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Colonic motor activity in acute colitis in conscious dogs
GASTROENTEROLOGY
1991;100:954-963
Colonic Motor Activity in Acute Colitis in Conscious Dogs ASHWANI
K. SETH1 and SUSHIL K. SARNA
Departments of Surgery, Physiology, and Medicine, Digestive Disease Research Center, Medical College of Wisconsin: and Zablocki Veterans Administration Medical Center, Milwaukee, Wisconsin
The changes in motor activity of the colon during acute colitis were investigated in six conscious dogs. The motor activity was recorded with seven straingauge transducers. Colitis was induced in the entire colon by luminal perfusion of acetic acid. The dogs exhibited urgency and diarrhea with mucus and blood during colitis. The mucosa was diffusely erythematous and friable and there were scattered ulcerations over the mucosal surface. The motor activity of the colon changed in several ways during colitis: (a) the total duration per hour and the mean duration of contractile states decreased significantly; (b) the cycle length of colonic migrating motor complexes was significantly prolonged, and the nonmigrating motor complexes were almost completely absent; and (d) the incidence of giant migrating contractions increased significantly. About half of the giant migrating contractions were followed by defecation. The remaining expelled mucus or gas. Sometimes, a migrating motor complex in the colon was also followed by defecation; this was never observed in the normal state. The motor activity of the colon was still decreased and the cycle length prolonged 21 days after induction of colitis. However, the dogs were asymptomatic at this time and the mucosa looked normal at colonoscopy. The incidence of giant migrating contractions was also normal at this time. It was concluded that the dog is a good model for the study of colitis because of the similarity of symptoms with human ulcerative colitis. The phasic contractions of the colon decreases during colitis but the incidence of giant migrating contractions is increased. The diarrhea in colitis may primarily be due to the large number of giant migrating contractions in the middle and the distal colon.
urgency of defecation. Studies in humans indicate that these symptoms may be associated with significant changes in motor activity of the sigmoid. The general finding of studies in the 1950s was that the incidence of phasic contractions in the sigmoid colon is decreased and that of giant migrating contractions (GMCs) increased during ulcerative colitis (1,2). However, these findings were not confirmed, or were confirmed only in part, by later investigations (3-6) so that a complete understanding of changes in motor activity in colitis is lacking. In fact, Chaudhary and Truelove (5) reported increased motor activity in patients with ulcerative colitis. Some of the reasons for the differences in these reports may be attributed to the limitations of studies in humans. Patients usually cannot serve as their own controls, which means that normal data are available from a different group. The severity and duration of disease varies in the study group and may affect findings. Because of easy access, most early human recordings were made only from the sigmoid colon which does not necessarily represent the motor activity of the entire colon. Finally, the recordings from humans have generally been of short duration. This limits the reliability of comparison of data with normal controls because the spatial and temporal patterns of colonic contractions are highly variable in time (7-10). Because of these limitations, we sought to study the motor activity of the colon in colitis in an experimental dog model. Our objective was to record motor activity of the entire colon with multiple strain-gauge transducers before and after inducing acute colitis and to relate the symptoms of colitis with changes in motor activity.
I
Abbreviations used in this paper: GMCs, giant migrating contractions; MMCs, migrating motor complexes. o 1991 by the American Gastroenterological Association 0016-5085/91/$3.00
nflammatory disorders of the colon, such as ulcerative colitis, are accompanied by diarrhea, passage of mucus and blood, abdominal pain, tenesmus, and
COLONIC MOTOR ACTIVITY IN COLITIS
April 1991
In the older literature from the 1950s (l-S), type I, type II, type III, and type IV nomenclature has been used to describe colonic contractions. Davidson et al. (3) commented that the nomenclature using numbers was confusing. We have used the more recent nomenclature of short-duration (equivalent to type I), longduration (equivalent to type II), and GMCs (equivalent to type IV). All three types of contractions have been identified in the dog and the human colon (8-14). This nomenclature is based on the two myogenic mechanisms of control of contractions in the colon. Short-duration contractions are controlled in time and space by electrical control activity (8,12,14), and long-duration contractions by contractile electrical complex (8,12,14). The myoelectric correlate of GMCs in the colon is not known yet. Type III contractions are redundant because they really represent type I or type II contractions with an accompanying change in baseline.
Methods Experiments were performed on six healthy conscious dogs, each weighing 20-25 kg. During general anesthesia with pentabarbital sodium (Abbott Laboratories, Chicago, IL; 30 mg/kg), the abdomen was opened by a midline laparotomy. The total length of the colon from the ileocoionic junction to the peritoneal reflection was measured soon after IV administration of 100 kg/kg of atropine sulfate (Ivernex Labs, Melrose Park, IL) to minimize shortening of the colon due to handling. The prospective sites for the implantation of seven strain-gauge transducers were immediately marked with 3-O Surgilon sutures (Davis & Geck, Danbury, CN). The first transducer was 5 cm distal to the ileocolonic junction and the last about 2 cm proximal to the peritoneal reflection. The remaining five transducers were spaced equidistant (5.6 2 1 cm apart) between the first and the last. The transducers were oriented to maximally record circular muscle contractions. An additional strain-gauge transducer was implanted on the ileum, 10 cm proximal to the ileocolonic junction. The lead wires were brought out through a stainless steel cannula as described previously (151. An
intraluminal catheter (ID 2.6 mm, OD 4.8 mm) was implanted between the first colonic strain-gauge transducer and the ileocolonic junction. The catheter was tunneled subcutaneously to the subscapular region and exteriorized. The catheter was housed in a protective jacket that each dog wore at all times. The dogs were allowed 10 days to recover from surgery. At this time, each dog had normal stools, generally once a day, and was free of ova and parasites. The dogs were fasted overnight before each experiment. We expected that during colitis the dogs would develop diarrhea. This means that the colon may have less than the usual quantity of fecal material in it during colitis. To insure that the observed changes in motor activity during colitis were not caused by a difference in the volume of fecal material in the colon, we performed experiments in the
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cleansed and uncleansed colon, both during control condition and during colitis. The experimental protocol was as follows (Table 1). The dogs were fasted for at least 18 hours. After this time, all the previously ingested food should have reached the colon, because small intestinal migrating motor complexes (MMCs) usually return in about 8-10 hours after the ingestion of two cans of dog food (- 1300 kcal). The next day, the colon was cleansed by perfusing 4 L of Colyte (Reed and Carnick, Piscataway, NJ) through the indwelling catheter. On the following day (day l), the dogs were anesthetized with l-1.5 mL of Telazol (A.H. Robins Co., Richmond, VA) and either 10 mL of normal saline or 10 mL of 75% acetic acid was perfused through the indwelling catheter depending on whether it was a control experiment or an experiment to induce colitis. Perfusion of acetic acid resulted in GMCs (15-17) and intense colonic motor activity so that most of the acetic acid was rapidly distributed over the entire colon and expelled in 5-10 minutes. Five minutes after the perfusion of saline or acetic acid, the colon was lavaged with 100 mL of normal saline. The dogs were kept fasted after this procedure. A 4-hour control recording was made the following day (day 2) in the fasted state when the colon was empty. Then each dog was fed two cans of dog food (- 1300 kcal P.D.; Hills Pet Products, Topeka, KS; 447 g each). In preliminary experiments, it was confirmed by colonoscopy that the procedure performed on day 1 thoroughly cleansed the entire colon. On day 3, a &hour control recording was made from the uncleansed colon. The colon was then cleansed again with Colyte as described before, and colonoscopy and biopsy were performed to verify normal mucosal appearance in control experiments or induction of colitis with acetic acid. On day 4, another &hour recording was made in the fasted state from the cleansed colon, and then the dogs were fed a
Table 1. Experimental
Day 0
1
2
3
4
5
6, 7
21
Protocol
Control experiment
Colitis experiment
Fast for 18 h a. Clean colon with Colyte b. Control saline perfusion a. 4 h fasted recording from cleansed colon b. Feed 1300-kcal meal a. 4 h fasted recording from uncleansed colon b. Clean the colon with Colyte c. Confirm normal colon with colonoscopy a. 4 h fasted recording from cleansed colon b. Feed 1300-kcal meal a. 4 h fasted recording from uncleansed colon b. Feed 1300-kcal meal a. 6 h fasted recording from uncleansed colon b. Feed 1300-kcal meal
Same a. Same b. Acetic acid perfusion a. Same
-
b. Same a. Same b. Same c. Confirm colitis with colonoscopy a. Same b. Same a. Same b. Same a. Same b. Same 6 h recording from uncleansed colon
