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Actions of Cholecystokinin and Secretin on the Motor Activity of the Small Intestine in Man
GASTROENTEROLOGY 67:35-4 1, 1974 © 1974 by The Willia ms & Wilkin s Co .
Vo l. 67. No. I Print ed in U.S .A.
Copyr i~ht
ACTIONS OF CHOLECYSTOKININ AND SECRETIN ON THE MOTOR ACTIVITY OF THE SMALL INTESTINE IN MAN JoRGE
G. G uTIERREz, M.D ., WILLIAM Y. CHEY, M.D. , AND VINCENT P. DINos o , M.D .
The Isaac Gordon Center for Digestive Diseases, and Department of Medicine, The Genesee Hospital: University of Rochester S chool of Medicin e and Dentistry, Rochester, New York; and Temple University H ealth Sciences Center, Philadelphia. Pennsylvania
Using an intraluminal pressure recording technique, we studied the actions of cholecystokinin and secretin on the motor activity of the upper small intestine in 24 healthy subjects. We showed that the "basal" motor activity of duodenum and jejunum was stimulated by cholecystokinin ( CCK). In doses of 1, 2, and 4 U per kg per hr, CCK stimulated the nonrhythmic type I waves. Secretin, on the other hand, i1;hibited the nonrhythmic type I and type III waves. The interactions of these two hormones showed that the CCK -stimulated upper intestinal motility was inhibited by secretin, and that the secretininhibited motility was stimulated by CCK. This study indicates that both CCK and secretin can play an important role on the autoregulation of intestinal motor function in man. ity of the stomach in man 5 and dogs, 6 and also decreases duodenal motility in man .7 The purpose of this study was to determine the actions and interactions of pure preparations of CCK and secretin (Gastrointestinal Hormone, Karolinska Institutet, Sweden) on the motor activity of the small bowel in man .
In recent years, there have been increasing interests in studying the effects of various gastrointestinal hormones on the motor function of the alimentary tract. In 1933, Jung and Greengard, 1 showed that a crude preparation of cholecystokinin (CCK) caused contraction ofthe guinea pig ileum in vitro, and Sandblom et al. 2 reported that it increased duodenal motor activity in in vivo experiments in anesthe tized dogs. Using highly pure CCK preparations made by Jorpes and Mutt, similar observations were made by Dahlgren 3 in 1966 in vivo in dogs , and in 1967 by Bedner et al. 4 in vitro, and it was thus concluded that these effects were due to the hormone itself. In 1969, it was reported that Jorpes and Mutt secretin inhibits the motor activ-
Materials and Methods Thirteen female and 11 male healthy volunteers , of ages ranging from 20 to 60 years, with no evidence of an organic gastrointestinal disease, participated in this study . All subjects were properly informed of the nature of this invest igation and voluntarily consen ted to participate in it. The motor activity was studied with an intraluminal pressure record ing t echnique . After an overnight fast, a two-lumen tube was passed orally, and the tip was placed in the upper jejunum under fluoroscopic observation. The tube was made of two silas tic catheters. The distal 20 em of one of the catheters was filled with mercury, and the tip was sealed with a solid metal olive with a transverse diamet er of 2 mm. Each catheter h ad an internal diameter of 1.6 mm , and a s ide opening of 1.0 by 2.0 mm. The distance between the two
Received July 24, 1973. Accepted December 31, 1973. Presented in part at the Resea rch Forum at the Annual Meet ing of the American Gast roenterologial Association, May, 1971. Address requests for reprin ts to: Dr . Jorge G. Gutierrez, 224 Alexander Street, Rochester, New York 14607.
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GUTIERREZ ET AL.
openings was 2.5 em. The distal opening was located a pproximatel y :20 em distal to the liga m ent of Treit z. and the proxim al opening was in the third portion of the duod enum. The position of the tube was checked f1uoroscopically at the beginning a nd at th e end of each experiment. The catheters were continuously perfused with demin eralized water at a rate of 0 .2 1 ml per min. Thi s rate of infusion was chosen from five different rat es : 0.04. 0.10. 0.21. 0.41 , and 0. 58 ml per min. whi ch were studi ed in 2 subj ec ts . For this purpose, two catheters with openings at the same level were used. Each infusion rate was kept consta nt in one of the cat hete rs, and was match ed against increasingly graded rates of infusion in th e other cat heter. The infusion rates of 0. 10 and 0.:21 ml per min gave as good recordings as the highest infus ion rate tested , 0.58 ml per min. and could b e kept lor long periods without inducing bowel activity. The intraluminal press ure changes were measured with Statham P-2:3 8 transducers (Statham Inst rumen ts. Los Angeles, Ca lif. ). and recorded on a Polyviso reco rder equipped with strain gauge amplifiers (Sanborn , Cambridge, Mass.) Respirations were recorded with a sta ndard pneumograph. After the cat h eters were properly positioned , the subjects were asked to rema in in the supin e pos iti on for the duration of the experiment. At least a 10-min period was allowed for sta bilizati on of the recording. This was followed by a 20-min period durin g which a 0.9% sod ium chlorid e solution was admin istered intra ve nously at a rat e of 0.299 ml per min , and t he motor activity was recorded as an index of the " basal" motor activity. At the end of the 20-min period , a hormonal preparation dissolved in 0.9% sodium chloride solution was administered through the sa me infusion set, and, again , 10 min were allowed for stabilization , and 20 min for the recording of the hormon al effect. Both porcine secretin and CCK employed in this investigation were s upplied by Jorpes and Mutt, Karolins ka Institutet, Sweden , during 1970 and 1971. It has been claimed that this secretin preparation has more than 90% purity and possesses 4000 clinical units per mg. This CCK preparation has approximately 10% purity and possesses 3000 Ivy dog units per mg. The CCK preparation does not contain mot ilin. In order to study the effects of the two hormones on spontaneous motor activity , the rates of infusion employed were 1 and 2 U per kg per hr for secretin , and 1, 2, and 4 U per kg per hr for CCK. The experiment using each dose of an individual hormonal preparation was always preceeded and followed by the administration of
