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Motor Responses of the Sigmoid Colon and Rectum to Exogenous Cholecystokinin and Secretin
Vol. 65, No. 3
GASTHOENTEHOI.OC:Y 65: 438-444, 1973 Copyright © 1973 by The Willia ms & Wilkins Co.
Printed in U.S.A.
MOTOR RESPONSES OF THE SIGMOID COLON AND RECTUM TO EXOGENOUS CHOLECYSTOKININ AND SECRETIN VICENTE
P.
DINOSO, JR ., M.D ., HooSHA NG MESHKINPO UR, M.D., STANLEY H. LORBER
M . D .• JORGE G. GUTIERREZ, M.D .• AND WILLIAM
Y.
CHEY, M . D.
Department of Medicine , T emple University Health Sciences Center, Philadelphia, Pennsylvania
The effects of exogenous cholecystokinin (CCK) and secretin on motor activity of the sigmoid colon and rectum were studied in 10 subjects. CCK stimulated and secretin inhibited basal motor activity of the sigmoid. In addition, CCK-induced motor activity of the sigmoid colon was inhibited by secretin. Neither CCK nor secretin influenced motor activity of the rectum. During the past 8 years, secretin and cholecystokinin (CCK) have been shown to influence the motor activity ·of various segments of the gastrointestinal tract. Studies in man have revealed that both secretin and CCK inhibit antral motility of the stomach . 1 • 2 In addition, CCK stimulates and secretin inhibits motor activity of the small intestine. 3 - 7 Secretin, exogenously administered or endogenously released, decreases the pressure of the lower esophageal sphincter probably by competitive inhibition with gastrin. 8 In a preliminary communication, 7 it was suggested that these two hormones influence the motor activity of the sigmoid colon. The purpose of this study was to make observations on the effects of these hormones on motor activity of both sigmoid colon and rectum in a larger number of patients.
Materials and Methods Ten subjects, five males <1nd five females , ranging in age from 22 to 68 years (mean 41.2) Received January 22, 1973. Accepted April 15, 1973. Address· requests for reprints to: Dr. V. P . Dinoso, Jr., Gastrointestinal Section, Temple University, Health Sciences Center, 3400 Broad St., Philadelphia, Pennsylvania 19140. Dr. Gutierrez's and Dr. Chey's present address is: The Isaac Gordon Center for Digestive Diseases, The Genesee Hospital, and the University of Rochester School of Medicine and Dentistry, Rochester, New York. 438
without gastrointestinal disease or symptoms referable to the colon, were studied. Subjects were given a light liquid supper and were fasted overnight. The descending colon and rectum were cleansed with normal saline solution 2 hr before a study. Two no. 10 French, radioopaque, rubber tubes with an internal diameter of 1.5 mm were introduced via a proctosigmoidoscope 25 and 10 em from the anal verge and taped firmly close to the anus to avoid movement. For accurate localization, tubes were provided with open metal tips and their positions checked fluoroscopically before and after each experiment. Tube positions were found to be essentially unchanged at the end of the study period in all subjects. Studies were performed in a quiet room. Intraluminal pressure changes and respiration were recorded by a Sanborn Polyviso-Recorder. Normal saline solution was perfused through open-tipped rubber catheters at a rate of 4 ml per hr by means of a Correl and Carrel monodrum. Basal motor activity was recorded for 30 min during which time an intravenous infusion of normal saline solution was maintained. Cholecystokinin [Gastrointestinal Hormone Unit (GIH), Karolinska lnstitutet, Sweden] was administered intravenously in successive doses of 0.5 , 1.0, and 2.0 U per kg per hr by means of a Harvard infusion pump for 30 min each, with intervening rest periods of 30 min during which time the infusion of saline solution was continued . If basal motor activity of the sigmoid colon was active, secretin (GIH , Karolinska lnstitutet) in doses of 0.5, 1.0, and 2.0 U per kg per hr was infused intravenously in a similar manner and its effect on spontaneous motor activity of the sigmoid and rectum recorded. In
September 1973
MOTOR RESPONSES OF SIGMOID COLON AND RECTUM
a third set of studies on the same subjects, the influence of secretin on motor activity of the sigmoid colon stimulated by an intravenous infusion of 1 U of CCK per kg per hr was investigated. Two experiments were performed per subject for each dose employed in the CCK studies, and one experiment was performed for each dose employed in the secretin studies. The changes in motor activity of the sigmoid colon and rectum were quantitated by determining the number of waves, amplitude index (sum of the amplitude of all waves in centimeters of H 2 0) and percentage of motor activity (percentage of time occupied by waves) per 30 min of observation. All the records were analyzed by one observer (V. P. D.). To minimize error produced by the introduction of artifacts, waves having an amplitude of less than 2.5 em of H 2 0 were excluded from analysis. 9 Changes in the types of waves were not analyzed in detail in this study although reference to patterns or types, i.e., simple monophasic, repetitive or rhythmic , or complex waves is made under discussion according to the criteria and descriptions of Bloom et al. 9 and Connell. 10 In counting the number of waves during periods of complex wave activity, each peak was counted as a wave. To exclude the possibility that the recording system employed failed to detect motor waves or small changes in intrarectal pressure, concurrent recordings were made using both open-tip and balloon techniques . With the latter technique and the balloon inflated with 4 ml of air to a diameter of 1.5 em, the sensitivity of the two systems was approximately the same. In this report, therefore, data on the motor activity of the rectum were obtained solely by the open-tip technique . Student's t-test for paired data was used to analyze the significance of the difference of the means between the control period and each period of hormone administration.