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1399-kcal meal as above. On days 5, 6, and 7, 4-6-hour recordings were made in the fasted state from the uncleansed colon. The dogs were then allowed to recover from colitis for about 21 days, after which a 6-hour recording was made from the uncleansed colon. At this time the dogs had semiformed stools but did not exhibit diarrhea or urgency. Before the start of this study, it was established in three other dogs by colonoscopy that perfusion of 10 mL of 75% acetic acid, as described above, induced colitis in all dogs. In these preliminary experiments, colonoscopy was performed on the lst, 3rd, and 5th days after the perfusion of acetic acid. The mucosa had apparently normal appearance on day 21. Recordings were made on a 12-channel Grass pen recorder (model 7D; Grass Instrument Co., Quincy, MA) with lower and upper cut-off frequencies set at direct current and 16 Hz, respectively. The signals were recorded simultaneously on an instrumentation tape recorder (Model 3968A; Hewlett-Packard Co., Palo Alta, CA) so that they could be played back later at a slower or a faster paper speed. As described previously (18), the first two strain-gauge transducers represented the proximal colon, the next three the middle colon, and the last two the distal colon. All data were analyzed visually. The following parameters of colonic motor activity were determined as reported previously (11,12,16,18,19): (a)The cycle length of colonic MMCs was determined in the entire colon. Each recording site in the colon exhibited alternating periods of quiescence and bursts of contractions called quiescent and contractile states, respectively. The occurrence of contractile states was redrawn on a chart paper by straight lines, and the start of each contractile state was connected with the start of the nearest contractile state at the adjacent recording sites. Solid lines were used for caudad and broken lines for orad migration. A contractile state starting anywhere in the colon and migrating greater than half its length in the aborad or the orad direction was called a colonic MMC (11,12,20). All other patterns of contractile states, i.e., those that did not migrate at all, migrated randomly in both directions, or migrated less than half the length of the colon were called nonmigrating motor complexes. The cycle length of a colonic MMC was the time lag between the start of two successive MMCs. (b) The total duration of contractile states per hour and their mean duration were determined at each recording site and then averaged for the proximal, middle, and distal colon as defined above. (c) The mean cycle length of individual contractile states, whether they migrated or not, was determined at each recording site and averaged for the proximal, middle, and distal colon. This parameter represents the cyclic occurrence of both MMCs and nonmigrating motor complexes (18).(c)The point of origin and the distance of migration of GMCs were determined as described previously (16,18). All data are expressed as mean f SE (n = number of dogs]. Colitis was induced only once in each dog. Onefactor analysis of variance with repeated measures and Dunnett’s test were used for statistical analysis of data. A P value of 10.05was considered statistically significant.
GASTROENTEROLOGYVol. lOO.No.4
Results All dogs had developed acute colitis in the entire colon when examined by colonoscopy on day 3 of the experiment. The mucosa appeared diffusely inflamed and markedly friable (Figure 1).There were scattered ulcerations and exudate over the mucosal surface. Symptomatically, colitis was moderately severe. The dogs defecated uncontrollably a total of 22 times during 120 hours of recording in the laboratory during colitis. By contrast, none of the dogs ever defecated during the same duration of the control recording period. In addition, the dogs also exhibited
Figure 1. Top. Mucosal appearance during colitis in the dog is characterized by edema, hemorrhagic lesions, and whitish mucosal exudate. The lumen lost its regular smooth appearance.
Bottom. Mucosal appearance of the normal dog colon. Unlike the human colon, the canine colon does not have haustral folds and does not exhibit the mucosal vascular net.
April 1991
COLONIC MOTOR ACTIVITY IN COLITIS
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and 2.8 + 0.9 minutes during colitis (P < 0.05; Figure 4B). The mean cycle length of contractile states increased in the proximal, middle, and distal colon from 32 + 4,31 + 2, and 33 -+ 4 minutes in the control state to 65 2 9, 63 + 7, and 111 + 15 minutes, respectively, during colitis (P < 0.05; Figure 4C). Colonic MotorActivity During Colitis Altogether, the contractile states became shorter in (Uncleansed Colon) duration and occurred less frequently during colitis than in the control state. The mean amplitude of Each dog exhibited spontaneous colonic MMCs contractions during colonic motor complexes deand nonmigrating motor complexes in the normal state as described previously [Figure 2 (11,12,18)].creased in the distal colon from 63 + 4 g to 54 + 4 g (P < 0.05). There was no significant change in the During colitis, the cycle length of colonic MMCs was proximal and the middle colon. significantly prolonged to 82 k 7 minutes compared The induction of colitis had no significant effect on with 49 -e 4 minutes during the control state the cycle length of MMCs in the ileum (control, None of the colonic MMCs migrated orad (P < 0.05). 126 + 8 minutes; during colitis, 123 + 7 minutes). during colitis, whereas 4% migrated orad during control. During control, two successive colonic MMCs were usually separated by one or more nonmigrating Effect of Colitis on Giant Migrating motor complexes. During colitis, the nonmigrating Contractions motor complexes were mostly absent so that two A total of three GMCs were observed in 120 successive colonic MMCs were separated by a quieshours of recording during the control state. All of cent state (Figure 3).Two colonic MMCs during these occurred only at the most proximal recording colitis were followed by defecation when they reached site in the proximal colon. None of these contractions the distal colon. This was never observed in the were associated with defecation. By contrast, 40 control state. GMCs occurred in 120 hours of recording during The total duration per hour of contractile activity colitis (Figure 5). Two of these contractions originated decreased dramatically in the proximal, middle, and in the proximal colon, 19 originated in the middle or distal colon from 13 + 1,12 + 0.9,and 15 + 1 min/h in the control state to 2.6+ 0.5,2 k 0.3,and 1.6~fr 0.8 the distal colon and migrated caudad. Nineteen GMCs appeared only on the last gauge or the one proximal to mm/h, respectively, during colitis (P < 0.05; Figure it. The mean distance of migration of these contrac4A). Similarly, the mean duration of contractile states tions was 10 + 1 cm, and they originated at a distance decreased significantly in the proximal, middle, and of 28 + 2 cm from the ileocolonic junction. Nineteen distal colon from 6.5 k 1, 6 k 0.3,and 9.0 + 0.6 of 40 GMCs in colitis were followed immediately by minutes in the control state to 2.5 + 0.2, 2.4 +- 0.3,
urgency, discomfort, and tenesmus. The stools were liquid and contained mucus and blood. Biopsies showed acute ulcerations with intense polymorphonuclear reaction.
Figure 2. Colonic motor complexes in the normal state. Each burst of contractions represents a contractile state. Solid lines indicate caudad and broken lines orad migration of contractile states. Contractile states that migrated greater than half the length of the colon were callcd MMCs. This length was represented by four gauges. The remaining patterns of contractile states were called nonmigrating motor complexes. The overall motor activity consists of a combination of MMCs and nomnigrating motor complexes. Cl-C7 represent the strain-gauge transducers, and the numbers after them represent the distance of gauges from the ileocoIonic junction.
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GASTROENTEROLOGYVol. 100, No. 4
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defecation. The rest were associated with expulsion of gas or simply tenesmus. Tenesmus in dogs was defined as straining without stools. The GMCs that were followed by defecation sometimes migrated up to the last gauge or the one proximal to it, but sometimes they migrated only up to the middle colon. This is in contrast to the normal state, in which the GMCs usually migrate up to the rectum or the sigmoid colon before defecation occurs (16). The GMCs in the normal state were distinct large-amplitude contractions that migrated caudad. The GMCs during colitis also exhibited distinct migration, but they were often mixed with the short- and long-duration contractions. However, this did not seem to affect their ability to expel feces or gas. Colonic Motor Activity During Colitis (Cleansed Colon) The changes in motor activity of the cleansed colon were similar to those of the uncleansed colon. The total duration per hour of contractile states and their mean duration decreased significantly in all parts of the colon (Figure 6A and B). The amplitude of contractions during motor complexes decreased from 65 + 2gto57 + 3ginthemiddleandfrom61? 3gto 53 + 1 g in the distal colon (P < 0.05). There was no significant change in the proximal colon. The mean cycle length of contractile states increased in the proximal, middle, and distal colon (Figure SC). A total of 27 GMCs occurred during 56 hours of recording from the cleansed colon; 10 GMCs appeared only at one site, whereas the remaining GMC migrated caudad.
Figure 3. Colonic motor complexes during colitis. The nonmigrating motor complexes were almost absent during colitis. During colitis, a GMC was often followed by a burst of pbasic contractions that formed the MMC. The duration of contractile states was significantly shorter during colitis than in the normal state (See Figure 4). CZ-C5 represent the colonic straingauge transducers, and the numbers after them represent their distance from the ileocolonic junction.