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0.9% sodium chloride solut ion for a period of 30 min. T o study the interactions of these hormones two different experiments were performed. In one experiment, secretin was infused at a constant rat e of 2 U per kg per hr throughout the study, and CCK at increasing rates of 2 and 4 U per kg per hr. In a second experiment, aft er a cont rol period of :30 min with 0.9% sodium chloride solution. CCK was administered at the rate of2 U per kg per hr and compared with the simultaneous administra tion of CCK and secretin at the rate of 2 U per kg per hr each in a subsequent day. The number of subjects studied in each experimental condition is mentioned with the res ults. For the anal ys is of the motor recording. we have adopted the class ification that Templeton and Lawson 8 used to describe the motility of the colon in dogs and defined further by others.•· '' For purposes of clarity we think it is necessary to review these definitions : ty pe I waves are single waves whi ch occur sin gly or in multipl e bursts of va ri a ble duration. The duration of each individual wave varies from 2 to 12 sec and the amplitude from 6 to 50 em of water. T y pe I waves occur in rhy thmic and nonrhythmi c patterns. The nonrhyt hmic or irregular patt e rn is seen more commonly than the rhyt hmi c type. Rhythmic type I waves consist of a sequence of waves of similar amplitude, morphology. and duration that occur in sets of 10 to 12 per min (usua lly at the rate of 11 per min) . The pattern was classified as rhythmic only when this repetition of nearly identical waves were present for at least a period of 1 min , and when successive waves showed variations less than 3 em of water in base line pressure .• Nonrhythm ic type I waves consist of a single wave or bursts of waves of different morphology , amplitude , and durations , and the frequency of waves per minute varied from 1 to 14. Type II wave is a wave norm ally seen only in the stomach. Type III wave consisted of a gradual elevation of the base line of no less than 6 em of water pressure and a duration of 15 sec to several minutes. T y pe I activity is almost always superimposed in this type of wave. The fo llowing parameters were meas ured for both rhythmic and nonrhythmic patterns : (1) number of waves per 20-m in periods; (2) amplitude index (sum of the amplitude of a ll of the waves per 20-min periods, and (3) percenta ge of activity (sum of duration of individual waves in seconds/total duration of test period in seconds x 100). The end-expiratory resting pressure was taken as the zero point. The respiratory def1ections had an average of 4 em of water and artifacts like those caused by minor increases in
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CCK AND SECRETIN IN HUMAN SMALL INTESTINE
intraabdom inal pressure generally did not exceed 6 em of water. For this reason, waves ofless tha n 6 em of water were not counted . Although we recogn ize that some true waves resulting from sma ll bowel motor activity were eliminated in t his fashion, we found this was necessary in ord er to co mpensate for respiratory interference and to eliminate some a rt ifacts . For the statistical analysis , Student's t-test for paired data was employed .
Results The effect of CCK on the spontaneous motor activity of the duod enum and upper jejunum. Five subjects were studied . The nonrhythmic type I waves increased significantly during the intravenous administration of CCK in comparison with those observed during the control period (fig. 1). During the administration of CCK in the dose of 1 U per kg per hr, the mean number of waves increased from 25.6 in a 20-min period to 40.6 (58.6%) in the duodenum, and from 16.8 to 48.0 (185.7%) in the jejunum (fig . 2A). The amplitude index increased from 261 to 415 (59%) in the
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duodenum, and from 232 to 598 (157.5%) in the jejun urn (fig. 2B). The percentage of activity also increased from 9.9% to 15.1% (52.5%) in the duodenum, and from 5.6% to 15.2% (171.4%) in the jejunum (fig. 2C). These changes are statistically significant (P < 0.05). As the dose of CCK was increased to 2 and 4 U per kg per hr, the values of all the parameters studied increased (fig. 2, A, B , and C). The rhythmic type I wave was an inconsistent finding in the control period (less than 10% in all records) and was never observed during CCK infusion. The mean number of type III waves increased from 0.2 in the control period to 0.2, 1.4, and 2.2 in the duodenum , and from 0.4 to 0.8, 3.2, and 4.2 in the jejunum when CCK was given in doses of 1, 2, and 4 U per kg per hr, respectively . The percentage of activity increased also from 0.4 to 0.8, 5.8%, and 6.6% in the duodenum , and 0.8 to 3.6, 7.7, and 14.4% in the jejunum, as CCK was given at a rate of 1, 2, and 4 U per kg per hr, respectively . A trend of increase in type III wave activity was
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FIG. 1. An example of in traluminal pressure recordings in the upper jejunum showing t he actions of cholecystokin in ( CC K ) and secretin on the spontaneous motor activity and interactions of t hese two hormones. Each lin e represents a different subject.
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GUTIERREZ ET AL.
38
~
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FIG . 2. A , Effects of cholecystokinin (CCK) on t he mean number of nonrhyt h mic type I waves per 20 min in the duodenum (D) and jejunum (J) in 5 subjects . II = ±SE. B, effect of CCK on the mean amplitude index per 20 min in the duodenum and jejunum in 5 subjects. I = ± SE. C, effect of CCK in the mean percentage of activity per 20 min in t he duodenum a nd jejunum in 5 subjects. II = ± SE.
noted after the adm inistration of CCK, b ut t he differences were not significant. CCK at the dose of 1 U per kg per hr did not cause any side effects. With the dose of 2 U per kg per hr, 2 subjects complained of mild abdominal cramps, and when t h e dose was increased to 4 U per kg per hr, all 5 subjects complained of mild to moderately severe abdominal cramps. One sub ject also had sweating. None of our subjects
developed nausea, vom it ing, fainting, or other untoward effects . The effect of secretin on spontaneous m otor activity of th e duoden um and upper jejunum. The effect of t he continuous intravenous infus ion of sec retin at the rate of 2 U per kg per h r was studied in 7 subjects. The nonrhythmic type I act ivity was significantly in h ibited in both the duodenum and jejunum (fig. 1). The results of the studies in these 7 subjects are summarized in figure 3. The administration of secretin resulted in 83% inhibition (P < 0.005) in t he mean number of nonrhythmic type I waves in the duoden um an d 86% (P < 0.005) in t h e jejunum . T he amplitude index decreased by 84% in t he duoden um (P < 0.01) and by 84% in the jejunum (P < 0.01) . The percentage of activity decreased from 12.9 to 1.9% in t he duodenum (P < 0 .005), and from 9.5 to 1% in the jejunum (P < 0 .01). Rhythmic type I activity occurred in about 10% of t he subjects during the control period, and in about 30% of t he subjects during secretin infusion; however t he difference was not significant. Type III waves were never observed during secretin infusion. Two additional subjects were studied with secretin in doses of 0 .5 U per kg per hr and 1 U per kg per hr. A decrease of 30% in t he number of nonrhythmic type I waves by the first dose and 40% by the latter was observed in both duodenum and jejunum. There were no side effects from secretin administration in t his group of subjects.