439
during the control period and 10 min after the start of the intravenous infusion of 0.5, 1.0, and 2.0 U per kg per hr of CCK is demonstrated in figure 2. Secretin on spontaneous motor activity of the sigmoid colon. In contrast to the increased motor activity of the sigmoid colon observed during CCK infusion, administration of secretin produced a decrease in the number of wavesr amplitude index, and percentage of motor activity
MEAN NUMBER OF WAVES PER 30 MINUTES
500
MEAN AMPLITUDE INDEX PER 30 MINUTES (Cm H20)
Results MEAN Effect of CCK on spontaneous motor PERCENTAGE ACTIVITY PER activity of the sigmoid colon. Two experi30 MINUTES ments were performed per subject for each dose of CCK employed. An increase in all three parameters of motor activity was observed in response to the intravenous administration of CCK which was greater CCK u/ kg-hr with higher doses of the hormone (fig. 1). I ±S.E. • p <.05 ••• p < 005 This increase in motor activity was statistically significant at or above the starting FIG. 1. The effect of cholecystokinin (CCK) on dose of 0.5 U per kg per hr. An example of spontaneous motor activity of the sigmoid colon. the pattern of motor activity observed NSS, normal saline solution.
DINOS O ET AL.
440
Vol. 65 , No . 3
NSS INFUSION
CCK 0 . 5 u / ~g . hr
Cm
H 0 2 30- CCK 2 .0 u f ~g.hr
10-
RESPIRATION
I
I "'-._I MIN .
FIG. 2. An example of t he motor activity of the sigmoid colon during the intravenous infusion of cholecystokinin (CCK) in doses of 0.5, 1.0, and 2.0 U per kg per hr. NSS , norm al saline solut ion.
(fig. 3). The level of significance of the. differences of the means, for each dose employed compared with the control, is given in the figure. Secretin on motor activity of the sigmoid colon induced by CCK. After administering CCK by intravenous infusion in a dose of 1 U per kg per hr for 30 min , secretin was added to the infusion in doses of 0.5, 1.0, and 2.0 U per kg per hr while continuing the background infusion of CCK. As in the first two experiments a rest period of 30 min was allowed in between dose changes during which time normal saline solution was infused. The decrease in motor activity was statistically significant at the dose of 2 U per kg per hr of secretin only for all the parameters of measurement (fig. 4). An example of the inhibitory effect of CCKinduced motor activity of the sigmoid colon produced by secretin is demonstrated in figure 5. CCK and secretin on the motor activity of the rectum. A wide range of variation in
basal motor activity of the rectum was observed among the 10 subjects studied which resulted in a relatively large standard error of the means in the three parameters used. In contrast to the clear cut effects on basal motor activity of the sigmoid colon produced by the hormones, neither the intravenous administration of CCK nor secretin was observed to influence rectal motor activity (table 1). In an effort to determine if basal motor activity in the rectum influenced the potential for an inhibitory response to secretin, the data were analyzed further by segregating results from those subjects with low and those with high basal activity (table 1). No significant difference in response to secretin was observed between these two groups . Discussion Our findings demonstrate that motor activity of the sigmoid colon in man, as measured by intraluminal pressure
441
MOTOR RESPONSES OF SIGMOID COLON AND RECTUM
September 1973
changes, is stimulated by cholecystokinin and inhibited by secretin. The effects of these two hormones on motor activity are similar to those reported for the small intestine 7 but differ from those observed in the antrum in man in which both hormones were reported to inhibit spontaneous motor activity,'· 2 The possibility that subjects with low initial basal motor activity were predisposed to high motor activity and vice versa, and that the changes we observed were unrelated to the administration of the hormones is highly unlikely. We have recorded basal motor activity of both sigmoid colon and rectum for periods of 1 to 8 hr and observed that the initial pattern oflow or high motor activity was not influenced
70
MEAN NUMBER OF WAVES PER 30 MINUTES
MEAN AMPLITUDE INDEX PER 30 MINUTES (Cm H,O)
200
100 MEAN NUMBER OF WAV ES
PER 30 MINUTES
70
500
N.S. MEAN PERCENTAGE ACTIVITY PER 30 MINUTES
MEAN AMPliTUDE INDEX
PER 30 M INUTES (Cm H 20 )
LO
1.± S.E .
