecutive activity fronts was considered as 10 units and the motilin and PP values at 0.5, 1.5, 2.5, 3.5, 4.5, 5.5, 6.5, 7.5, 8.5 and 9.5 units were calculated by linear interpolation of the actually measured levels. The values were also transformed into normal variates (u = ( X .Y)/S). When the normal variates were averaged for corresponding units a sinusoidal curve was obtained for both motilin and PP (Fig. 1). Obviously the fluctuations of motilin and PP paralleled each other very closely. The data for both hormones were also arranged into a continuous string (the transformed data from the 13 cycles were put in one sequence) and analysed by autocovariance. For motilin as well as for pancreatic polypeptide (Fig. 2) the autocovariance fluctuated sinusoidally, reaching positive and negative peaks every 10 lags indicating that both hormone levels fluctuated in accordance with the different phases of the MMC. In view of these findings basal motilin and basal PP levels were always computed by averaging the
*0.6 A 0
÷O.Z,
n
o- +0.2 0 Z
o
-0.2 -0.~ -0.6 5.5 10 TIME units
Fig. 1. T r a n s f o r m e d m o t i l i n and PP values as a function of time units.
44
LU o +0.3 Z <
<
0
0 ¢J 0
5 -0.3
t
<
t
t
t
J
t
l
t
l
T
f
L
t
t
J
50
100 TIME LAGS
Fig. 2. Autocovariance of transformed PP values. Arrows indicate expected location of positive and negative peaks.
values over the time interval between two activity fronts. Plasma levels of motilin and of PP varied between different subjects. Interindividual variation of basal levels were within a range of 9-204 pM for motilin (57 -+ 61 pM, mean -+ S.D.) and 5-107 pM for PP (27 -+ 31 pM, mean -+ S.D.). A continental breakfast of 450 kcal (1882 kJ) invariably disrupted the MMC in all 9volunteers and changed the interdigestive pattern into a pattern of digestive motility. Concurrently plasma motilin levels tended to decrease after a short initial rise, but compared to the basal level only the value obtained 67.5 min after the start of the meal reached the P < 0.05 significance level. In contrast plasma PP levels rose significantly after the meal (Fig. 3). The mean
MEAL
160
£ i\
pM
I
t
11,0
ppp AF
120
AF
AF
\;
t
100 80
o
60 /,0 20 0
-'o, ~Y"
.~
"•0'•
'd
b.o.# 1
10 0.133.
l
J
11
12
I
1 p.m.
I
M°titin
I
I
I
3
/.
5 TIME (hr) M.R.
Fig. 3. Motilin and PP levels in one volunteer (MR) after a continental breakfast of 450 kcal (1882 kJ) given 20 rain after the occurrence of an activity front (AF).
i.min
i)
33 21 32 29
mean
42
mean VH. V.G. C.F.
48 42 35
infusion (min)
Time to MMC from
C.J. D.F. V.R.
Volunteer
54
19 20 124
71
61 95 58
Basal a
245
180 196 360
222
220 292 208
Infusion pcak
Motilin (pM)
724
903 980 290
312
363 308 360
Peak in ~g of basal
aBasal levels are computed by averaging plasma levels over one period of the interdigestive complex.
3.50 3.50 3.50
1.75 1.75 1.75
Dose (pmol.kg
Motilin infusion experiments
TABLE I
22
26 14 25
23
13 47 10
Basal a
86
1O0 92 65
55
39 103 23
Infusion peak
446
4(X) 680 260
2(X)
3(X) 219 230
Peak in % of basal
Pancreatic polypeptide (pM)
46 TABLE II Effect of infusion of pancreatic polypeptide ( I pmol-kg Volunteer
I. min I) on plasma motilin levels
Pancreatic polypeptide plasma levels in pM
Motilin plasma levels in pM
Basal level a
Plateau level b
Basal level a
Plateau level ~
L.B, V.I. C.W. M.S.
5+2 24+4 18+6 25+3
158±10 180± l0 214± 16 250± 12
11± 4 23± 6 36+20 17 + 3
5+2 4±2 5+2 3~2
M e a n ± S.D.
18±9
200<40
22 + 10
4~ I
Basal levels are computed by averaging plasma levels over one period of the interdigestive complex. b Plateau levels are computed by averaging plasma levels over one hour, beginning 30 min after the start of the PP infusion. Computed by averaging the motilin levels in the same samples as those used to compute plateau PP levels.