DUODENUM
JEJUNUM
r::J .9 '4 No Cl ( ) '4 Of INHIBITION ~ SECRETIN 2u/Kg/hr • p< .005
FIG. 3. Effect of secretin on the mean number of nonrhythmic type I waves studied in 7 subjects.
July 1974
39
CCK AND SECRETIN IN HUMAN SMALL INTESTINE
The motor activity of the duodenum and jejunum affected by the interactions between CCK and secretin. Twelve subjects were studied. Two were given a prolonged infusion of secretin, 5 were given a background infusion of secretin and graded doses of CCK, and 5 were given CCK first and CCK plus secretin in a second experiment. In order to minimize the variations in the basal or "spontaneous" motor activity observed during the intravenous infusion of 0.9% sodium chloride solution, the inhibitory effect of secretin during prolonged intravenous infusion was studied in 2 subjects. Secretin was administered for 90 min at the rate of 2 U per kg per hr. The inhibitory effect of secretin on the motor activity was maintained throughout the entire infusion period, and almost a complete inhibition of the motor activity occurred in both duodenum and jejunum. As shown in figure 1, the administration of CCK in the dose of 2 U per kg per hr resulted in a significant increase in the motor activity influenced by secretin. The results obtained from the 5 subjects studied are summarized in figure 4. The mean number of nonrhythmic type I waves increased from 2.4 to 32.4 in the duodenum (P < 0.005) and from 1.0 to 48.2 in the jejunum (P < 0.005). The amplitude index increased from 36 to 314 in the duodenum (P < 0.005) and from 10 to 618 in the jejunum (P < 0.005). The percentage of
motor activity increased also from 0.9% to 12.4% (P < 0.005) in the duodenum, and from 0.2% to 19.7% (P < 0.005) in the jejunum. As the dose was increased to 4 U per kg per hr, the motor activity increased further in all of the parameters measured. During the simultaneous infusion of CCK and secretin, rhythmic type I waves were not observed at any time. Moreover, type III waves were not seen when CCK was given at the dose of 2 U per kg per hr and were present in only 2 subjects at the dose of 4 U per kg per hr. Five additional subjects were studied to determine the inhibitory effect of secretin on CCKstimulated motor activity of duodenum and jejunum. Each subject was studied on 2 consecutive days. Special efforts were made to select the subjects who had similar basal motor activity on both days. The 1st day after a control period of 30 min, CCK was administered for 30 min in the dose of 2 U per kg per hr each. The addition of secretin to the solution containing CCK resulted in a significantly less stimulatory effect by CCK (fig. 5), indicating that secretin inhibited the CCK-stimulated motor activity of the small intestine. Discussion Our results indicate that the continuous intravenous infusion of CCK stimulates the nonrhythmic type I activity. A clear trend of increase in type III waves was noted, particularly after the administration of CCK in higher doses; however, this DUODENUM
es~ l't5~
~~
~~ ~~
~~ FIG. 4. Effect of cholecystokinin (CCK) on the
motor activity inhibited by secretin studied in 5 subjects. Control represents the " spontaneous" motor activity during the intravenous infusion of 0.9% NaCl solution. Secretin infusion (2 U per kg per hr) was maintained throughout the experiment.
80 70 60 50 4()
30 20 10 0
f &
JEJUNUM CCK AlONE
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FIG. 5. Inhibitory effect of secretin on cholecystokinin- (CCK) stimulated nonrhythmic type I waves studied in 5 subjects .
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GUTIERREZ ET AL.
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was not statistically significant. The rhyth- stimulation of certain types of waves such mic type I activity was observed in 10% of as nonrhythmic type I, may suggest that the total motor activity recorded during the stimulatory effects of CCK at this dose the control periods in this study, but was level could be physiological. reported to occur in less than 2% by We have also shown that secretin inhibothers. 11 Rhythmic type I activity was its the nonrhythmic type I waves and type never observed during CCK infusion sug- III waves. The effect of secretin on the gesting that this hormone preparation rhythmic type I activity was not quite clear abolishes this type of activity. from these studies, since this type of activIt was interesting to observe that , during ity is rather infrequent in the control experthe infusion of CCK at the dose of 4 U per iments. Although we did not have enough kg per hr, some sets of waves occurred at a number of subjects studied during the rate up to 14 per min which exceed clearly infusion of secretin in doses of 0.5 and 1 U the basic electrical rhythm of 11 per per kg per hr, the trend of response seemed minute. 9 Since we did not measure the to be similar to that obtained with 2 U per electric activity of the smooth muscle in kg per hr. That is to say, it inhibited the the upper small bowel simultaneously with nonrhythmic type I waves. The inhibitory the recording of the intraluminal pressure effect of secretin given by slow intravenous changes, we do not know if the rate of "slow infusion is in agreement with the results waves" ( 11 per min) is increased by the observed during intravenous bolus infecinfusion of large doses of CCK. However, tion of secretin (1 U per kg) during which this could be a reasonable explanation the activity of the duodenum was inhibited enough to obtain hypotonic since it has been shown that pentagastrin long increases the freq~ency of antral electrical duodenograms. 19 We have also shown in a waves in man 12 and duodenal basal electri- cineradiographic study 19 that these two cal rhythm in dogs. 1 3 When CCK was given hormones interact with each other. We at the rate of 1 and 2 U per kg per hr, observed that the motor activity of the however, the highest number of waves small bowel stimulated by CCK was inhibrecorded in 1 min did not exceed 12 at any ited by secretin and the motor activity time. inhibited by secretin was stimulated by In previous studies we have demon- CCK . Similar conclusions have been strated that the administration of CCK in reached in the present study. a dose of 1 U per kg as an intravenous CCK produces propulsive activity when bolus, stimulates the motility of the small given as an intravenous bolus of 1 U per kg bowel and decreases significantly the intes- of body weight. 14 - 17 Although the type III tinal transit time 14 corroborating earlier waves are observed more frequently by the observations by other investigators. 1 5 - 17 administration of CCK at a rate of 2 or 4 U However, those experiments are very likely per kg per hr, CCK at a rate of 1.0 U per kg not physiological since the blood level of per hr stimulates only the nonrhythmic such hormones after intravenous bolus in- type I waves that have been known to be fusions may reach concentrations not seen associated with mixing. 20 When CCK and in various physiological states. In our pre- secretin are given simultaneously (2 U per liminary studies with secretin, the blood kg per hr) the type III waves are not level of radioimmunoassayable secretin observed and the only type of activity reaches more than 5 ng per ml of serum present is the nonrhythmic type I waves. immediately after the intravenous ad- Under these circumstances only the mixministration of secretin in a dose of 1 U per ing activity of the bowel would be facilikg as a bolus. 18 Hormonal blood levels of tated when these two hormones interact this magnitude have not been observed in with each other. We are aware that prophysiological experiments in man. 18 The pulsion can occur in the absence of type III demonstration in these studies that a dose waves. 21 • 22 However, the organized sequenas small as 1 U per kg per hr, produces tial timing of type I waves that can cause
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CCK AND SECRETIN IN HUMAN SMALL INTESTINE
propulsion 21 are not seen during the simultaneous infusion of CCK and secretin. The stimulatory effect of CCK on the motor activity of the small bowel in man is in agreement with the observed stimulation of duodenal and jejunal motor activity by the C-terminal octapeptide of CCK in dogs. 23 The observations in this study that small doses of CCK and secretin have definite effects on the small bowel motor activity suggest strongly that these hormones may participate in the autoregulation of small bowel motility in man. REFERENCES 1. Jung FT, Greengard H: Response of the isolated
2.
