Canine small bowel motor patterns and contractions are not neurally regulated during enteric nutrient infusion

Kevin E. Behrns, Michael G. Sarr, Russell B. Hanson, and Alan R. Zinsmeister

Department of Surgery, Gastroenterology Research Unit, and the Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905

    ABSTRACT
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Abstract
Introduction
Methods
Results
Discussion
References

The aims of this study were to determine the effects of duodenal and jejunoileal nutrient infusions on small intestinal motor patterns and intestinal contractions in neurally intact and neurally isolated small bowel. Fifteen dogs were prepared with duodenal and jejunal infusion and manometry catheters and a diverting jejunal cannula. Ten of the dogs underwent in situ neural isolation of the jejunoileum. A mixed nutrient meal (0.5 kcal/ml) was infused into the duodenum or jejunum at 3 ml/min for 5 h. Control experiments involved infusion of a balanced salt solution. Manometric data collected on-line to a microcomputer were analyzed for direction, distance, and velocity of spread of single pressure waves (SPW) and clustered contractions. Isolated duodenal and jejunoileal nutrient infusions inhibited the fasting motor pattern in neurally intact and neurally isolated small bowel. Motor activity (motility index) increased slightly during nutrient infusion within groups, but there were few differences between groups. Neither neural isolation nor nutrient infusion had a consistent effect on spread of SPW or migration of clustered contractions. Isolated duodenal and jejunoileal nutrient infusions in the dog inhibit fasting motor patterns and increase motor activity slightly but have little effect on characteristics of individual and clustered contractions. Extrinsic innervation to the jejunoileum or intrinsic neural continuity of the jejunum with the duodenum had little effect on single or grouped contractions. Although the changes in motor activity demonstrated in this study appear small, alterations in intestinal transit and absorption may still occur and may be of importance physiologically.

motility; migrating motor complex; single pressure waves; clustered contractions; neural regulation

    INTRODUCTION
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Abstract
Introduction
Methods
Results
Discussion
References

IN MOST NONRUMINANT MAMMALS, ingestion of a meal converts the interdigestive migrating motor complex (MMC) to a pattern of intermittent contractions characteristic of the fed pattern of motility (17). These postprandial motor changes are presumably related to changes in neurohormonal input to gastrointestinal smooth muscle. Both nutritive and nonnutritive factors have been implicated as stimuli that produce these neurohormonal changes. Several groups (8, 23) have shown that caloric density and nutrient composition are stimuli that alter motor patterns, whereas other studies have demonstrated that nonnutrient factors such as gastric distension (7) and nonnutrient duodenal flow (15) may also be important modulators of postprandial gastrointestinal motor patterns. Nutritive factors are thought to produce changes in the gastrointestinal hormonal and neural milieu and thereby mediate at least some of the changes in patterns of motility. Several studies (10, 22) have demonstrated that nutrient infusion into an enterically isolated segment of small intestine during fasting induces postprandial motor patterns in regions distant to the site of infusion. These changes in motor patterns are thought to be mediated by circulating regulatory substances and not neural pathways because changes in motor patterns are noted throughout the gastrointestinal tract when intestinal segments neurally isolated from the remainder of the gut are perfused with nutrients (10, 26). Neural pathways, however, may modulate motor changes produced by nutrient and nonnutrient factors such as gastric distension (7).

Until recently, changes in overall intestinal motor patterns and concomitant alterations in gastric emptying and intestinal transit were the only outcome variables that could be used objectively to monitor motor changes after ingestion of nutrients (9). Application of computer technology, however, has allowed objective evaluation of both single pressure waves (SPW) and small groups of isolated intestinal contractions called clustered contractions. Using these computer-assisted techniques, Ehrlein et al. (9) found that nutrient infusion decreases the frequency and the length of aborally spreading contractions in various anatomic regions of the small intestine (5). To date, no study has investigated the effect of isolated intestinal nutrient infusion on characteristics of SPW in the segment of intestine infused or in the distant bowel not exposed to the infusate. Furthermore, the role of neural pathways in modulating the characteristics of local and distant SPW and clustered contractions in response to infused nutrients has not been investigated.

The aims of this study were to examine in vivo neural mechanisms that mediate the effects of isolated duodenal and jejunoileal nutrient infusions on local and distant motor patterns, on the quantity of contractile activity, and on characteristics (direction, distance, and velocity) of spread of SPW and of migration of clustered contractions. We investigated these variables in the neurally intact dog and in dogs after a model of in situ jejunoileal neural isolation (extrinsic denervation and disruption of enteric nervous continuity with the remainder of the gut). We hypothesized that nutrient infusion into either the duodenum or the jejunoileum would convert the MMC to a fed pattern of motility, increase the quantity of contractile activity, and decrease the proportion and length of spread of contractions in the duodenum and jejunum, irrespective of the site of infusion, in both neurally intact and neurally isolated animals.