The GMCs in the cleansed colon originated at a distance of 22 f 2 cm from the ileocolonic junction and migrated caudad a length of 11 + 1 cm. Ten of 27 GMCs in the cleansed colon were followed by expulsion of gas or a bloody mucoid discharge. Colonic Motor Activity After Symptomatic Recovery From Colitis The dogs were symptom-free about 8-10 days after induction of colitis. The postrecovery recordings were made between the 20th and 22nd days after inducing colitis. At this time, the GMCs were absent and the rest of colonic motor activity recovered partially. The total duration per hour and the mean duration of contractile states were significantly greater than those during colitis but still less than those before colitis (P < 0.05; Figure 4). The cycle length of colonic MMCs, 66 + 5 minutes, recovered partially but it was still significantly greater than that during control, 49 + 4 minutes (P < 0.05). Discussion
Motor activity of the human rectosigmoid in ulcerative colitis has previously been described using balloon kymographs (l-3) and manometry (4-6). Kern et al. (1) and Spriggs et al. (2) reported a decrease in the percentage presence of phasic contractions in a majority of patients, in others there was no change, and in some the percentage presence of phasic contractions was actually increased. In addition to the decreased percentage presence of phasic contractions,
COLONIC MOTOR ACTIVITY IN COLITIS
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18 16
10 8 6 4
PROXIMAL COLON
2 0 PROXIMAL COLON
MIDDLE COLON
MIDDLE COLON
DISTAL COLON
&TAL COLON Figure 4. A. The total duration of contractile states per hour in the normal state, during colitis, and after symptomatic recovery in the uncleansed proximal, middle, and distal colon. There was a significant decrease in the total duration per hour during colitis, and it recovered only partially after symptomatic recovery. B. The mean duration
of contractile states also decreased significantly during colitis in the uncleansed proximal, middle, and distal colon, and it recovered only partially when the dogs were symptomfree, 21 days after the induction of colitis.
0B
PROXIMAL COLON
MIDDLE COLON
DISTAL COLON
both groups reported increased incidence of GMCs (type IV waves) in patients with ulcerative colitis compared with control subjects. Recently, Rao et al. (6) confirmed the reduction of phasic contractions in the rectum of patients with ulcerative colitis but did not report any GMCs. They postulated that the occurrence of GMCs in previous studies was an artifact of the method of balloon recording. By contrast, Davidson et al. (3) and Snape et al. (4) did not find any difference in the percentage presence of phasic contractions and motility indices, respectively, between normal subjects and patients with ulcerative colitis in the fasting state. Kern et al. (1)hypothesized that the variations in the percentage presence of phasic contractions among patients with ulcerative colitis may be caused by the differences in the severity of symptoms, such as frequency of bowel movements, at the time of study.
C. The cycle length of contractile states was significantly prolonged during colitis in the uncleansed proximal, middle, and distal colon. The cycle length became normal when the dogs were symptom-free, 21 days after the induction of colitis. *P < 0.05 vs. control; tP < 0.05 vs. colitis. Open bars, control; hatched bars, colitis: crosshatched bars, symptomatic recovery: n = 6.
They reported a strong correlation between severity of diarrhea at the time of study and the decrease in the percentage presence of phasic contractions. The patients in the study of Davidson et al. (3) did not have diarrhea at the time of the recordings. Chaudhary et al. (5) disagreed with the hypothesis of Kern et al. and reported little or no difference in phasic contractions between normal subjects and patients with moderate or severe symptoms of ulcerative colitis. On the contrary, they reported that colonic motor activity was less in patients who were symptom-free but exhibited active ulcerative colitis when examined with a sigmoidoscope. Our findings agree with the hypothesis of Kern et al. (1)and indicate that during reasonably uniform conditions of experimental colitis, when symptoms are similar to those in human ulcerative colitis, the normal motor pattern of the colon is significantly
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GASTROENTEROLOGYVol. 100, No. 4
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1
Proximal Colon
1
Middle Colon
4
I
Defecation
altered. First, the total duration of contractile states per hour and their mean duration are significantly decreased. Second, the cycle length of colonic MMCs is significantly prolonged. Both changes represent a reduction in the percentage presence of phasic contractions of the colon. Third, the incidence of GMCs in the middle and the distal colon is significantly increased. The failure of some investigators to record GMCs during colitis may partly be attributable to the short duration of their recordings. Although the incidence of GMCs was increased during colitis, they occurred, on average, once every 3 hours. They could be missed if the duration of recording is short. Our study extends the previous findings in the human rectosigmoid to the entire colon, There was no apparent difference in the severity of colitis between the proximal, middle, and distal colon in our model. Correspondingly, the changes in motor activity during colitis were parallel in all three parts of the colon. Basically, the motor changes in colitis may be divided into two groups: (a) the reduction in the occurrence of short- and long-duration contractions organized as MMCs and nonmigrating motor complexes in the canine colon; and (b) excessive occurrence of GMCs. The reduction in the occurrence of short- and long-duration contractions has previously been reported during diarrhea in humans and dogs (19,21). The hypothesis is that the phasic contractions, which are largely disorganized in time and space in the colon, mix and knead the fecal contents and regulate their slow net distal propulsion (11). When these contractions are absent or reduced, the contents may move rapidly through the colon. According to this hypothesis, the transit should be faster
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Figure 5. A GMC originating in the middle colon and migrating to the most distal recording site in the colon. The GMC was followed by defecation. The GMCs in colitis were sometimes followed by phasic contractions forming contractile states. CZ-C9 rep resent the strain-gauge transducers, and the numbers after them represent their distances from the ileocoIonic junction.
throughout the colon in patients with colitis than in normal subjects. However, Rao et al. (22) reported that in patients with active colitis the transit was actually slower in the ascending colon and faster in the middle and the distal colon than in normal subjects. The above contradiction may be explained by considering diarrhea to occur for two different reasons, one due to excessive secretions in the small intestine or the colon (secretory diarrhea) and the other due to rapid propulsion of luminal contents by GMCs (motor diarrhea). Transit through the colon in secretory diarrhea in the absence of colonic contractions may be faster because there is no contractile resistance to the flow of contents against hydrostatic pressures generated by the entry of secretions into the colon. On the other hand, if the contents of the colon are viscous or solid, the absence of contractions or a significant reduction in their occurrence may result in little or no propulsion, resulting in stasis. This hypothesis is supported by findings that the transit of a liquid meal is faster through the colon than that of a solid meal (22). The faster transit time in the middle and the distal colon reported by Rao et al. in active colitis may be caused by excessive occurrence of GMCs in those parts of the colon. In the normal state, the spontaneous GMCs usually occur in the proximal colon, where they cause occasional mass movements, once or twice a day (13,16,23). In the distal or the middle colon, the GMCs occur just before defecation (16). During colitis, there was a dramatic increase in the incidence of GMCs in the middle and the distal colon. About half of these contractions produced defecation of fluid stools, sometimes stained with blood, and the rest expelled gas.
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The dogs were uncomfortable when these GMCs occurred. We propose that the symptoms of urgency, tenesmus, and passage of mucus during colitis may largely be caused by the excessive occurrence of GMCs. Frequent occurrence of GMCs when the mucosa is inflamed and friable may also cause bleeding. The precise mechanisms for the initiation of an excessive number of GMCs in the middle and the distal but not the proximal colon in colitis are not known. There was no apparent difference in injury to the mucosa between the proximal, middle, and distal colon. We would like to hypothesize that the stimulus for the excessive number of GMCs was the fecal contents or accumulation of mucus. The sensory mechanisms in the colonic wall may be sensitized
6. A. The total duration of contractile states per hour decreased significantly in the cleansed proximal, middle, and distal colon during colitis.