3.
4.
5.
6.
7.
8.
9.
gall bladder to cholecystokinin. Am J Physiol 103:275-278, 1933 Sandblom PH, Voegtlin WL, Ivy AC: The effect of cholecystokinin on the choledocho-duodenal mechanism (sphincter of Oddi). Am J Physiol 113:1 75- 180, 1935 Dahlgren S: Cholecystokinin: pharmacology and clinical use. Acta Chir Scand (Suppl) 357:256-260, 1966 Hedner P, Persson H, Rorsman G: Effect of cholecystokinin on small intestine. Acta Physiol Scand 70:250- 254, 1967 Dinoso V Jr, Chey WY, Hendricks J , et al: Intestinal mucosal hormones and motor function of the stomach in man . J Appl Physiol 26:326-329, 1969 Chey WY, Kosay S , Hendricks Jet a!: Effect of secretin on motor activity of sto mach and Heidenhain pouch in dogs . Am J Phys iol 217:848-852, 1969 Chey WY, Lorber SH, Kusackcioglu 0, et a!: Effect of secretin and pancreozymin-cholecystokinin on motor function of the stomach and duodenum (abstr). Fed Proc 26:383, 1967 Templeton ED , Lawson H: Studies in the motor activity of the large intestine; I. Normal motility in the dog, recorded by the Tandem balloon method. Am J Physiol 96 :667-676, 1931 Foulk WT, Code CF, Morlock CG, et a!: A study of the motility patterns and the basic rhythm in the duodenum and upper part of the jejunum of human beings. Gastroenterology 26:601-611 , 1954
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10. Fink S: The intraluminal pressures in the intact human intestine. Gastroenterology 36:661-671 , 1959 11. Friedman G, Waye JD , Weingarten L, eta!: The patterns of simultaneous intraluminal pressure changes in the human proximal small intestine. Gastroenterology 47:258- 268, 1964 12. Kwong NK, Brown BH, Whittaker GE , et a!: Response of the electrical activity, motor activity and acid secretion of the human sto mach to pentagastrin and histamine stimulation. Scand J Gastroenterol 6:145- 153, 1971 13. Cooke AR, Chvasta TE, Weisbrodt NW: Effect of pentagastrin on emptying and electrical and motor activity of the dog stomach. Am J Physiol 223:934- 938, 1972 14. Gutierrez JG , Chey WY, Dinoso V Jr, et al: Effect of intestinal hormones on motor function of the small bowel and sigmoid colon in man (abstr). Gastroenterology 60:672, 1971 15. Monod ME: Action enterokinetique de Ia cecekine. Arch Fr Mal App Dig 53:607- 608, 1964 16. Morin G , Besa ncon F, Grall A, et a!: Technique d'acceleration du transit du grele. Arch Fr Mal App Dig 54:1285-1290, 1965 17. Parker JG, Beneventano TC: Acceleration of small bowel contrast study by cholecystokinin, Gastroenterology 58:679- 684, 1970 18. Boehm M, Oliai A, Chey WY: The production of specific anti-secretin sera at its use in the radioimmunoassay of secretin (abstr). Gastroenterology 64:703, 1973 19. Chey WY, Woloshin HG, Gutierrez Jet a!: Use of cholecystokinin and secretin for radiographic examination of the small intestine (abstr). Gastroenterology 62:672, 1972 20. Ramorino ML, Colagrande C: Intestinal motility preliminary studies with telemetering capsules and synchronized fluorocinematography. Am J Dig Dis 9:64- 71 , 1964 21. Tasaka K, Farrar JT: Mechanics of small bowel movements in the unanesthetized dog (abstr). Clin Res 14:50, 1966 22. Ritchie JA, Salem SN: Upper intestinal motility in ulcerative colitis, idiopathic steatorrhea and the irritable colon syndrome. Gut 6:325- 337, 1965 23. Chey WY, Gutierrez JG, Yoshimori M , eta!: Gut hormones on gastrointestinal motor functions. Endocrinology of the Gut. Edited by WY Chey and FP Brooks. Thorofare NJ, CB Slack Inc, 1974, p 194- 211
Vo l. 67. No. I Print ed in U.S .A.