!<- SuE/~~~::: ---.1
N.S. NOT SIGNIFICANT ' p <.OS
N.S.
" p <.01
FIG. 4. The effect of secretin on motor activity of the sigmoid colon induced by cholecystokinin (CCK), 1 U per kg per hr.
MEAN
PERCENTAGE ACTIVITY
PER 30 MINUTES
NSS SECR ETIN u/ kg-hr
I ±s.E
N .S. NOT SIGN IFI CANT "' p
• p < .05
•• p <.01
<.OOS
FIG. 3. The effect of the secretin on spontaneous motor activity of the sigmoid colon . NSS, normal saline solution.
by the intravenous administration of normal saline. A similar observation has been reported by Connell. 10 The means for both spontaneous and CCK-induced motor activity of the sigmoid colon reveal partial inhibition only in response to the highest dose of secretin employed (2 U per kg per hr.) . However,
442
Vol. 65, No.3
DINOSO ET AL. X . A - 68 -m
S 1 u /k g.h•
t S 2 ufkg.h•
RESPIRATION
I
I ""'-...!MIN.
FIG. 5. An example of the inhibition of cholecystokinin ( CCK)~induced motor activity of the sigmoid by 1 and 2 U per kg per hr of secretin (S). Secretin was administered after 10 min of sustained motor activity. TABLE
1. Effect of cholecystokinin (CCK) and secretin on spontaneous motor activity of the rectum Experiment
No. of waves
Amplitude index
Activity
%
CCK in 10 subjects NSSa 0.5 ........ ... . . . . .. . ... . ... . . . . 1.0 ... . . . .... . .. . .. .. ............ . 2~
. . ............. . ........... ... .
Secretin in 6 subjects with low basal motor activity NSS 0.5 ......... . . ... .. .. ..... . ...... . 1.0 .............. .. ....... . ..... . . 2.0 .. . . . . ··· · ······ ··········· Secretin in 4 subjects with high basal motor activity NSS 0.5 .............. . .. ..... . .... . .. . 1.0 .. ..... . ................ . . . . . . . 2.0 ...... . .......... . .... . ..... . . a
12.88 14.25 10.38 20.75
±
25.40 24.50 35.40 29.00
±
81.75 88.67 83.25 75 .50
± ± ±
± ± ±
± ± ± ±
3.42 3.44 3.06 4.88
40.25 52.75 35.38 68.86
5.75 2.96 2.50 6.35
115.50 98.50 78.50 126.00
9 .81 21.86 17.61 15.33
409.25 ± 421.00 ± 433.50 ± 482.00 ±
± ± ± ±
± ± ± ±
11.86 15.04 10.28 16.06
13.90 ± 15.60 ± 12.20 ± 15 .67 ±
4.18 4.10 3.70 3.97
45.98 30.85 40.27 86.74
26.00 ± 18.60 ± 24.00 ± 26.00 ±
5.87 2.96 4.40 5.82
79.17 146.40 86 .76 93.29
88.33 96.00 93.00 97.33
6.69 1.00 3.00 1.45
± ± ± ±
NSS , normal saline solution.