Figure
B. The mean duration of contractile states decreased significantly the cleansed proximal, middle, and distal colon during colitis.
in
C. The cycle length of contractile states was prolonged significantly in the cleansed proximal, middle, and distal colon during colitis.
because of mucosal inflammation so as to initiate defecation reflex at lower thresholds of chemical and mechanical irritation. Rao et al. (6) also reported that the sigmoid in patients with ulcerative colitis was hypersensitive to the infusion of saline. Furthermore, clinical observations indicate that the symptoms of urgency and frequency of defecation are exaggerated in patients with ulcerative colitis postprandially, presumably because the entry of new digesta into the colon. In support of this, we reported recently that the frequency of GMCs and the incidence of defecation is .increased significantly after a meal during experimental colitis in dogs (24). The metabolism of arachadonic acid in the mucosa is increased in acetic acid-induced colitis in rats (25)
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and in human inflammatory bowel disease (26). The increased production of prostaglandin may play a role in the inhibition of phasic contractions and stimulation of GMCs in colitis. Staumont et al. (27) report that close intraarterial perfusion of prostaglandin E, mimics the decrease in phasic contractions and the stimulation of GMCs in dogs. They also reported that a similar motor response of the colon to sennosides was blocked by indomethacin that blocks the synthesis of prostaglandins. However, other mechanisms independent of prostaglandin synthesis may also be involved. For example, the phasic contractions of the colon are inhibited in diarrhea induced by castor oil (16), which is not known to increase the synthesis of prostaglandins. Systematic studies of motor activity during relapses and remissions of colitis have not been performed in humans. However, our findings indicate that several parameters of motor activity, such as total duration of contractile activity per hour, mean duration of contractile states, and frequency of colonic MMCs, may still be less than normal even though the symptoms may be absent and mucosa may appear normal during a relapse. We did not study our dogs longer than 3 weeks to determine whether these changes were permanent because of irrevocable neural, chemical, or myogenic changes in the colon wall once colitis was induced. The major factor that normalized when symptoms were absent was the occurrence of GMCs, which may play a major role in the production of these symptoms. This suggests the occurrence of motor rather than secretory diarrhea in colitis, as defined above. Experimental colitis produced in dogs by exposure of the mucosa to acetic acid seems to be a good model of colitis in humans because of the similarity of symptoms. However, we are not certain whether the morphological changes in experimental colitis are similar to those in patients with inflammatory bowel disorders. Thus far, the organization of colonic contractions into MMCs and nonmigrating motor complexes has been established only in the rat and the dog colon (11,12,18,28). Although cyclic occurrence of contractile states at individual sites has been reported in the human colon, their migration has not been observed (7,293. This may be a species difference or it may be caused by the cleansing procedure required for the placement of the manometric tube into the colon and the empty state of the colon at the time of recording. We recently reported (30) that perfusion of absorbable or nonabsorbable solutions into the colon disrupts MMCs in the dog colon. This disruption of colonic MMCs lasts for several hours after the colon is cleansed in this manner. Regardless of whether contractions in the human colon are organized as MMCs
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and nonmigrating motor complexes, the total amount of contractile activity is decreased similarly, in both dogs and humans, in colitis. In conclusion, experimental colitis induced by exposure of the colonic mucosa to acetic acid produces symptoms similar to those observed in human ulcerative colitis. The total incidence of contractile activity decreases during colitis, but the incidence of GMCs is significantly increased. These GMCs are associated with urgency, tenesmus, and passing of feces, mucus, and gas. The diarrhea produced in colitis may primarily be attributable to the large number of GMCs in the middle and the distal colon. All parameters of phasic contractions in the colon are not normalized when the colon heals and the dogs are symptom-free, but the incidence of GMCs returns to normal.
References 1. Kern FJ, Almy TP, Abbot FK, Bogdonoff MD. The motility of the distal colon in nonspecific ulcerative colitis. Gastroenterology 1951;19:492-503. 2. Spriggs EA, Code CF, Bargen JA, Curtiss RK, Hightower NC Jr. Motility of the pelvic colon and rectum of normal persons and patients with ulcerative colitis. Gastroenterology 1951;19:480491. 3. Davidson M, Sleisenger MH, Almy TP, Levine SZ. Studies of distal colonic motility in children. II. Propulsive activity in diarrhea1 states. Pediatrics 1956;17:820-832. 4. Snape WJ Jr, Matarazzo SA, Cohen S. Abnormal gastrocolonic response in patients with ulcerative colitis. Gut 1980;21:392396. 5. Chaudhary NA, Truelove SC. Human colonic motility: a comparative study of normal subjects, patients with ulcerative colitis, and patients with the irritable colon syndrome. I. Resting patterns of motility. Gastroenterology 1961;40:1-36. 6. Rao SSC, Read NW, Stobart JAH, Haynes WG, Benjamin S, Holdsworth CD. Anorectal contractility under basal conditions and during rectal infusion of saline in ulcerative colitis. Gut 1988;29:769-777. 7. Narducci F, Bassotti G, Gaburri M, Morelli A. Twenty four hour manometric recording of colonic motor activity in healthy man. Gut 1987;28:17-25. 8. Sarna SK, Latimer P, Campbell D, Waterfall WE. Electrical and contractile activities of the human rectosigmoid. Gut 1982;23: 698-705. 9. Latimer P, Sarna SK, Campbell D, Latimer MR, Waterfall W, Daniel EE. Colonic motor and myoelectrical activity: a comparative study of normal subjects, psychoneurotic patients, and patients with irritable bowel syndrome. Gastroenterology 1981; 80:893-901. 10. Dinoso VP Jr, Murthy SNS, Goldstein J, Rosner B. Basal motor activity of the distal colon: a reappraisal. Gastroenterology 1983;85:637-642. 11. Sarna SK, Condon R, Cowles V. Colonic migrating and nonmigrating motor complexes in dogs. Am J Physiol1984;246:G355G360.12. 12. Sarna SK. Myoelectric
correlates of colonic motor complexes and contractile activity. Am J Physiol 1986;250:G113-G220. 13. Hardcastle JD, Mann CV. Study of large bowel peristalsis. Gut 1968;9:412-520. 14. Fioramonti J, Bueno L. Diurnal changes in colonic motor
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15.
16.
17. 18. 19.
20.
21.
profile in conscious dogs. Dig Dis Sci 1983;28:257-264. Sarna SK. In vivo myoelectric activity: methods, analysis and interpretation. In: Wood JD, ed. Handbook of physiology, gastrointestinal motility and circulation. Bethesda, MD: American Physiological Society, 1989:817-863. Karaus M, Sarna SK. Giant migrating contractions during defecation in the dog colon. Gastroenterology 1987;92:925933. Sarna SK, Prasad KR, Lang IM. Giant migrating contractions of the canine cecum. Am J Physiol1988;254:G595-G601. Sarna SK, Lang IM. Colonic motor response to a meal in dogs. Am J Physiol1989;257:G30-G35. Karaus M, Sarna SK, Ammon I-IV, Wienbeck M. Effects of oral laxatives on colonic motor complexes in dogs. Gut 1987;28: 1112-1119. Flourie B, Phillips S, Richter H III, Azpiroz F. Cyclic motility in canine colon: responses to feeding and perfusion. Dig Dis Sci 1989;34:1185-1192. Connell AM. The motility of the pelvic colon. Part II. Paradoxical motility in diarrhoea and constipation. Gut 1962;3:342-
25. 26.
27.
28.
29.
30.
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acute colitis (abstr). Gastroenterology 1990;98:A667. Sharon P, Stenson WF. Metabolism of arachidonic acid in acetic acid colitis in rats. Gastroenterology 1985;88:55-63. Sharon P, Stenson WF. Enhanced synthesis of leukotriene B by colonid mucosa in inflammatory bowel disease. Gastroenterology 1984;86:453-460. Staumont G, Fioramonti J, Frexinos J, Bueno L. Changes in colonic motility induced by sennosides in dogs: evidence of a prostaglandinmediation. Gut 1988;29:1180-1187. Ferre JP, Ruckebusch Y. Myoelectrical activity and propulsion in the large intestine of fed and fasted rats. J Physiol Lond 1985;362:93-106. Bassotti G, Gaburri M, Imbimbo BP, Rossi L, Farroni F, Pelli MA, Morelli A. Colonic mass movements in idiopathic chronic constipation. Gut 1988;29:1172-1179. Sarna SK. Perfusion of non-caloric absorbable and nonabsorbable solutions disrupt colonic motor activity (abstr). Gastroenterology 1990;98:A387.
348. 22.
23. 24.
Rao SSC, Read NW, Brown C, Bruce C, Holdsworth CD. Studies on the mechanism of bowel disturbance in ulcerative colitis. Gastroenterology 1987;93:934-940. Ritchie J. Mass peristalsis in the human colon after contact with oxyphenisatin. Gut 1972;13:211-219. Sethi AK, Sarna SK. Colonic motor response to a meal during
Received March 27,199O. Accepted August 31,199O. Address requests for reprints to: Sushi1 K. Sarna, Ph.D., Surgical Research 151, Zablocki Veterans Administration Medical Center, 5000 West National Avenue, Milwaukee, Wisconsin 53295. Supported in part by grants from NIDDK DK32346 and Veterans Administration Medical Research Service (to S.K.S.).