Copyr i~ht
ACTIONS OF CHOLECYSTOKININ AND SECRETIN ON THE MOTOR ACTIVITY OF THE SMALL INTESTINE IN MAN JoRGE
G. G uTIERREz, M.D ., WILLIAM Y. CHEY, M.D. , AND VINCENT P. DINos o , M.D .
The Isaac Gordon Center for Digestive Diseases, and Department of Medicine, The Genesee Hospital: University of Rochester S chool of Medicin e and Dentistry, Rochester, New York; and Temple University H ealth Sciences Center, Philadelphia. Pennsylvania
Using an intraluminal pressure recording technique, we studied the actions of cholecystokinin and secretin on the motor activity of the upper small intestine in 24 healthy subjects. We showed that the "basal" motor activity of duodenum and jejunum was stimulated by cholecystokinin ( CCK). In doses of 1, 2, and 4 U per kg per hr, CCK stimulated the nonrhythmic type I waves. Secretin, on the other hand, i1;hibited the nonrhythmic type I and type III waves. The interactions of these two hormones showed that the CCK -stimulated upper intestinal motility was inhibited by secretin, and that the secretininhibited motility was stimulated by CCK. This study indicates that both CCK and secretin can play an important role on the autoregulation of intestinal motor function in man. ity of the stomach in man 5 and dogs, 6 and also decreases duodenal motility in man .7 The purpose of this study was to determine the actions and interactions of pure preparations of CCK and secretin (Gastrointestinal Hormone, Karolinska Institutet, Sweden) on the motor activity of the small bowel in man .
In recent years, there have been increasing interests in studying the effects of various gastrointestinal hormones on the motor function of the alimentary tract. In 1933, Jung and Greengard, 1 showed that a crude preparation of cholecystokinin (CCK) caused contraction ofthe guinea pig ileum in vitro, and Sandblom et al. 2 reported that it increased duodenal motor activity in in vivo experiments in anesthe tized dogs. Using highly pure CCK preparations made by Jorpes and Mutt, similar observations were made by Dahlgren 3 in 1966 in vivo in dogs , and in 1967 by Bedner et al. 4 in vitro, and it was thus concluded that these effects were due to the hormone itself. In 1969, it was reported that Jorpes and Mutt secretin inhibits the motor activ-
Materials and Methods Thirteen female and 11 male healthy volunteers , of ages ranging from 20 to 60 years, with no evidence of an organic gastrointestinal disease, participated in this study . All subjects were properly informed of the nature of this invest igation and voluntarily consen ted to participate in it. The motor activity was studied with an intraluminal pressure record ing t echnique . After an overnight fast, a two-lumen tube was passed orally, and the tip was placed in the upper jejunum under fluoroscopic observation. The tube was made of two silas tic catheters. The distal 20 em of one of the catheters was filled with mercury, and the tip was sealed with a solid metal olive with a transverse diamet er of 2 mm. Each catheter h ad an internal diameter of 1.6 mm , and a s ide opening of 1.0 by 2.0 mm. The distance between the two
Received July 24, 1973. Accepted December 31, 1973. Presented in part at the Resea rch Forum at the Annual Meet ing of the American Gast roenterologial Association, May, 1971. Address requests for reprin ts to: Dr . Jorge G. Gutierrez, 224 Alexander Street, Rochester, New York 14607.
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36
GUTIERREZ ET AL.
openings was 2.5 em. The distal opening was located a pproximatel y :20 em distal to the liga m ent of Treit z. and the proxim al opening was in the third portion of the duod enum. The position of the tube was checked f1uoroscopically at the beginning a nd at th e end of each experiment. The catheters were continuously perfused with demin eralized water at a rate of 0 .2 1 ml per min. Thi s rate of infusion was chosen from five different rat es : 0.04. 0.10. 0.21. 0.41 , and 0. 58 ml per min. whi ch were studi ed in 2 subj ec ts . For this purpose, two catheters with openings at the same level were used. Each infusion rate was kept consta nt in one of the cat hete rs, and was match ed against increasingly graded rates of infusion in th e other cat heter. The infusion rates of 0. 10 and 0.:21 ml per min gave as good recordings as the highest infus ion rate tested , 0.58 ml per min. and could b e kept lor long periods without inducing bowel activity. The intraluminal press ure changes were measured with Statham P-2:3 8 transducers (Statham Inst rumen ts. Los Angeles, Ca lif. ). and recorded on a Polyviso reco rder equipped with strain gauge amplifiers (Sanborn , Cambridge, Mass.) Respirations were recorded with a sta ndard pneumograph. After the cat h eters were properly positioned , the subjects were asked to rema in in the supin e pos iti on for the duration of the experiment. At least a 10-min period was allowed for sta bilizati on of the recording. This was followed by a 20-min period durin g which a 0.9% sod ium chlorid e solution was admin istered intra ve nously at a rat e of 0.299 ml per min , and t he motor activity was recorded as an index of the " basal" motor activity. At the end of the 20-min period , a hormonal preparation dissolved in 0.9% sodium chloride solution was administered through the sa me infusion set, and, again , 10 min were allowed for stabilization , and 20 min for the recording of the hormon al effect. Both porcine secretin and CCK employed in this investigation were s upplied by Jorpes and Mutt, Karolins ka Institutet, Sweden , during 1970 and 1971. It has been claimed that this secretin preparation has more than 90% purity and possesses 4000 clinical units per mg. This CCK preparation has approximately 10% purity and possesses 3000 Ivy dog units per mg. The CCK preparation does not contain mot ilin. In order to study the effects of the two hormones on spontaneous motor activity , the rates of infusion employed were 1 and 2 U per kg per hr for secretin , and 1, 2, and 4 U per kg per hr for CCK. The experiment using each dose of an individual hormonal preparation was always preceeded and followed by the administration of
Vol. 67, No. I
0.9% sodium chloride solut ion for a period of 30 min. T o study the interactions of these hormones two different experiments were performed. In one experiment, secretin was infused at a constant rat e of 2 U per kg per hr throughout the study, and CCK at increasing rates of 2 and 4 U per kg per hr. In a second experiment, aft er a cont rol period of :30 min with 0.9% sodium chloride solution. CCK was administered at the rate of2 U per kg per hr and compared with the simultaneous administra tion of CCK and secretin at the rate of 2 U per kg per hr each in a subsequent day. The number of subjects studied in each experimental condition is mentioned with the res ults. For the anal ys is of the motor recording. we have adopted the class ification that Templeton and Lawson 8 used to describe the motility of the colon in dogs and defined further by others.•· '' For purposes of clarity we think it is necessary to review these definitions : ty pe I waves are single waves whi ch occur sin gly or in multipl e bursts of va ri a ble duration. The duration of each individual wave varies from 2 to 12 sec and the amplitude from 6 to 50 em of water. T y pe I waves occur in rhy thmic and nonrhythmi c patterns. The nonrhyt hmic or irregular patt e rn is seen more commonly than the rhyt hmi c type. Rhythmic type I waves consist of a sequence of waves of similar amplitude, morphology. and duration that occur in sets of 10 to 12 per min (usua lly at the rate of 11 per min) . The pattern was classified as rhythmic only when this repetition of nearly identical waves were present for at least a period of 1 min , and when successive waves showed variations less than 3 em of water in base line pressure .• Nonrhythm ic type I waves consist of a single wave or bursts of waves of different morphology , amplitude , and durations , and the frequency of waves per minute varied from 1 to 14. Type II wave is a wave norm ally seen only in the stomach. Type III wave consisted of a gradual elevation of the base line of no less than 6 em of water pressure and a duration of 15 sec to several minutes. T y pe I activity is almost always superimposed in this type of wave. The fo llowing parameters were meas ured for both rhythmic and nonrhythmic patterns : (1) number of waves per 20-m in periods; (2) amplitude index (sum of the amplitude of a ll of the waves per 20-min periods, and (3) percenta ge of activity (sum of duration of individual waves in seconds/total duration of test period in seconds x 100). The end-expiratory resting pressure was taken as the zero point. The respiratory def1ections had an average of 4 em of water and artifacts like those caused by minor increases in
July 1974
CCK AND SECRETIN IN HUMAN SMALL INTESTINE
intraabdom inal pressure generally did not exceed 6 em of water. For this reason, waves ofless tha n 6 em of water were not counted . Although we recogn ize that some true waves resulting from sma ll bowel motor activity were eliminated in t his fashion, we found this was necessary in ord er to co mpensate for respiratory interference and to eliminate some a rt ifacts . For the statistical analysis , Student's t-test for paired data was employed .