differences in response were observed, and, in some instances, motor inhibition of basal or stimulated activity was complete. Such variations suggest that secretin may be a weak inhibitor of motor activity of the sigmoid colon and/or that responses to the hormone are dependent upon multiple factors. The highest level of motor activity in-
duced by 2 U per kg per hr of CCK (CCK experiments, fig. 1) was similar to the sustained motor activity of the sigmoid colon observed during the control period of the secretin experiments (fig. 3). This observation suggests that the sigmoid colon may have a maximal response to stimulation with CCK which does not increase further beyond that observed during pe-
Sept ember 1973
MOTOR RESPONSES OF SIGMOID COLON AND RECTUM
riods of heightened motor activity of the sigmoid colon. Indeed, in a few subjects, we administered 4 U per kg per hr of CCK intravenously and found no further increase in any of the parameters measured (unpublished observations). Since the blood concentrations of CCK in man are not measurable at present, it is difficult to know if the doses of hormone employed in this study were in the physiologic range. Recently, serum levels of secretin have been approximated to be 1 to 2 m U per mi. 11 Although blood levels of secretin produced by the intravenous administration of GIH secretin have not been determined in man, immunoreative secretin levels in 1 dog after injection of 1 U of GIH secretin per kg per 30 min into the portal vein ranged from 3 to 6 m U per ml (Dr. Gunther Boden, personal communication). This suggests that in our study, particularly when low doses of secretin were used, blood levels of secretin might have been near the physiologic range. The increase in the number of waves after the intravenous administration of CCK included all forms of waves such as simple monophasic, repetitive, and complex waves. 9 • 1 ° Conversely, during secretin administration, all forms of waves were diminished in number. Four subjects experienced lower abdominal cramps and flatulence during the infusion of 1 or 2 U per kg per hr of CCK. The reason for the development of these symptoms in these subjects and their absence in the other 6 was not apparent. Thaincreases in indices of motor activity in the subjects who experienced these symptoms were not markedly different from those who did not. Individual levels in sensitivity to colonic contractions or variations in luminal diameters might, in part, explain this observation. In contrast to the observations reported above the sigmoid colon, there was no significant or consistent change in basal motor activity of the rectum in response to the intravenous infusion of either CCK or secretin. This correlates well with the observation that none of the subjects developed an urge to defecate. We think that the
443
differences in the responses of the sigmoid colon and rectum to exogenous secretin and cholecystokinin are real rather than technical. As mentioned briefly under "Materials and Method," we recorded intrarectal pressures using both open-tip and balloon techniques (balloon inflated with 5 ml, diameter, 1.5 em) and found, as described in the text, identical changes in the three parameters of motor activity measured. Hill and co-workers 12 compared resting intrarectal pressures obtained by an open-tip unit, a differential transformer pressure transducer, and a 7- by 7-mm balloon and observed that the first two systems provided the most accurate measurements. Connell 10 employed miniature balloons with dimensions close to ours to measure motor activity in the rectum and obtained results almost identical to those we recorded with an open-tip system. Mean percentage of duration of motor activity for control subjects was 64.6% in his study and 65.6% in ours. The physiologic significance of these observations on motor activity of the sigmoid colon awaits demonstration of the effect of endogenously released CCK and secretin. Misiewicz et a!. 13 have observed that there is a postcibal increase in motor activity of the sigmoid colon and none in the rectum in subjects without colonic symptoms. They have presented some evidence that gastrin is probably not the hormone mediating these changes. 14 The possible role of CCK and secretin in the production of postcibal changes in motor activity of the sigmoid colon remains to be clarified. REFERENCES 1. Johnson LP, Brown JC, Magee DF: Effect of
2.
3. 4.
5.
secretin and cholecystokinin-pancreozymin extracts on gastric motility in man. Gut 7:52-57, 1966 Dinoso V, Chey WY, Hendricks J, et al : Intestinal mucosal hormones and motor function of the stomach in man. J Appl Physiol26:326-329, 1969 Monod E: Action entero-kinetique de Ia cecekin. Arch Mal Appl Dig 53:607-608, 1964 Morin G, Besancon F, Grall A, et al: Technique d'acceleration du grele. Arch Mal Appl Dig 54:1285-1290, 1965 Parker JG, Beneventano TC: Acceleration of
444
6.
7.
8.
9.
10.
DINOSO ET AL.
small bowel contrast study by cholecystokinin. Gastroenterology 58 :679- 684, 1970 Chey WY, Woloshin HG, Gutierrez JG, et al : Use of cholecystokinin and secretin for radiographic examination of the small intestine (abstr). Gastroenterology 62:733, 1972 Gutierrez JG, Chey WY, Dinoso V, eta! : Effect of intestinal hormones on motor function of the small bowel and sigmoid colon in man (abstr). Gastroenterology 60:672, 1971 Cohen S, Lipshutz W: Hormonal regulation of human lower esophageal sphincter competence: Interaction of gastrin and secretin. J Clin Invest 50:449-454, 1971 Bloom AA, LoPriesti P , Farrar JT: Motility of the intact human color. Gastroenterology 54:232-240, 1968 Connell AM : The motility of the pelvic colon: I.
11.
12.
13.
14.
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Motility in norm als and in patients with asymptomatic duodenal ulcer. Gut 2:175-186, 1961 Boden G, Chey WY: Preparation and specificity of antiserum to synthetic secretin and its use in a radioimmunoassay (RIA) . Endocrinology 92: June, 1973 Hill JR, Kelley ML, Schlegel JF, et a!: Pressure profile of the rectum and anus of healthy persons . Dis Colon Rect 26:203-209, 1960 Misiewicz JJ, Connell AM, Pontes FA : Comparison of the effect of meals and prostigmine on the proximal and distal colon in patients with and without diarrhea . Gut 7:468-473, 1966 Misiewicz JJ, Waller SL, Holdstock DJ: Gastrointestinal motility and gastric secretion during intravenous infusions of gastrin. II . Gut 10:723-729, 1969
GASTHOENTEHOI.OC:Y 65: 438-444, 1973 Copyright © 1973 by The Willia ms & Wilkins Co.