1991;100:954-963
Colonic Motor Activity in Acute Colitis in Conscious Dogs ASHWANI
K. SETH1 and SUSHIL K. SARNA
Departments of Surgery, Physiology, and Medicine, Digestive Disease Research Center, Medical College of Wisconsin: and Zablocki Veterans Administration Medical Center, Milwaukee, Wisconsin
The changes in motor activity of the colon during acute colitis were investigated in six conscious dogs. The motor activity was recorded with seven straingauge transducers. Colitis was induced in the entire colon by luminal perfusion of acetic acid. The dogs exhibited urgency and diarrhea with mucus and blood during colitis. The mucosa was diffusely erythematous and friable and there were scattered ulcerations over the mucosal surface. The motor activity of the colon changed in several ways during colitis: (a) the total duration per hour and the mean duration of contractile states decreased significantly; (b) the cycle length of colonic migrating motor complexes was significantly prolonged, and the nonmigrating motor complexes were almost completely absent; and (d) the incidence of giant migrating contractions increased significantly. About half of the giant migrating contractions were followed by defecation. The remaining expelled mucus or gas. Sometimes, a migrating motor complex in the colon was also followed by defecation; this was never observed in the normal state. The motor activity of the colon was still decreased and the cycle length prolonged 21 days after induction of colitis. However, the dogs were asymptomatic at this time and the mucosa looked normal at colonoscopy. The incidence of giant migrating contractions was also normal at this time. It was concluded that the dog is a good model for the study of colitis because of the similarity of symptoms with human ulcerative colitis. The phasic contractions of the colon decreases during colitis but the incidence of giant migrating contractions is increased. The diarrhea in colitis may primarily be due to the large number of giant migrating contractions in the middle and the distal colon.
urgency of defecation. Studies in humans indicate that these symptoms may be associated with significant changes in motor activity of the sigmoid. The general finding of studies in the 1950s was that the incidence of phasic contractions in the sigmoid colon is decreased and that of giant migrating contractions (GMCs) increased during ulcerative colitis (1,2). However, these findings were not confirmed, or were confirmed only in part, by later investigations (3-6) so that a complete understanding of changes in motor activity in colitis is lacking. In fact, Chaudhary and Truelove (5) reported increased motor activity in patients with ulcerative colitis. Some of the reasons for the differences in these reports may be attributed to the limitations of studies in humans. Patients usually cannot serve as their own controls, which means that normal data are available from a different group. The severity and duration of disease varies in the study group and may affect findings. Because of easy access, most early human recordings were made only from the sigmoid colon which does not necessarily represent the motor activity of the entire colon. Finally, the recordings from humans have generally been of short duration. This limits the reliability of comparison of data with normal controls because the spatial and temporal patterns of colonic contractions are highly variable in time (7-10). Because of these limitations, we sought to study the motor activity of the colon in colitis in an experimental dog model. Our objective was to record motor activity of the entire colon with multiple strain-gauge transducers before and after inducing acute colitis and to relate the symptoms of colitis with changes in motor activity.
I
Abbreviations used in this paper: GMCs, giant migrating contractions; MMCs, migrating motor complexes. o 1991 by the American Gastroenterological Association 0016-5085/91/$3.00
nflammatory disorders of the colon, such as ulcerative colitis, are accompanied by diarrhea, passage of mucus and blood, abdominal pain, tenesmus, and
COLONIC MOTOR ACTIVITY IN COLITIS
April 1991
In the older literature from the 1950s (l-S), type I, type II, type III, and type IV nomenclature has been used to describe colonic contractions. Davidson et al. (3) commented that the nomenclature using numbers was confusing. We have used the more recent nomenclature of short-duration (equivalent to type I), longduration (equivalent to type II), and GMCs (equivalent to type IV). All three types of contractions have been identified in the dog and the human colon (8-14). This nomenclature is based on the two myogenic mechanisms of control of contractions in the colon. Short-duration contractions are controlled in time and space by electrical control activity (8,12,14), and long-duration contractions by contractile electrical complex (8,12,14). The myoelectric correlate of GMCs in the colon is not known yet. Type III contractions are redundant because they really represent type I or type II contractions with an accompanying change in baseline.
Methods Experiments were performed on six healthy conscious dogs, each weighing 20-25 kg. During general anesthesia with pentabarbital sodium (Abbott Laboratories, Chicago, IL; 30 mg/kg), the abdomen was opened by a midline laparotomy. The total length of the colon from the ileocoionic junction to the peritoneal reflection was measured soon after IV administration of 100 kg/kg of atropine sulfate (Ivernex Labs, Melrose Park, IL) to minimize shortening of the colon due to handling. The prospective sites for the implantation of seven strain-gauge transducers were immediately marked with 3-O Surgilon sutures (Davis & Geck, Danbury, CN). The first transducer was 5 cm distal to the ileocolonic junction and the last about 2 cm proximal to the peritoneal reflection. The remaining five transducers were spaced equidistant (5.6 2 1 cm apart) between the first and the last. The transducers were oriented to maximally record circular muscle contractions. An additional strain-gauge transducer was implanted on the ileum, 10 cm proximal to the ileocolonic junction. The lead wires were brought out through a stainless steel cannula as described previously (151. An
intraluminal catheter (ID 2.6 mm, OD 4.8 mm) was implanted between the first colonic strain-gauge transducer and the ileocolonic junction. The catheter was tunneled subcutaneously to the subscapular region and exteriorized. The catheter was housed in a protective jacket that each dog wore at all times. The dogs were allowed 10 days to recover from surgery. At this time, each dog had normal stools, generally once a day, and was free of ova and parasites. The dogs were fasted overnight before each experiment. We expected that during colitis the dogs would develop diarrhea. This means that the colon may have less than the usual quantity of fecal material in it during colitis. To insure that the observed changes in motor activity during colitis were not caused by a difference in the volume of fecal material in the colon, we performed experiments in the
955
cleansed and uncleansed colon, both during control condition and during colitis. The experimental protocol was as follows (Table 1). The dogs were fasted for at least 18 hours. After this time, all the previously ingested food should have reached the colon, because small intestinal migrating motor complexes (MMCs) usually return in about 8-10 hours after the ingestion of two cans of dog food (- 1300 kcal). The next day, the colon was cleansed by perfusing 4 L of Colyte (Reed and Carnick, Piscataway, NJ) through the indwelling catheter. On the following day (day l), the dogs were anesthetized with l-1.5 mL of Telazol (A.H. Robins Co., Richmond, VA) and either 10 mL of normal saline or 10 mL of 75% acetic acid was perfused through the indwelling catheter depending on whether it was a control experiment or an experiment to induce colitis. Perfusion of acetic acid resulted in GMCs (15-17) and intense colonic motor activity so that most of the acetic acid was rapidly distributed over the entire colon and expelled in 5-10 minutes. Five minutes after the perfusion of saline or acetic acid, the colon was lavaged with 100 mL of normal saline. The dogs were kept fasted after this procedure. A 4-hour control recording was made the following day (day 2) in the fasted state when the colon was empty. Then each dog was fed two cans of dog food (- 1300 kcal P.D.; Hills Pet Products, Topeka, KS; 447 g each). In preliminary experiments, it was confirmed by colonoscopy that the procedure performed on day 1 thoroughly cleansed the entire colon. On day 3, a &hour control recording was made from the uncleansed colon. The colon was then cleansed again with Colyte as described before, and colonoscopy and biopsy were performed to verify normal mucosal appearance in control experiments or induction of colitis with acetic acid. On day 4, another &hour recording was made in the fasted state from the cleansed colon, and then the dogs were fed a
Table 1. Experimental
Day 0
1
2
3
4
5
6, 7
21
Protocol
Control experiment
Colitis experiment
Fast for 18 h a. Clean colon with Colyte b. Control saline perfusion a. 4 h fasted recording from cleansed colon b. Feed 1300-kcal meal a. 4 h fasted recording from uncleansed colon b. Clean the colon with Colyte c. Confirm normal colon with colonoscopy a. 4 h fasted recording from cleansed colon b. Feed 1300-kcal meal a. 4 h fasted recording from uncleansed colon b. Feed 1300-kcal meal a. 6 h fasted recording from uncleansed colon b. Feed 1300-kcal meal
Same a. Same b. Acetic acid perfusion a. Same
-
b. Same a. Same b. Same c. Confirm colitis with colonoscopy a. Same b. Same a. Same b. Same a. Same b. Same 6 h recording from uncleansed colon
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SETHI AND SARNA
1399-kcal meal as above. On days 5, 6, and 7, 4-6-hour recordings were made in the fasted state from the uncleansed colon. The dogs were then allowed to recover from colitis for about 21 days, after which a 6-hour recording was made from the uncleansed colon. At this time the dogs had semiformed stools but did not exhibit diarrhea or urgency. Before the start of this study, it was established in three other dogs by colonoscopy that perfusion of 10 mL of 75% acetic acid, as described above, induced colitis in all dogs. In these preliminary experiments, colonoscopy was performed on the lst, 3rd, and 5th days after the perfusion of acetic acid. The mucosa had apparently normal appearance on day 21. Recordings were made on a 12-channel Grass pen recorder (model 7D; Grass Instrument Co., Quincy, MA) with lower and upper cut-off frequencies set at direct current and 16 Hz, respectively. The signals were recorded simultaneously on an instrumentation tape recorder (Model 3968A; Hewlett-Packard Co., Palo Alta, CA) so that they could be played back later at a slower or a faster paper speed. As described previously (18), the first two strain-gauge transducers represented the proximal colon, the next three the middle colon, and the last two the distal colon. All data were analyzed visually. The following parameters of colonic motor activity were determined as reported previously (11,12,16,18,19): (a)The cycle length of colonic MMCs was determined in the entire colon. Each recording site in the colon exhibited alternating periods of quiescence and bursts of contractions called quiescent and contractile states, respectively. The occurrence of contractile states was redrawn on a chart paper by straight lines, and the start of each contractile state was connected with the start of the nearest contractile state at the adjacent recording sites. Solid lines were used for caudad and broken lines for orad migration. A contractile state starting anywhere in the colon and migrating greater than half its length in the aborad or the orad direction was called a colonic MMC (11,12,20). All other patterns of contractile states, i.e., those that did not migrate at all, migrated randomly in both directions, or migrated less than half the length of the colon were called nonmigrating motor complexes. The cycle length of a colonic MMC was the time lag between the start of two successive MMCs. (b) The total duration of contractile states per hour and their mean duration were determined at each recording site and then averaged for the proximal, middle, and distal colon as defined above. (c) The mean cycle length of individual contractile states, whether they migrated or not, was determined at each recording site and averaged for the proximal, middle, and distal colon. This parameter represents the cyclic occurrence of both MMCs and nonmigrating motor complexes (18).(c)The point of origin and the distance of migration of GMCs were determined as described previously (16,18). All data are expressed as mean f SE (n = number of dogs]. Colitis was induced only once in each dog. Onefactor analysis of variance with repeated measures and Dunnett’s test were used for statistical analysis of data. A P value of 10.05was considered statistically significant.