Results The effect of CCK on the spontaneous motor activity of the duod enum and upper jejunum. Five subjects were studied . The nonrhythmic type I waves increased significantly during the intravenous administration of CCK in comparison with those observed during the control period (fig. 1). During the administration of CCK in the dose of 1 U per kg per hr, the mean number of waves increased from 25.6 in a 20-min period to 40.6 (58.6%) in the duodenum, and from 16.8 to 48.0 (185.7%) in the jejunum (fig . 2A). The amplitude index increased from 261 to 415 (59%) in the
37
duodenum, and from 232 to 598 (157.5%) in the jejun urn (fig. 2B). The percentage of activity also increased from 9.9% to 15.1% (52.5%) in the duodenum, and from 5.6% to 15.2% (171.4%) in the jejunum (fig. 2C). These changes are statistically significant (P < 0.05). As the dose of CCK was increased to 2 and 4 U per kg per hr, the values of all the parameters studied increased (fig. 2, A, B , and C). The rhythmic type I wave was an inconsistent finding in the control period (less than 10% in all records) and was never observed during CCK infusion. The mean number of type III waves increased from 0.2 in the control period to 0.2, 1.4, and 2.2 in the duodenum , and from 0.4 to 0.8, 3.2, and 4.2 in the jejunum when CCK was given in doses of 1, 2, and 4 U per kg per hr, respectively . The percentage of activity increased also from 0.4 to 0.8, 5.8%, and 6.6% in the duodenum , and 0.8 to 3.6, 7.7, and 14.4% in the jejunum, as CCK was given at a rate of 1, 2, and 4 U per kg per hr, respectively . A trend of increase in type III wave activity was
' '""10
~ l ~;.liN£ ,.,.
(!M .....
I!'I ~If<~ICI' t...g l~-~ . .
A ... A A.
c - ~~------_y ·~--~~--~~--~ ~WWJ~~v· · ~
f"'"JO
::l:h·J:_)L-J~~)~-.,~~ ~
t
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:;l"> 0 ~~ ~!OWN ' "'''-'UI!
2,./ Kg/ N
~tt
•
FIG. 1. An example of in traluminal pressure recordings in the upper jejunum showing t he actions of cholecystokin in ( CC K ) and secretin on the spontaneous motor activity and interactions of t hese two hormones. Each lin e represents a different subject.
Vol . 67, No . 1
GUTIERREZ ET AL.
38
~
A .9'1.NaCI
~ C:S
100 80 t;ls~ 60 ~~ ;:s~ < t;ls 40 <:<>..: 20
.........---...
CCK u / Kg /hr
• p
~ ~
0
1u
0
B.. 9'X.NaCI
~
~ "' ~~ ;§ ~
~f:\::
2u
4u
CCK u/Kg/hr
mod.• p <.05 • p
800
<.01
600
"'{~ 400
<
200
~
0
~
0
c. >....
~ >::::;::::
~~
C:S~ ~~
:::::<>..: ~ ~
50 40
.9%NaCI .........---...
lu
2u
CCK u/Kg/hr
.. (J)
• p
30 20 10 0
4u
, (D)
0
1u
2u
4u
FIG . 2. A , Effects of cholecystokinin (CCK) on t he mean number of nonrhyt h mic type I waves per 20 min in the duodenum (D) and jejunum (J) in 5 subjects . II = ±SE. B, effect of CCK on the mean amplitude index per 20 min in the duodenum and jejunum in 5 subjects. I = ± SE. C, effect of CCK in the mean percentage of activity per 20 min in t he duodenum a nd jejunum in 5 subjects. II = ± SE.
noted after the adm inistration of CCK, b ut t he differences were not significant. CCK at the dose of 1 U per kg per hr did not cause any side effects. With the dose of 2 U per kg per hr, 2 subjects complained of mild abdominal cramps, and when t h e dose was increased to 4 U per kg per hr, all 5 subjects complained of mild to moderately severe abdominal cramps. One sub ject also had sweating. None of our subjects
developed nausea, vom it ing, fainting, or other untoward effects . The effect of secretin on spontaneous m otor activity of th e duoden um and upper jejunum. The effect of t he continuous intravenous infus ion of sec retin at the rate of 2 U per kg per h r was studied in 7 subjects. The nonrhythmic type I act ivity was significantly in h ibited in both the duodenum and jejunum (fig. 1). The results of the studies in these 7 subjects are summarized in figure 3. The administration of secretin resulted in 83% inhibition (P < 0.005) in t he mean number of nonrhythmic type I waves in the duoden um an d 86% (P < 0.005) in t h e jejunum . T he amplitude index decreased by 84% in t he duoden um (P < 0.01) and by 84% in the jejunum (P < 0.01) . The percentage of activity decreased from 12.9 to 1.9% in t he duodenum (P < 0 .005), and from 9.5 to 1% in the jejunum (P < 0 .01). Rhythmic type I activity occurred in about 10% of t he subjects during the control period, and in about 30% of t he subjects during secretin infusion; however t he difference was not significant. Type III waves were never observed during secretin infusion. Two additional subjects were studied with secretin in doses of 0 .5 U per kg per hr and 1 U per kg per hr. A decrease of 30% in t he number of nonrhythmic type I waves by the first dose and 40% by the latter was observed in both duodenum and jejunum. There were no side effects from secretin administration in t his group of subjects.