Printed in U.S.A.
MOTOR RESPONSES OF THE SIGMOID COLON AND RECTUM TO EXOGENOUS CHOLECYSTOKININ AND SECRETIN VICENTE
P.
DINOSO, JR ., M.D ., HooSHA NG MESHKINPO UR, M.D., STANLEY H. LORBER
M . D .• JORGE G. GUTIERREZ, M.D .• AND WILLIAM
Y.
CHEY, M . D.
Department of Medicine , T emple University Health Sciences Center, Philadelphia, Pennsylvania
The effects of exogenous cholecystokinin (CCK) and secretin on motor activity of the sigmoid colon and rectum were studied in 10 subjects. CCK stimulated and secretin inhibited basal motor activity of the sigmoid. In addition, CCK-induced motor activity of the sigmoid colon was inhibited by secretin. Neither CCK nor secretin influenced motor activity of the rectum. During the past 8 years, secretin and cholecystokinin (CCK) have been shown to influence the motor activity ·of various segments of the gastrointestinal tract. Studies in man have revealed that both secretin and CCK inhibit antral motility of the stomach . 1 • 2 In addition, CCK stimulates and secretin inhibits motor activity of the small intestine. 3 - 7 Secretin, exogenously administered or endogenously released, decreases the pressure of the lower esophageal sphincter probably by competitive inhibition with gastrin. 8 In a preliminary communication, 7 it was suggested that these two hormones influence the motor activity of the sigmoid colon. The purpose of this study was to make observations on the effects of these hormones on motor activity of both sigmoid colon and rectum in a larger number of patients.
Materials and Methods Ten subjects, five males <1nd five females , ranging in age from 22 to 68 years (mean 41.2) Received January 22, 1973. Accepted April 15, 1973. Address· requests for reprints to: Dr. V. P . Dinoso, Jr., Gastrointestinal Section, Temple University, Health Sciences Center, 3400 Broad St., Philadelphia, Pennsylvania 19140. Dr. Gutierrez's and Dr. Chey's present address is: The Isaac Gordon Center for Digestive Diseases, The Genesee Hospital, and the University of Rochester School of Medicine and Dentistry, Rochester, New York. 438
without gastrointestinal disease or symptoms referable to the colon, were studied. Subjects were given a light liquid supper and were fasted overnight. The descending colon and rectum were cleansed with normal saline solution 2 hr before a study. Two no. 10 French, radioopaque, rubber tubes with an internal diameter of 1.5 mm were introduced via a proctosigmoidoscope 25 and 10 em from the anal verge and taped firmly close to the anus to avoid movement. For accurate localization, tubes were provided with open metal tips and their positions checked fluoroscopically before and after each experiment. Tube positions were found to be essentially unchanged at the end of the study period in all subjects. Studies were performed in a quiet room. Intraluminal pressure changes and respiration were recorded by a Sanborn Polyviso-Recorder. Normal saline solution was perfused through open-tipped rubber catheters at a rate of 4 ml per hr by means of a Correl and Carrel monodrum. Basal motor activity was recorded for 30 min during which time an intravenous infusion of normal saline solution was maintained. Cholecystokinin [Gastrointestinal Hormone Unit (GIH), Karolinska lnstitutet, Sweden] was administered intravenously in successive doses of 0.5 , 1.0, and 2.0 U per kg per hr by means of a Harvard infusion pump for 30 min each, with intervening rest periods of 30 min during which time the infusion of saline solution was continued . If basal motor activity of the sigmoid colon was active, secretin (GIH , Karolinska lnstitutet) in doses of 0.5, 1.0, and 2.0 U per kg per hr was infused intravenously in a similar manner and its effect on spontaneous motor activity of the sigmoid and rectum recorded. In
September 1973
MOTOR RESPONSES OF SIGMOID COLON AND RECTUM
a third set of studies on the same subjects, the influence of secretin on motor activity of the sigmoid colon stimulated by an intravenous infusion of 1 U of CCK per kg per hr was investigated. Two experiments were performed per subject for each dose employed in the CCK studies, and one experiment was performed for each dose employed in the secretin studies. The changes in motor activity of the sigmoid colon and rectum were quantitated by determining the number of waves, amplitude index (sum of the amplitude of all waves in centimeters of H 2 0) and percentage of motor activity (percentage of time occupied by waves) per 30 min of observation. All the records were analyzed by one observer (V. P. D.). To minimize error produced by the introduction of artifacts, waves having an amplitude of less than 2.5 em of H 2 0 were excluded from analysis. 9 Changes in the types of waves were not analyzed in detail in this study although reference to patterns or types, i.e., simple monophasic, repetitive or rhythmic , or complex waves is made under discussion according to the criteria and descriptions of Bloom et al. 9 and Connell. 10 In counting the number of waves during periods of complex wave activity, each peak was counted as a wave. To exclude the possibility that the recording system employed failed to detect motor waves or small changes in intrarectal pressure, concurrent recordings were made using both open-tip and balloon techniques . With the latter technique and the balloon inflated with 4 ml of air to a diameter of 1.5 em, the sensitivity of the two systems was approximately the same. In this report, therefore, data on the motor activity of the rectum were obtained solely by the open-tip technique . Student's t-test for paired data was used to analyze the significance of the difference of the means between the control period and each period of hormone administration.