GASTROENTEROLOGYVol. lOO.No.4
Results All dogs had developed acute colitis in the entire colon when examined by colonoscopy on day 3 of the experiment. The mucosa appeared diffusely inflamed and markedly friable (Figure 1).There were scattered ulcerations and exudate over the mucosal surface. Symptomatically, colitis was moderately severe. The dogs defecated uncontrollably a total of 22 times during 120 hours of recording in the laboratory during colitis. By contrast, none of the dogs ever defecated during the same duration of the control recording period. In addition, the dogs also exhibited
Figure 1. Top. Mucosal appearance during colitis in the dog is characterized by edema, hemorrhagic lesions, and whitish mucosal exudate. The lumen lost its regular smooth appearance.
Bottom. Mucosal appearance of the normal dog colon. Unlike the human colon, the canine colon does not have haustral folds and does not exhibit the mucosal vascular net.
April 1991
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957
and 2.8 + 0.9 minutes during colitis (P < 0.05; Figure 4B). The mean cycle length of contractile states increased in the proximal, middle, and distal colon from 32 + 4,31 + 2, and 33 -+ 4 minutes in the control state to 65 2 9, 63 + 7, and 111 + 15 minutes, respectively, during colitis (P < 0.05; Figure 4C). Colonic MotorActivity During Colitis Altogether, the contractile states became shorter in (Uncleansed Colon) duration and occurred less frequently during colitis than in the control state. The mean amplitude of Each dog exhibited spontaneous colonic MMCs contractions during colonic motor complexes deand nonmigrating motor complexes in the normal state as described previously [Figure 2 (11,12,18)].creased in the distal colon from 63 + 4 g to 54 + 4 g (P < 0.05). There was no significant change in the During colitis, the cycle length of colonic MMCs was proximal and the middle colon. significantly prolonged to 82 k 7 minutes compared The induction of colitis had no significant effect on with 49 -e 4 minutes during the control state the cycle length of MMCs in the ileum (control, None of the colonic MMCs migrated orad (P < 0.05). 126 + 8 minutes; during colitis, 123 + 7 minutes). during colitis, whereas 4% migrated orad during control. During control, two successive colonic MMCs were usually separated by one or more nonmigrating Effect of Colitis on Giant Migrating motor complexes. During colitis, the nonmigrating Contractions motor complexes were mostly absent so that two A total of three GMCs were observed in 120 successive colonic MMCs were separated by a quieshours of recording during the control state. All of cent state (Figure 3).Two colonic MMCs during these occurred only at the most proximal recording colitis were followed by defecation when they reached site in the proximal colon. None of these contractions the distal colon. This was never observed in the were associated with defecation. By contrast, 40 control state. GMCs occurred in 120 hours of recording during The total duration per hour of contractile activity colitis (Figure 5). Two of these contractions originated decreased dramatically in the proximal, middle, and in the proximal colon, 19 originated in the middle or distal colon from 13 + 1,12 + 0.9,and 15 + 1 min/h in the control state to 2.6+ 0.5,2 k 0.3,and 1.6~fr 0.8 the distal colon and migrated caudad. Nineteen GMCs appeared only on the last gauge or the one proximal to mm/h, respectively, during colitis (P < 0.05; Figure it. The mean distance of migration of these contrac4A). Similarly, the mean duration of contractile states tions was 10 + 1 cm, and they originated at a distance decreased significantly in the proximal, middle, and of 28 + 2 cm from the ileocolonic junction. Nineteen distal colon from 6.5 k 1, 6 k 0.3,and 9.0 + 0.6 of 40 GMCs in colitis were followed immediately by minutes in the control state to 2.5 + 0.2, 2.4 +- 0.3,
urgency, discomfort, and tenesmus. The stools were liquid and contained mucus and blood. Biopsies showed acute ulcerations with intense polymorphonuclear reaction.
Figure 2. Colonic motor complexes in the normal state. Each burst of contractions represents a contractile state. Solid lines indicate caudad and broken lines orad migration of contractile states. Contractile states that migrated greater than half the length of the colon were callcd MMCs. This length was represented by four gauges. The remaining patterns of contractile states were called nonmigrating motor complexes. The overall motor activity consists of a combination of MMCs and nomnigrating motor complexes. Cl-C7 represent the strain-gauge transducers, and the numbers after them represent the distance of gauges from the ileocoIonic junction.
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defecation. The rest were associated with expulsion of gas or simply tenesmus. Tenesmus in dogs was defined as straining without stools. The GMCs that were followed by defecation sometimes migrated up to the last gauge or the one proximal to it, but sometimes they migrated only up to the middle colon. This is in contrast to the normal state, in which the GMCs usually migrate up to the rectum or the sigmoid colon before defecation occurs (16). The GMCs in the normal state were distinct large-amplitude contractions that migrated caudad. The GMCs during colitis also exhibited distinct migration, but they were often mixed with the short- and long-duration contractions. However, this did not seem to affect their ability to expel feces or gas. Colonic Motor Activity During Colitis (Cleansed Colon) The changes in motor activity of the cleansed colon were similar to those of the uncleansed colon. The total duration per hour of contractile states and their mean duration decreased significantly in all parts of the colon (Figure 6A and B). The amplitude of contractions during motor complexes decreased from 65 + 2gto57 + 3ginthemiddleandfrom61? 3gto 53 + 1 g in the distal colon (P < 0.05). There was no significant change in the proximal colon. The mean cycle length of contractile states increased in the proximal, middle, and distal colon (Figure SC). A total of 27 GMCs occurred during 56 hours of recording from the cleansed colon; 10 GMCs appeared only at one site, whereas the remaining GMC migrated caudad.
Figure 3. Colonic motor complexes during colitis. The nonmigrating motor complexes were almost absent during colitis. During colitis, a GMC was often followed by a burst of pbasic contractions that formed the MMC. The duration of contractile states was significantly shorter during colitis than in the normal state (See Figure 4). CZ-C5 represent the colonic straingauge transducers, and the numbers after them represent their distance from the ileocolonic junction.