DUODENUM
JEJUNUM
r::J .9 '4 No Cl ( ) '4 Of INHIBITION ~ SECRETIN 2u/Kg/hr • p< .005
FIG. 3. Effect of secretin on the mean number of nonrhythmic type I waves studied in 7 subjects.
July 1974
39
CCK AND SECRETIN IN HUMAN SMALL INTESTINE
The motor activity of the duodenum and jejunum affected by the interactions between CCK and secretin. Twelve subjects were studied. Two were given a prolonged infusion of secretin, 5 were given a background infusion of secretin and graded doses of CCK, and 5 were given CCK first and CCK plus secretin in a second experiment. In order to minimize the variations in the basal or "spontaneous" motor activity observed during the intravenous infusion of 0.9% sodium chloride solution, the inhibitory effect of secretin during prolonged intravenous infusion was studied in 2 subjects. Secretin was administered for 90 min at the rate of 2 U per kg per hr. The inhibitory effect of secretin on the motor activity was maintained throughout the entire infusion period, and almost a complete inhibition of the motor activity occurred in both duodenum and jejunum. As shown in figure 1, the administration of CCK in the dose of 2 U per kg per hr resulted in a significant increase in the motor activity influenced by secretin. The results obtained from the 5 subjects studied are summarized in figure 4. The mean number of nonrhythmic type I waves increased from 2.4 to 32.4 in the duodenum (P < 0.005) and from 1.0 to 48.2 in the jejunum (P < 0.005). The amplitude index increased from 36 to 314 in the duodenum (P < 0.005) and from 10 to 618 in the jejunum (P < 0.005). The percentage of
motor activity increased also from 0.9% to 12.4% (P < 0.005) in the duodenum, and from 0.2% to 19.7% (P < 0.005) in the jejunum. As the dose was increased to 4 U per kg per hr, the motor activity increased further in all of the parameters measured. During the simultaneous infusion of CCK and secretin, rhythmic type I waves were not observed at any time. Moreover, type III waves were not seen when CCK was given at the dose of 2 U per kg per hr and were present in only 2 subjects at the dose of 4 U per kg per hr. Five additional subjects were studied to determine the inhibitory effect of secretin on CCKstimulated motor activity of duodenum and jejunum. Each subject was studied on 2 consecutive days. Special efforts were made to select the subjects who had similar basal motor activity on both days. The 1st day after a control period of 30 min, CCK was administered for 30 min in the dose of 2 U per kg per hr each. The addition of secretin to the solution containing CCK resulted in a significantly less stimulatory effect by CCK (fig. 5), indicating that secretin inhibited the CCK-stimulated motor activity of the small intestine. Discussion Our results indicate that the continuous intravenous infusion of CCK stimulates the nonrhythmic type I activity. A clear trend of increase in type III waves was noted, particularly after the administration of CCK in higher doses; however, this DUODENUM
es~ l't5~
~~
~~ ~~
~~ FIG. 4. Effect of cholecystokinin (CCK) on the
motor activity inhibited by secretin studied in 5 subjects. Control represents the " spontaneous" motor activity during the intravenous infusion of 0.9% NaCl solution. Secretin infusion (2 U per kg per hr) was maintained throughout the experiment.
80 70 60 50 4()
30 20 10 0
f &
JEJUNUM CCK AlONE
"p< 05
i"'
AlONE
• CCK • SECRETIN 2v/Kg/hr
CCK • SECRETIN 2u/Kg/hr
&
6-~ '\~
\:;~()j
FIG. 5. Inhibitory effect of secretin on cholecystokinin- (CCK) stimulated nonrhythmic type I waves studied in 5 subjects .
40
GUTIERREZ ET AL.
Vol. 67, No. I
was not statistically significant. The rhyth- stimulation of certain types of waves such mic type I activity was observed in 10% of as nonrhythmic type I, may suggest that the total motor activity recorded during the stimulatory effects of CCK at this dose the control periods in this study, but was level could be physiological. reported to occur in less than 2% by We have also shown that secretin inhibothers. 11 Rhythmic type I activity was its the nonrhythmic type I waves and type never observed during CCK infusion sug- III waves. The effect of secretin on the gesting that this hormone preparation rhythmic type I activity was not quite clear abolishes this type of activity. from these studies, since this type of activIt was interesting to observe that , during ity is rather infrequent in the control experthe infusion of CCK at the dose of 4 U per iments. Although we did not have enough kg per hr, some sets of waves occurred at a number of subjects studied during the rate up to 14 per min which exceed clearly infusion of secretin in doses of 0.5 and 1 U the basic electrical rhythm of 11 per per kg per hr, the trend of response seemed minute. 9 Since we did not measure the to be similar to that obtained with 2 U per electric activity of the smooth muscle in kg per hr. That is to say, it inhibited the the upper small bowel simultaneously with nonrhythmic type I waves. The inhibitory the recording of the intraluminal pressure effect of secretin given by slow intravenous changes, we do not know if the rate of "slow infusion is in agreement with the results waves" ( 11 per min) is increased by the observed during intravenous bolus infecinfusion of large doses of CCK. However, tion of secretin (1 U per kg) during which this could be a reasonable explanation the activity of the duodenum was inhibited enough to obtain hypotonic since it has been shown that pentagastrin long increases the freq~ency of antral electrical duodenograms. 