439
during the control period and 10 min after the start of the intravenous infusion of 0.5, 1.0, and 2.0 U per kg per hr of CCK is demonstrated in figure 2. Secretin on spontaneous motor activity of the sigmoid colon. In contrast to the increased motor activity of the sigmoid colon observed during CCK infusion, administration of secretin produced a decrease in the number of wavesr amplitude index, and percentage of motor activity
MEAN NUMBER OF WAVES PER 30 MINUTES
500
MEAN AMPLITUDE INDEX PER 30 MINUTES (Cm H20)
Results MEAN Effect of CCK on spontaneous motor PERCENTAGE ACTIVITY PER activity of the sigmoid colon. Two experi30 MINUTES ments were performed per subject for each dose of CCK employed. An increase in all three parameters of motor activity was observed in response to the intravenous administration of CCK which was greater CCK u/ kg-hr with higher doses of the hormone (fig. 1). I ±S.E. • p <.05 ••• p < 005 This increase in motor activity was statistically significant at or above the starting FIG. 1. The effect of cholecystokinin (CCK) on dose of 0.5 U per kg per hr. An example of spontaneous motor activity of the sigmoid colon. the pattern of motor activity observed NSS, normal saline solution.
DINOS O ET AL.
440
Vol. 65 , No . 3
NSS INFUSION
CCK 0 . 5 u / ~g . hr
Cm
H 0 2 30- CCK 2 .0 u f ~g.hr
10-
RESPIRATION
I
I "'-._I MIN .
FIG. 2. An example of t he motor activity of the sigmoid colon during the intravenous infusion of cholecystokinin (CCK) in doses of 0.5, 1.0, and 2.0 U per kg per hr. NSS , norm al saline solut ion.
(fig. 3). The level of significance of the. differences of the means, for each dose employed compared with the control, is given in the figure. Secretin on motor activity of the sigmoid colon induced by CCK. After administering CCK by intravenous infusion in a dose of 1 U per kg per hr for 30 min , secretin was added to the infusion in doses of 0.5, 1.0, and 2.0 U per kg per hr while continuing the background infusion of CCK. As in the first two experiments a rest period of 30 min was allowed in between dose changes during which time normal saline solution was infused. The decrease in motor activity was statistically significant at the dose of 2 U per kg per hr of secretin only for all the parameters of measurement (fig. 4). An example of the inhibitory effect of CCKinduced motor activity of the sigmoid colon produced by secretin is demonstrated in figure 5. CCK and secretin on the motor activity of the rectum. A wide range of variation in
basal motor activity of the rectum was observed among the 10 subjects studied which resulted in a relatively large standard error of the means in the three parameters used. In contrast to the clear cut effects on basal motor activity of the sigmoid colon produced by the hormones, neither the intravenous administration of CCK nor secretin was observed to influence rectal motor activity (table 1). In an effort to determine if basal motor activity in the rectum influenced the potential for an inhibitory response to secretin, the data were analyzed further by segregating results from those subjects with low and those with high basal activity (table 1). No significant difference in response to secretin was observed between these two groups . Discussion Our findings demonstrate that motor activity of the sigmoid colon in man, as measured by intraluminal pressure
441
MOTOR RESPONSES OF SIGMOID COLON AND RECTUM
September 1973
changes, is stimulated by cholecystokinin and inhibited by secretin. The effects of these two hormones on motor activity are similar to those reported for the small intestine 7 but differ from those observed in the antrum in man in which both hormones were reported to inhibit spontaneous motor activity,'· 2 The possibility that subjects with low initial basal motor activity were predisposed to high motor activity and vice versa, and that the changes we observed were unrelated to the administration of the hormones is highly unlikely. We have recorded basal motor activity of both sigmoid colon and rectum for periods of 1 to 8 hr and observed that the initial pattern oflow or high motor activity was not influenced
70
MEAN NUMBER OF WAVES PER 30 MINUTES
MEAN AMPLITUDE INDEX PER 30 MINUTES (Cm H,O)
200
100 MEAN NUMBER OF WAV ES
PER 30 MINUTES
70
500
N.S. MEAN PERCENTAGE ACTIVITY PER 30 MINUTES
MEAN AMPliTUDE INDEX
PER 30 M INUTES (Cm H 20 )
LO
1.± S.E .