PP level during the first postprandial hour was 72.8 -+ 39.1 pM (mean -+ S.E.M.) as compared to a fasting level of 15.5-+7.8 pM. All postprandial values differed significantly from the basal level. Infusion of pure porcine motilin (Table I) at a dose of 1,75 pmol. k g - I . min-] induced an activity front after 42 min and a rise in plasma motilin level to a peak value of 312% of the basal pre-infusion level. At a dose of 3.50 pmol. k g - I • min- ] the activity front appeared 29 min after the start of
180 PP (o1
i
MOTILIN
160
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80
15
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~
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Fig. 4. Motilin and PP-levels in one volunteer (LB) during PP infusion (1 pmol-kg started at 0 rain. Activity fronts (AE) indicated by arrows.
l-rain
]) which
47 the infusion and the peak motilin level was 724% of the basal level. The motilin infusions produced a rise in plasma PP as well, which started some 15 min after that of motilin. Peak levels were 200 and 446% of the basal pre-infusion levels (Table I). In the last series of experiments bovine PP was infused intravenously in 4 volunteers at a rate of 1 p m o l . k g - I . m i n - ~ for 2h. Infusion of PP had no effect on the occurrence of the activity front which was neither induced nor abolished. Table II summarizes the plasma PP and motilin levels during the PP infusion. In contrast with the motilin-infusions, infusion of PP rapidly led to plateau levels within 30 min after the start of the infusion. Plasma motilin levels decreased dramatically during PP-infusion becoming almost undetectable in all four volunteers. An example of the results of one volunteer is given in Figure 4.
Discussion Many investigators have attempted during the past ten years to elucidate the nature of the control system that regulates the initiation and distal progression of the MMC and its disruption by feeding. It has become clear that hormonal factors are very important for the initiation of the complex in the upper part of the tract [14,15]. A circulating hormone cannot be a candidate for this control function if its plasma level does not change cyclically in accordance with the different phases of the MMC, and if it is not able to induce an MMC when it is exogenously administered in physiological doses or endogenously released. Several previous studies and the present study indicate that both these requirements are fulfilled for motilin [4,5,7,9,14,19]. The present study also confirms the previous observationthat plasma motilin levels are low after feeding when the MMC is disrupted. Apart from motilin, PP is the only gastrointestinal hormone which is known to change cyclically during fasting [8]. It has also been demonstrated that cyclic fluctuations of PP levels parallel the cyclic changes in acid secretion in man [12] and that a peak in plasma PP precedes the onset of the activity front of the MMC in the duodenum of dogs [6]. Our data confirm these observations in man. In the fasting state plasma PP levels fluctuate cyclically in accordance with the different phases of the human MMC and are highest in the late phase II period preceding the onset of the activity front in the gastroduodenal area. However, the second prerequisite for PP to be a good candidate for the initiation of the MMC has not been fulfilled: infusion of bovine PP, even in doses that produce very high plasma PP levels, neither induced an activity front nor prevented its occurrence. The fact that plasma PP levels are high after a meal while the MMC is disrupted further argues against PP as a candidate for the initiation of the MMC. One could even speculate that the high postprandial PP levels have a role in the disruption of the MMC. Our data, however, clearly indicate that exogenous infusion of PP in doses that produce plasma PP levels above the postprandial values, do not disrupt the MMC. The most intriguing finding of this study was that exogenous infusion of PP induced a fall in plasma motilin level without inhibiting the activity front of the MMC. Clearly, a rise in plasma motilin level is not an absolute prerequisite for the
48
activity front of the MMC to occur in the small intestine of man. One, therefore, is tempted to conclude that the plasma motilin fluctuations that occur in the interdigestive state are nothing more than epiphenomenon; the same could be true for the PP fluctuations. In fact, plasma fluctuations of these two hormones could be related to the secretory component of the MMC [16] by being either part of it or by being involved in its regulation. Whatever the interpretation of the relation between hormone fluctuations and the activity front of the MMC, it remains true that motilin infusion is able to trigger the development of an activity front. In our experiments intravenous infusion of porcine motilin induced a rise in plasma PP. It is quite possible that motilin infusion induces still other effects which account for the induction of an activity front. It should be remembered that in the fasting state motilin and PP levels are increased several minutes before the activity front. Motilin could be involved in a chain of events leading towards the activity front, triggered at the motilin point during motilin infusion. That MMC's occur under PP infusion and at low motilin levels, could be due either to the fact that this pathway is bypassed, or that different pathways exist.