    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

Preparation of Dogs

Surgical procedures and subsequent care and conduct of experiments were performed after approval from and according to criteria set forth by the Animal Care and Use Committee of the Mayo Foundation in accordance with the guidelines of the National Institutes of Health and the Public Health Service Policy on the humane use and care of laboratory animals. The experimental preparation has been described in detail previously (3) and is outlined briefly below.

Group 1. Five healthy female mongrel dogs weighing 15-24 kg were anesthetized with intravenous methohexital sodium (12.5 mg/kg), and anesthesia was maintained with 1.5% halothane. Optimal measurement and placement of small bowel manometry catheters were ensured by preoperative administration of subcutaneous atropine sulfate (0.04 mg/kg). Through a midline celiotomy, a flanged cannula for decompression was placed in the midcorpus of the stomach and exteriorized through the anterior abdominal wall. A duodenal infusion catheter (2.4 mm OD, 1.6 mm ID) was placed 8 cm distal to the pylorus via a duodenotomy. Similarly, a jejunal infusion catheter (3.6 mm OD, 3.2 mm ID) was inserted 40 cm distal to the duodenojejunal junction. Four duodenal and four jejunal manometry catheters (1.5 mm OD, 0.5 mm ID and 1.0 cm in length) were each positioned at 8-cm intervals beginning 10 cm distal to the respective infusion catheters through separate enterotomies. The infusion and manometry catheters were embedded in two metal cannulas, which were exteriorized through the anterior abdominal wall. A side-diverting, modified Gregory-Thomas cannula (16 mm OD, 10 mm ID) was placed in the very proximal jejunum 10 cm distal to the duodenojejunal junction through a longitudinal jejunotomy and brought out through the anterior abdominal wall. After the celiotomy was closed, a concomitant episiotomy of the vaginal introitus was performed to facilitate placement of a urinary bladder catheter.

Group 2. Ten additional dogs underwent identical hardware placement and our model of in situ neural isolation of the jejunoileum (19, 21); all neural, myogenous, lymphatic, and connective tissue continuity with the jejunoileum was transected, except for the superior mesenteric artery and vein. The proximal jejunum (just distal to the diverting proximal jejunal cannula) and the terminal ileum were transected, and the mesentery was divided and ligated radially back from the transection sites to the proximal superior mesenteric artery and vein. All connective, neural, and lymphatic tissues surrounding these vessels were ligated and divided so that these vessels were isolated for at least 1 cm. With optical magnification, the adventitia of these vessels was stripped meticulously. Hence, the entire jejunoileum was isolated neurally so that the only remaining neural input possible to the jejunoileum was through the media of the superior mesenteric artery and vein. Intestinal continuity was reestablished by an end-to-side jejunojejunostomy to preclude reestablishment of enteric neural continuity with the duodenum and by an end-to-end ileoileostomy (1). Extrinsic denervation of this model of neural isolation has been confirmed previously by measuring tissue catecholamine concentrations, which decreased to undetectable concentrations after neural isolation and persisted for at least 4 mo (20). After surgery and during the course of the study, dogs with neurally intact intestine maintained a stable weight, with normal appetites and without changes in fluid status or gastrointestinal function. Dogs with neurally isolated small bowel, however, lost 10-15% of their body weight despite normal appetites. In addition, these dogs had watery diarrhea for 2 wk, but had semiformed stool by 8 wk postoperatively. All experiments were completed by 8 wk postoperatively in group 2.

Conduct of Experiments

Following a 2-wk recovery, dogs were studied after an overnight fast, while fully conscious and resting comfortably in a Pavlov sling. An indwelling balloon catheter was inserted into the bladder to prevent distension during infusion studies. During all experiments the gastric cannula was opened to allow gastric decompression and to quantitate duodenogastric reflux. The proximal jejunal diverting cannula was also opened during all experiments; the bile and pancreatic juice collected before intestinal infusion were collected and reinfused in the duodenal infusion catheter at the conclusion of the experiment. Small intestinal motor activity was recorded continuously with manometry catheters perfused with deionized, degassed water (0.1 ml/min), using a low-compliance, pneumohydraulic capillary infusion system. Changes in intestinal pressure were measured with Statham P23 pressure transducers (Statham Instruments, Westminister, CA) connected to a Grass model 7D multi-pen polygraph (Grass Instrument, Quincy, MA) and digitized simultaneously at 4 Hz and recorded on-line to a microcomputer as described previously (3, 4).