!<- SuE/~~~::: ---.1
N.S. NOT SIGNIFICANT ' p <.OS
N.S.
" p <.01
FIG. 4. The effect of secretin on motor activity of the sigmoid colon induced by cholecystokinin (CCK), 1 U per kg per hr.
MEAN
PERCENTAGE ACTIVITY
PER 30 MINUTES
NSS SECR ETIN u/ kg-hr
I ±s.E
N .S. NOT SIGN IFI CANT "' p
• p < .05
•• p <.01
<.OOS
FIG. 3. The effect of the secretin on spontaneous motor activity of the sigmoid colon . NSS, normal saline solution.
by the intravenous administration of normal saline. A similar observation has been reported by Connell. 10 The means for both spontaneous and CCK-induced motor activity of the sigmoid colon reveal partial inhibition only in response to the highest dose of secretin employed (2 U per kg per hr.) . However,
442
Vol. 65, No.3
DINOSO ET AL. X . A - 68 -m
S 1 u /k g.h•
t S 2 ufkg.h•
RESPIRATION
I
I ""'-...!MIN.
FIG. 5. An example of the inhibition of cholecystokinin ( CCK)~induced motor activity of the sigmoid by 1 and 2 U per kg per hr of secretin (S). Secretin was administered after 10 min of sustained motor activity. TABLE
1. Effect of cholecystokinin (CCK) and secretin on spontaneous motor activity of the rectum Experiment
No. of waves
Amplitude index
Activity
%
CCK in 10 subjects NSSa 0.5 ........ ... . . . . .. . ... . ... . . . . 1.0 ... . . . .... . .. . .. .. ............ . 2~
. . ............. . ........... ... .
Secretin in 6 subjects with low basal motor activity NSS 0.5 ......... . . ... .. .. ..... . ...... . 1.0 .............. .. ....... . ..... . . 2.0 .. . . . . ··· · ······ ··········· Secretin in 4 subjects with high basal motor activity NSS 0.5 .............. . .. ..... . .... . .. . 1.0 .. ..... . ................ . . . . . . . 2.0 ...... . .......... . .... . ..... . . a
12.88 14.25 10.38 20.75
±
25.40 24.50 35.40 29.00
±
81.75 88.67 83.25 75 .50
± ± ±
± ± ±
± ± ± ±
3.42 3.44 3.06 4.88
40.25 52.75 35.38 68.86
5.75 2.96 2.50 6.35
115.50 98.50 78.50 126.00
9 .81 21.86 17.61 15.33
409.25 ± 421.00 ± 433.50 ± 482.00 ±
± ± ± ±
± ± ± ±
11.86 15.04 10.28 16.06
13.90 ± 15.60 ± 12.20 ± 15 .67 ±
4.18 4.10 3.70 3.97
45.98 30.85 40.27 86.74
26.00 ± 18.60 ± 24.00 ± 26.00 ±
5.87 2.96 4.40 5.82
79.17 146.40 86 .76 93.29
88.33 96.00 93.00 97.33
6.69 1.00 3.00 1.45
± ± ± ±
NSS , normal saline solution.