The GMCs in the cleansed colon originated at a distance of 22 f 2 cm from the ileocolonic junction and migrated caudad a length of 11 + 1 cm. Ten of 27 GMCs in the cleansed colon were followed by expulsion of gas or a bloody mucoid discharge. Colonic Motor Activity After Symptomatic Recovery From Colitis The dogs were symptom-free about 8-10 days after induction of colitis. The postrecovery recordings were made between the 20th and 22nd days after inducing colitis. At this time, the GMCs were absent and the rest of colonic motor activity recovered partially. The total duration per hour and the mean duration of contractile states were significantly greater than those during colitis but still less than those before colitis (P < 0.05; Figure 4). The cycle length of colonic MMCs, 66 + 5 minutes, recovered partially but it was still significantly greater than that during control, 49 + 4 minutes (P < 0.05). Discussion
Motor activity of the human rectosigmoid in ulcerative colitis has previously been described using balloon kymographs (l-3) and manometry (4-6). Kern et al. (1) and Spriggs et al. (2) reported a decrease in the percentage presence of phasic contractions in a majority of patients, in others there was no change, and in some the percentage presence of phasic contractions was actually increased. In addition to the decreased percentage presence of phasic contractions,
COLONIC MOTOR ACTIVITY IN COLITIS
April 1991
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18 16
10 8 6 4
PROXIMAL COLON
2 0 PROXIMAL COLON
MIDDLE COLON
MIDDLE COLON
DISTAL COLON
&TAL COLON Figure 4. A. The total duration of contractile states per hour in the normal state, during colitis, and after symptomatic recovery in the uncleansed proximal, middle, and distal colon. There was a significant decrease in the total duration per hour during colitis, and it recovered only partially after symptomatic recovery. B. The mean duration
of contractile states also decreased significantly during colitis in the uncleansed proximal, middle, and distal colon, and it recovered only partially when the dogs were symptomfree, 21 days after the induction of colitis.
0B
PROXIMAL COLON
MIDDLE COLON
DISTAL COLON
both groups reported increased incidence of GMCs (type IV waves) in patients with ulcerative colitis compared with control subjects. Recently, Rao et al. (6) confirmed the reduction of phasic contractions in the rectum of patients with ulcerative colitis but did not report any GMCs. They postulated that the occurrence of GMCs in previous studies was an artifact of the method of balloon recording. By contrast, Davidson et al. (3) and Snape et al. (4) did not find any difference in the percentage presence of phasic contractions and motility indices, respectively, between normal subjects and patients with ulcerative colitis in the fasting state. Kern et al. (1)hypothesized that the variations in the percentage presence of phasic contractions among patients with ulcerative colitis may be caused by the differences in the severity of symptoms, such as frequency of bowel movements, at the time of study.
C. The cycle length of contractile states was significantly prolonged during colitis in the uncleansed proximal, middle, and distal colon. The cycle length became normal when the dogs were symptom-free, 21 days after the induction of colitis. *P < 0.05 vs. control; tP < 0.05 vs. colitis. Open bars, control; hatched bars, colitis: crosshatched bars, symptomatic recovery: n = 6.
They reported a strong correlation between severity of diarrhea at the time of study and the decrease in the percentage presence of phasic contractions. The patients in the study of Davidson et al. (3) did not have diarrhea at the time of the recordings. Chaudhary et al. (5) disagreed with the hypothesis of Kern et al. and reported little or no difference in phasic contractions between normal subjects and patients with moderate or severe symptoms of ulcerative colitis. On the contrary, they reported that colonic motor activity was less in patients who were symptom-free but exhibited active ulcerative colitis when examined with a sigmoidoscope. Our findings agree with the hypothesis of Kern et al. (1)and indicate that during reasonably uniform conditions of experimental colitis, when symptoms are similar to those in human ulcerative colitis, the normal motor pattern of the colon is significantly
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SETH1 AND SARNA
1
Proximal Colon
1
Middle Colon
4
I
Defecation
altered. First, the total duration of contractile states per hour and their mean duration are significantly decreased. Second, the cycle length of colonic MMCs is significantly prolonged. Both changes represent a reduction in the percentage presence of phasic contractions of the colon. Third, the incidence of GMCs in the middle and the distal colon is significantly increased. The failure of some investigators to record GMCs during colitis may partly be attributable to the short duration of their recordings. Although the incidence of GMCs was increased during colitis, they occurred, on average, once every 3 hours. They could be missed if the duration of recording is short. Our study extends the previous findings in the human rectosigmoid to the entire colon, There was no apparent difference in the severity of colitis between the proximal, middle, and distal colon in our model. Correspondingly, the changes in motor activity during colitis were parallel in all three parts of the colon. Basically, the motor changes in colitis may be divided into two groups: (a) the reduction in the occurrence of short- and long-duration contractions organized as MMCs and nonmigrating motor complexes in the canine colon; and (b) excessive occurrence of GMCs. The reduction in the occurrence of short- and long-duration contractions has previously been reported during diarrhea in humans and dogs (19,21). The hypothesis is that the phasic contractions, which are largely disorganized in time and space in the colon, mix and knead the fecal contents and regulate their slow net distal propulsion (11). When these contractions are absent or reduced, the contents may move rapidly through the colon. According to this hypothesis, the transit should be faster
5 min
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Figure 5. A GMC originating in the middle colon and migrating to the most distal recording site in the colon. The GMC was followed by defecation. The GMCs in colitis were sometimes followed by phasic contractions forming contractile states. CZ-C9 rep resent the strain-gauge transducers, and the numbers after them represent their distances from the ileocoIonic junction.
throughout the colon in patients with colitis than in normal subjects. However, Rao et al. (22) reported that in patients with active colitis the transit was actually slower in the ascending colon and faster in the middle and the distal colon than in normal subjects. The above contradiction may be explained by considering diarrhea to occur for two different reasons, one due to excessive secretions in the small intestine or the colon (secretory diarrhea) and the other due to rapid propulsion of luminal contents by GMCs (motor diarrhea). Transit through the colon in secretory diarrhea in the absence of colonic contractions may be faster because there is no contractile resistance to the flow of contents against hydrostatic pressures generated by the entry of secretions into the colon. On the other hand, if the contents of the colon are viscous or solid, the absence of contractions or a significant reduction in their occurrence may result in little or no propulsion, resulting in stasis. This hypothesis is supported by findings that the transit of a liquid meal is faster through the colon than that of a solid meal (22). The faster transit time in the middle and the distal colon reported by Rao et al. in active colitis may be caused by excessive occurrence of GMCs in those parts of the colon. In the normal state, the spontaneous GMCs usually occur in the proximal colon, where they cause occasional mass movements, once or twice a day (13,16,23). In the distal or the middle colon, the GMCs occur just before defecation (16). During colitis, there was a dramatic increase in the incidence of GMCs in the middle and the distal colon. About half of these contractions produced defecation of fluid stools, sometimes stained with blood, and the rest expelled gas.
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20 0 Control EZdColitis
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L
Distal Colon
The dogs were uncomfortable when these GMCs occurred. We propose that the symptoms of urgency, tenesmus, and passage of mucus during colitis may largely be caused by the excessive occurrence of GMCs. Frequent occurrence of GMCs when the mucosa is inflamed and friable may also cause bleeding. The precise mechanisms for the initiation of an excessive number of GMCs in the middle and the distal but not the proximal colon in colitis are not known. There was no apparent difference in injury to the mucosa between the proximal, middle, and distal colon. We would like to hypothesize that the stimulus for the excessive number of GMCs was the fecal contents or accumulation of mucus. The sensory mechanisms in the colonic wall may be sensitized
6. A. The total duration of contractile states per hour decreased significantly in the cleansed proximal, middle, and distal colon during colitis.