References 1 Adrian, T.E., Bloom, S.R., Bryant, M.G., Polak, J.M., Heitz, P. and Barnes, A.J., Distribution and release of human pancreatic polypeptide, Gut, 17 (1976) 940-944. 2 Code, C.H.F. and Marlett, J.A., The interdigestive myoelectric complex of the stomach and small bowel of dogs, J. Physiol. (London), 246 (1975) 289-309. 3 Di Magno, E.P., Hendricks, J.C., Go, V.L.W. and Dozois, R.R., Relationships among canine fasting pancreatic and biliary secretions, pancreatic duct pressure, and duodenal phase III motor activity-Boldyreff revisited, Dig. Dis. Sci., 24 (1979) 689-693. 4 Itoh, Z., Honda, R., Hiwatashi, K., Takeuchi, S., Aizawa, I., Takayanagi, R. and Couch, E.F., Motilin-induced mechanical activity in the canine alimentary tract, Scand. J. Gastroenterol., I1 (Suppl. 39) (1976) 93-110. 5 Itoh, Z., Takeuchi, S., Aizawa, I., Mori, K., Taminato, T., Seino, Y., Imura, H. and Yanaihara, H., Changes in plasma motilin concentration and gastrointestinal contractile activity in conscious dogs, Dig. Dis. 23 (1978) 929-935. 6 Keane, F.B., Di Magno, E.P., Dozois, R.R. and Go, V.L.W., Relationships among canine interdigestive exocrine pancreatic and biliary flow, duodenal motor activity, plasma pancreatic polypeptide, and motilin. Gastroenterology, 78 (1978) 310-316. 7 Lee, K.Y., Chey, W.Y., Tai, H.H., Wagner, D. and Yajima, H., Cyclic changes in plasma motilin levels and interdigestive myoelectric activity of canine antrum and duodenum, Gastroenterology, 72 (1977) 1162.
8 Lux, G., Femppel, J., Lederer, P., Rrsch, W., Bloom, S.R. and Domschke, W., Pancreatic polypeptide, motilin and somatostatin levels during interdigestive motility in man, Gastroenterology, 78 (1980) 1212. 9 Lux, G.. Lederer, P., Femppel, J., Rrsch, W. and Domschke, W., Spontaneous and 13-nle-motilininduced interdigestive motor activity of esophagus, stomach and small intestine in man. In J. Christensen (ed.), Proceedings of the 7th. International Symposium on Gastrointestinal Motility, Iowa, U.S.A., September 11-14, 1979, Raven Press, New York, 1980, pp. 269-277. 10 Peeters, T.L., Vantrappen, G. and Janssens, J., Bile acid output and the interdigestive migrating motor complex in normals and in cholecystectomized patients, Gastroenterology, 79 (1980) 678-681. 11 Peeters, T.L., Vantrappen, G. and Janssens, J., Fasting plasma motilin levels are related to the interdigestive motor complex, Gastroenterology, 79 (1980) 716-719.
49 12 Schwartz, T.W., Stanquist, B., Olbe, L. and Stadil, F., Synchronous oscillations in the basal secretion of pancreatic polypeptide and gastric acid, Gastroenterology, 76 (1979) 14-19. 13 Szurszewski, J.H., A migrating electric complex of the canine small intestine, Am. J. Physiol., 217 (1969) 1757-1763. 14 Thomas, P.A. and Kelly, K.A., Hormonal control of interdigestive motor cycles of canine proximal stomach, Am. J. Physiol. 237 (1979) E192-EI97. 15 Thomas, P.A., Kelly, K.A. and Go, V.L.W., Does motilin regulate canine interdigestive gastric motility?, Dig. Dis., 24 (1979) 577-582. 16 Vantrappen, G., Peeters, T.L. and Janssens, J., The secretory component of the interdigestive migrating motor complex in man, Scand. J. Gastroenterol., 14 (1979) 663-667. 17 Vantrappen, G., Janssens, J., Hellemans, J. and Ghoos, Y., The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine, J. Clin. Invest., 59 (1977) 1158-1166.
18 Vantrappen, G., Janssens, J., Peeters, T., Bloom, S.R., Christofides, N. and Hellemans, J., Intraduodenal pH, motilin and interdigestive migrating motor complex in man, Scand. J. Gastroenterol., 13 (Suppl. 49) (1978) 190. 19 Vantrappen, G., Janssens, J., Peeters, T.L., Bloom, S.R., Christofides, N.D. and Hellemans, J., Motilin and the interdigestive migrating motor complex in man, Am. J. Dig. Dis., 24 (1979) 497-500.