differences in response were observed, and, in some instances, motor inhibition of basal or stimulated activity was complete. Such variations suggest that secretin may be a weak inhibitor of motor activity of the sigmoid colon and/or that responses to the hormone are dependent upon multiple factors. The highest level of motor activity in-
duced by 2 U per kg per hr of CCK (CCK experiments, fig. 1) was similar to the sustained motor activity of the sigmoid colon observed during the control period of the secretin experiments (fig. 3). This observation suggests that the sigmoid colon may have a maximal response to stimulation with CCK which does not increase further beyond that observed during pe-
Sept ember 1973
MOTOR RESPONSES OF SIGMOID COLON AND RECTUM
riods of heightened motor activity of the sigmoid colon. Indeed, in a few subjects, we administered 4 U per kg per hr of CCK intravenously and found no further increase in any of the parameters measured (unpublished observations). Since the blood concentrations of CCK in man are not measurable at present, it is difficult to know if the doses of hormone employed in this study were in the physiologic range. Recently, serum levels of secretin have been approximated to be 1 to 2 m U per mi. 11 Although blood levels of secretin produced by the intravenous administration of GIH secretin have not been determined in man, immunoreative secretin levels in 1 dog after injection of 1 U of GIH secretin per kg per 30 min into the portal vein ranged from 3 to 6 m U per ml (Dr. Gunther Boden, personal communication). This suggests that in our study, particularly when low doses of secretin were used, blood levels of secretin might have been near the physiologic range. The increase in the number of waves after the intravenous administration of CCK included all forms of waves such as simple monophasic, repetitive, and complex waves. 9 • 1 ° Conversely, during secretin administration, all forms of waves were diminished in number. Four subjects experienced lower abdominal cramps and flatulence during the infusion of 1 or 2 U per kg per hr of CCK. The reason for the development of these symptoms in these subjects and their absence in the other 6 was not apparent. Thaincreases in indices of motor activity in the subjects who experienced these symptoms were not markedly different from those who did not. Individual levels in sensitivity to colonic contractions or variations in luminal diameters might, in part, explain this observation. In contrast to the observations reported above the sigmoid colon, there was no significant or consistent change in basal motor activity of the rectum in response to the intravenous infusion of either CCK or secretin. This correlates well with the observation that none of the subjects developed an urge to defecate. We think that the
443
differences in the responses of the sigmoid colon and rectum to exogenous secretin and cholecystokinin are real rather than technical. As mentioned briefly under "Materials and Method," we recorded intrarectal pressures using both open-tip and balloon techniques (balloon inflated with 5 ml, diameter, 1.5 em) and found, as described in the text, identical changes in the three parameters of motor activity measured. Hill and co-workers 12 compared resting intrarectal pressures obtained by an open-tip unit, a differential transformer pressure transducer, and a 7- by 7-mm balloon and observed that the first two systems provided the most accurate measurements. Connell 10 employed miniature balloons with dimensions close to ours to measure motor activity in the rectum and obtained results almost identical to those we recorded with an open-tip system. Mean percentage of duration of motor activity for control subjects was 64.6% in his study and 65.6% in ours. The physiologic significance of these observations on motor activity of the sigmoid colon awaits demonstration of the effect of endogenously released CCK and secretin. Misiewicz et a!. 13 have observed that there is a postcibal increase in motor activity of the sigmoid colon and none in the rectum in subjects without colonic symptoms. They have presented some evidence that gastrin is probably not the hormone mediating these changes. 14 The possible role of CCK and secretin in the production of postcibal changes in motor activity of the sigmoid colon remains to be clarified. REFERENCES 1. Johnson LP, Brown JC, Magee DF: Effect of
2.
3. 4.
5.
secretin and cholecystokinin-pancreozymin extracts on gastric motility in man. Gut 7:52-57, 1966 Dinoso V, Chey WY, Hendricks J, et al : Intestinal mucosal hormones and motor function of the stomach in man. J Appl Physiol26:326-329, 1969 Monod E: Action entero-kinetique de Ia cecekin. Arch Mal Appl Dig 53:607-608, 1964 Morin G, Besancon F, Grall A, et al: Technique d'acceleration du grele. Arch Mal Appl Dig 54:1285-1290, 1965 Parker JG, Beneventano TC: Acceleration of
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6.
7.
8.
9.
10.
DINOSO ET AL.
small bowel contrast study by cholecystokinin. Gastroenterology 58 :679- 684, 1970 Chey WY, Woloshin HG, Gutierrez JG, et al : Use of cholecystokinin and secretin for radiographic examination of the small intestine (abstr). Gastroenterology 62:733, 1972 Gutierrez JG, Chey WY, Dinoso V, eta! : Effect of intestinal hormones on motor function of the small bowel and sigmoid colon in man (abstr). Gastroenterology 60:672, 1971 Cohen S, Lipshutz W: Hormonal regulation of human lower esophageal sphincter competence: Interaction of gastrin and secretin. J Clin Invest 50:449-454, 1971 Bloom AA, LoPriesti P , Farrar JT: Motility of the intact human color. Gastroenterology 54:232-240, 1968 Connell AM : The motility of the pelvic colon: I.
11.
12.
13.
14.
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Motility in norm als and in patients with asymptomatic duodenal ulcer. Gut 2:175-186, 1961 Boden G, Chey WY: Preparation and specificity of antiserum to synthetic secretin and its use in a radioimmunoassay (RIA) . Endocrinology 92: June, 1973 Hill JR, Kelley ML, Schlegel JF, et a!: Pressure profile of the rectum and anus of healthy persons . Dis Colon Rect 26:203-209, 1960 Misiewicz JJ, Connell AM, Pontes FA : Comparison of the effect of meals and prostigmine on the proximal and distal colon in patients with and without diarrhea . Gut 7:468-473, 1966 Misiewicz JJ, Waller SL, Holdstock DJ: Gastrointestinal motility and gastric secretion during intravenous infusions of gastrin. II . Gut 10:723-729, 1969