Figure
B. The mean duration of contractile states decreased significantly the cleansed proximal, middle, and distal colon during colitis.
in
C. The cycle length of contractile states was prolonged significantly in the cleansed proximal, middle, and distal colon during colitis.
because of mucosal inflammation so as to initiate defecation reflex at lower thresholds of chemical and mechanical irritation. Rao et al. (6) also reported that the sigmoid in patients with ulcerative colitis was hypersensitive to the infusion of saline. Furthermore, clinical observations indicate that the symptoms of urgency and frequency of defecation are exaggerated in patients with ulcerative colitis postprandially, presumably because the entry of new digesta into the colon. In support of this, we reported recently that the frequency of GMCs and the incidence of defecation is .increased significantly after a meal during experimental colitis in dogs (24). The metabolism of arachadonic acid in the mucosa is increased in acetic acid-induced colitis in rats (25)
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and in human inflammatory bowel disease (26). The increased production of prostaglandin may play a role in the inhibition of phasic contractions and stimulation of GMCs in colitis. Staumont et al. (27) report that close intraarterial perfusion of prostaglandin E, mimics the decrease in phasic contractions and the stimulation of GMCs in dogs. They also reported that a similar motor response of the colon to sennosides was blocked by indomethacin that blocks the synthesis of prostaglandins. However, other mechanisms independent of prostaglandin synthesis may also be involved. For example, the phasic contractions of the colon are inhibited in diarrhea induced by castor oil (16), which is not known to increase the synthesis of prostaglandins. Systematic studies of motor activity during relapses and remissions of colitis have not been performed in humans. However, our findings indicate that several parameters of motor activity, such as total duration of contractile activity per hour, mean duration of contractile states, and frequency of colonic MMCs, may still be less than normal even though the symptoms may be absent and mucosa may appear normal during a relapse. We did not study our dogs longer than 3 weeks to determine whether these changes were permanent because of irrevocable neural, chemical, or myogenic changes in the colon wall once colitis was induced. The major factor that normalized when symptoms were absent was the occurrence of GMCs, which may play a major role in the production of these symptoms. This suggests the occurrence of motor rather than secretory diarrhea in colitis, as defined above. Experimental colitis produced in dogs by exposure of the mucosa to acetic acid seems to be a good model of colitis in humans because of the similarity of symptoms. However, we are not certain whether the morphological changes in experimental colitis are similar to those in patients with inflammatory bowel disorders. Thus far, the organization of colonic contractions into MMCs and nonmigrating motor complexes has been established only in the rat and the dog colon (11,12,18,28). Although cyclic occurrence of contractile states at individual sites has been reported in the human colon, their migration has not been observed (7,293. This may be a species difference or it may be caused by the cleansing procedure required for the placement of the manometric tube into the colon and the empty state of the colon at the time of recording. We recently reported (30) that perfusion of absorbable or nonabsorbable solutions into the colon disrupts MMCs in the dog colon. This disruption of colonic MMCs lasts for several hours after the colon is cleansed in this manner. Regardless of whether contractions in the human colon are organized as MMCs
GASTROENTEROLOGY Vol. 100, No. 4
and nonmigrating motor complexes, the total amount of contractile activity is decreased similarly, in both dogs and humans, in colitis. In conclusion, experimental colitis induced by exposure of the colonic mucosa to acetic acid produces symptoms similar to those observed in human ulcerative colitis. The total incidence of contractile activity decreases during colitis, but the incidence of GMCs is significantly increased. These GMCs are associated with urgency, tenesmus, and passing of feces, mucus, and gas. The diarrhea produced in colitis may primarily be attributable to the large number of GMCs in the middle and the distal colon. All parameters of phasic contractions in the colon are not normalized when the colon heals and the dogs are symptom-free, but the incidence of GMCs returns to normal.
References 1. Kern FJ, Almy TP, Abbot FK, Bogdonoff MD. The motility of the distal colon in nonspecific ulcerative colitis. Gastroenterology 1951;19:492-503. 2. Spriggs EA, Code CF, Bargen JA, Curtiss RK, Hightower NC Jr. Motility of the pelvic colon and rectum of normal persons and patients with ulcerative colitis. Gastroenterology 1951;19:480491. 3. Davidson M, Sleisenger MH, Almy TP, Levine SZ. Studies of distal colonic motility in children. II. Propulsive activity in diarrhea1 states. Pediatrics 1956;17:820-832. 4. Snape WJ Jr, Matarazzo SA, Cohen S. Abnormal gastrocolonic response in patients with ulcerative colitis. Gut 1980;21:392396. 5. Chaudhary NA, Truelove SC. Human colonic motility: a comparative study of normal subjects, patients with ulcerative colitis, and patients with the irritable colon syndrome. I. Resting patterns of motility. Gastroenterology 1961;40:1-36. 6. Rao SSC, Read NW, Stobart JAH, Haynes WG, Benjamin S, Holdsworth CD. Anorectal contractility under basal conditions and during rectal infusion of saline in ulcerative colitis. Gut 1988;29:769-777. 7. Narducci F, Bassotti G, Gaburri M, Morelli A. Twenty four hour manometric recording of colonic motor activity in healthy man. Gut 1987;28:17-25. 8. Sarna SK, Latimer P, Campbell D, Waterfall WE. Electrical and contractile activities of the human rectosigmoid. Gut 1982;23: 698-705. 9. Latimer P, Sarna SK, Campbell D, Latimer MR, Waterfall W, Daniel EE. Colonic motor and myoelectrical activity: a comparative study of normal subjects, psychoneurotic patients, and patients with irritable bowel syndrome. Gastroenterology 1981; 80:893-901. 10. Dinoso VP Jr, Murthy SNS, Goldstein J, Rosner B. Basal motor activity of the distal colon: a reappraisal. Gastroenterology 1983;85:637-642. 11. Sarna SK, Condon R, Cowles V. Colonic migrating and nonmigrating motor complexes in dogs. Am J Physiol1984;246:G355G360.12. 12. Sarna SK. Myoelectric
correlates of colonic motor complexes and contractile activity. Am J Physiol 1986;250:G113-G220. 13. Hardcastle JD, Mann CV. Study of large bowel peristalsis. Gut 1968;9:412-520. 14. Fioramonti J, Bueno L. Diurnal changes in colonic motor
COLONIC MOTOR ACTIVITY IN COLITIS
April 1991
15.
16.
17. 18. 19.
20.
21.
profile in conscious dogs. Dig Dis Sci 1983;28:257-264. Sarna SK. In vivo myoelectric activity: methods, analysis and interpretation. In: Wood JD, ed. Handbook of physiology, gastrointestinal motility and circulation. Bethesda, MD: American Physiological Society, 1989:817-863. Karaus M, Sarna SK. Giant migrating contractions during defecation in the dog colon. Gastroenterology 1987;92:925933. Sarna SK, Prasad KR, Lang IM. Giant migrating contractions of the canine cecum. Am J Physiol1988;254:G595-G601. Sarna SK, Lang IM. Colonic motor response to a meal in dogs. Am J Physiol1989;257:G30-G35. Karaus M, Sarna SK, Ammon I-IV, Wienbeck M. Effects of oral laxatives on colonic motor complexes in dogs. Gut 1987;28: 1112-1119. Flourie B, Phillips S, Richter H III, Azpiroz F. Cyclic motility in canine colon: responses to feeding and perfusion. Dig Dis Sci 1989;34:1185-1192. Connell AM. The motility of the pelvic colon. Part II. Paradoxical motility in diarrhoea and constipation. Gut 1962;3:342-
25. 26.
27.
28.
29.
30.
963
acute colitis (abstr). Gastroenterology 1990;98:A667. Sharon P, Stenson WF. Metabolism of arachidonic acid in acetic acid colitis in rats. Gastroenterology 1985;88:55-63. Sharon P, Stenson WF. Enhanced synthesis of leukotriene B by colonid mucosa in inflammatory bowel disease. Gastroenterology 1984;86:453-460. Staumont G, Fioramonti J, Frexinos J, Bueno L. Changes in colonic motility induced by sennosides in dogs: evidence of a prostaglandinmediation. Gut 1988;29:1180-1187. Ferre JP, Ruckebusch Y. Myoelectrical activity and propulsion in the large intestine of fed and fasted rats. J Physiol Lond 1985;362:93-106. Bassotti G, Gaburri M, Imbimbo BP, Rossi L, Farroni F, Pelli MA, Morelli A. Colonic mass movements in idiopathic chronic constipation. Gut 1988;29:1172-1179. Sarna SK. Perfusion of non-caloric absorbable and nonabsorbable solutions disrupt colonic motor activity (abstr). Gastroenterology 1990;98:A387.
348. 22.
23. 24.
Rao SSC, Read NW, Brown C, Bruce C, Holdsworth CD. Studies on the mechanism of bowel disturbance in ulcerative colitis. Gastroenterology 1987;93:934-940. Ritchie J. Mass peristalsis in the human colon after contact with oxyphenisatin. Gut 1972;13:211-219. Sethi AK, Sarna SK. Colonic motor response to a meal during
Received March 27,199O. Accepted August 31,199O. Address requests for reprints to: Sushi1 K. Sarna, Ph.D., Surgical Research 151, Zablocki Veterans Administration Medical Center, 5000 West National Avenue, Milwaukee, Wisconsin 53295. Supported in part by grants from NIDDK DK32346 and Veterans Administration Medical Research Service (to S.K.S.).