19 We have also shown in a waves in man 12 and duodenal basal electri- cineradiographic study 19 that these two cal rhythm in dogs. 1 3 When CCK was given hormones interact with each other. We at the rate of 1 and 2 U per kg per hr, observed that the motor activity of the however, the highest number of waves small bowel stimulated by CCK was inhibrecorded in 1 min did not exceed 12 at any ited by secretin and the motor activity time. inhibited by secretin was stimulated by In previous studies we have demon- CCK . Similar conclusions have been strated that the administration of CCK in reached in the present study. a dose of 1 U per kg as an intravenous CCK produces propulsive activity when bolus, stimulates the motility of the small given as an intravenous bolus of 1 U per kg bowel and decreases significantly the intes- of body weight. 14 - 17 Although the type III tinal transit time 14 corroborating earlier waves are observed more frequently by the observations by other investigators. 1 5 - 17 administration of CCK at a rate of 2 or 4 U However, those experiments are very likely per kg per hr, CCK at a rate of 1.0 U per kg not physiological since the blood level of per hr stimulates only the nonrhythmic such hormones after intravenous bolus in- type I waves that have been known to be fusions may reach concentrations not seen associated with mixing. 20 When CCK and in various physiological states. In our pre- secretin are given simultaneously (2 U per liminary studies with secretin, the blood kg per hr) the type III waves are not level of radioimmunoassayable secretin observed and the only type of activity reaches more than 5 ng per ml of serum present is the nonrhythmic type I waves. immediately after the intravenous ad- Under these circumstances only the mixministration of secretin in a dose of 1 U per ing activity of the bowel would be facilikg as a bolus. 18 Hormonal blood levels of tated when these two hormones interact this magnitude have not been observed in with each other. We are aware that prophysiological experiments in man. 18 The pulsion can occur in the absence of type III demonstration in these studies that a dose waves. 21 • 22 However, the organized sequenas small as 1 U per kg per hr, produces tial timing of type I waves that can cause
July 1974
CCK AND SECRETIN IN HUMAN SMALL INTESTINE
propulsion 21 are not seen during the simultaneous infusion of CCK and secretin. The stimulatory effect of CCK on the motor activity of the small bowel in man is in agreement with the observed stimulation of duodenal and jejunal motor activity by the C-terminal octapeptide of CCK in dogs. 23 The observations in this study that small doses of CCK and secretin have definite effects on the small bowel motor activity suggest strongly that these hormones may participate in the autoregulation of small bowel motility in man. REFERENCES 1. Jung FT, Greengard H: Response of the isolated
2.
3.
4.
5.
6.
7.
8.
9.
gall bladder to cholecystokinin. Am J Physiol 103:275-278, 1933 Sandblom PH, Voegtlin WL, Ivy AC: The effect of cholecystokinin on the choledocho-duodenal mechanism (sphincter of Oddi). Am J Physiol 113:1 75- 180, 1935 Dahlgren S: Cholecystokinin: pharmacology and clinical use. Acta Chir Scand (Suppl) 357:256-260, 1966 Hedner P, Persson H, Rorsman G: Effect of cholecystokinin on small intestine. Acta Physiol Scand 70:250- 254, 1967 Dinoso V Jr, Chey WY, Hendricks J , et al: Intestinal mucosal hormones and motor function of the stomach in man . J Appl Physiol 26:326-329, 1969 Chey WY, Kosay S , Hendricks Jet a!: Effect of secretin on motor activity of sto mach and Heidenhain pouch in dogs . Am J Phys iol 217:848-852, 1969 Chey WY, Lorber SH, Kusackcioglu 0, et a!: Effect of secretin and pancreozymin-cholecystokinin on motor function of the stomach and duodenum (abstr). Fed Proc 26:383, 1967 Templeton ED , Lawson H: Studies in the motor activity of the large intestine; I. Normal motility in the dog, recorded by the Tandem balloon method. Am J Physiol 96 :667-676, 1931 Foulk WT, Code CF, Morlock CG, et a!: A study of the motility patterns and the basic rhythm in the duodenum and upper part of the jejunum of human beings. Gastroenterology 26:601-611 , 1954
41
10. Fink S: The intraluminal pressures in the intact human intestine. Gastroenterology 36:661-671 , 1959 11. Friedman G, Waye JD , Weingarten L, eta!: The patterns of simultaneous intraluminal pressure changes in the human proximal small intestine. Gastroenterology 47:258- 268, 1964 12. Kwong NK, Brown BH, Whittaker GE , et a!: Response of the electrical activity, motor activity and acid secretion of the human sto mach to pentagastrin and histamine stimulation. Scand J Gastroenterol 6:145- 153, 1971 13. Cooke AR, Chvasta TE, Weisbrodt NW: Effect of pentagastrin on emptying and electrical and motor activity of the dog stomach. Am J Physiol 223:934- 938, 1972 14. Gutierrez JG , Chey WY, Dinoso V Jr, et al: Effect of intestinal hormones on motor function of the small bowel and sigmoid colon in man (abstr). Gastroenterology 60:672, 1971 15. Monod ME: Action enterokinetique de Ia cecekine. Arch Fr Mal App Dig 53:607- 608, 1964 16. Morin G , Besa ncon F, Grall A, et a!: Technique d'acceleration du transit du grele. Arch Fr Mal App Dig 54:1285-1290, 1965 17. Parker JG, Beneventano TC: Acceleration of small bowel contrast study by cholecystokinin, Gastroenterology 58:679- 684, 1970 18. Boehm M, Oliai A, Chey WY: The production of specific anti-secretin sera at its use in the radioimmunoassay of secretin (abstr). Gastroenterology 64:703, 1973 19. Chey WY, Woloshin HG, Gutierrez Jet a!: Use of cholecystokinin and secretin for radiographic examination of the small intestine (abstr). Gastroenterology 62:672, 1972 20. Ramorino ML, Colagrande C: Intestinal motility preliminary studies with telemetering capsules and synchronized fluorocinematography. Am J Dig Dis 9:64- 71 , 1964 21. Tasaka K, Farrar JT: Mechanics of small bowel movements in the unanesthetized dog (abstr). Clin Res 14:50, 1966 22. Ritchie JA, Salem SN: Upper intestinal motility in ulcerative colitis, idiopathic steatorrhea and the irritable colon syndrome. Gut 6:325- 337, 1965 23. Chey WY, Gutierrez JG, Yoshimori M , eta!: Gut hormones on gastrointestinal motor functions. Endocrinology of the Gut. Edited by WY Chey and FP Brooks. Thorofare NJ, CB Slack Inc, 1974, p 194- 211