Experiments were begun after phase III of the MMC had passed through all recording sites. The duodenum or the jejunoileum in neurally intact animals was infused with either a noncaloric, isosmolar, balanced salt solution (SS) designed to reproduce the electrolyte content [(in mM) 140 Na+, 5.0 K+, 110 Cl-, and 35 HCO-3] of the proximal small intestine or a mixed nutrient solution (M) consisting of 50% Meritene (46% carbohydrate, 24% protein, 30% fat, 0.5 kcal/ml) at a rate of 3 ml/min for 5 h (Table 1), using a constant- rate peristaltic pump (Gilison Minpuls 2, Middleton, WI). On separate days, each dog also underwent duodenal infusion with the mixed nutrient Meritene solution (M), whereas the jejunoileum was infused with either the chyme (C) exiting the diverting proximal jejunal cannula or the noncaloric electrolyte solution (SS). The jejunoileal infusion rates during these latter experiments were determined by the rate at which chyme exited the diverting proximal jejunal cannula. Experiments were performed in random order on separate days.

                              
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Table 1.   Experimental design

Because evidence exists that enteric neural regeneration may occur with time in the neurally isolated jejunoileum (18), and because we wanted to complete all experiments within 8 wk postoperatively, two separate subgroups of five dogs each within group 2 underwent identical jejunoileal neural isolation procedures. As part of a larger series of studies (2-4), one group of dogs after neural isolation of the jejunoileum underwent isolated duodenal and jejunoileal nonnutrient infusions [with the identical noncaloric electrolyte solution (SS)]; duodenal and jejunoileal infusions at a rate of 3 ml/min were two such experiments. This group of dogs with neurally isolated jejunoileum served as the control arm of the current study. A second group of five dogs with neurally isolated jejunoileum did not undergo the nonnutrient infusions but underwent duodenal and jejunal nutrient infusions with or without concomitant jejunoileal chyme (C) or electrolyte infusion (SS) and jejunoileal nutrient infusion (M). In all dogs fasting motor patterns were assessed for 5 h on three separate occasions when no duodenal or jejunal infusions were administered.

Previous studies in our laboratory have shown that the side-diverting proximal jejunal cannula was effective in diverting jejunal content from the duodenum in both the neurally intact dogs and the dogs with neurally isolated jejunoileum (4). The percentage of jejunal content refluxing at the proximal jejunal cannula into the duodenum was 6 ± 3% at an infusion rate of 3 ml/min. In addition, dual-marker perfusion studies showed that the proximal jejunal cannula was effective in diverting >97% of duodenal content from the jejunum at a duodenal infusion rate of 3 ml/min.

Analysis of Data

Motor patterns. Manometric tracings were analyzed for motor patterns by visual inspection of the hard copies and the computer reproductions. The presence or absence of the MMC in the duodenum and jejunum was noted using the criteria of Code and Marlett (6) and our previous study (15) modified for motor tracings. Characteristics of the MMC, including the period, duration of phases, and the time to the first phase III after the beginning of the infusion, were determined and reported previously (3). A pattern of intermittent contractions after nutrient infusion was considered a fed-like motor pattern.

Motor activity. To quantitate motor activity, the manometric data were filtered to remove minor fluctuations in pressure and artifact (pressure rise or fall occurring simultaneously on six of eight recording channels). Pressure waves were identified as positive deflections from the baseline (flat areas with <2.8 mmHg change/0.25 s). To exclude respiratory artifact, pressure peaks were used in calculations only when the amplitude was >10 mmHg. The amplitude of each peak was defined as the distance from the baseline to the apex of the peak. Motility was quantified by a motility index for each 30-min period after the infusion began. The motility index (MI) was defined as MI = loge (sum of amplitudes × frequency of pressure waves + 1).

Spread of SPW. Spread of SPW within the duodenum and jejunum was determined with the four duodenal and the four jejunal recording sites using individual short, surgically implanted manometric catheters that preclude intestinal "sleeving." The peak of the pressure wave was designated as the index time of each wave, and the direction of spread of the pressure wave was classified as antegrade (aborad), retrograde (orad), simultaneous (at least two waves occurring simultaneously on consecutive different channels within 0.25 s), or stationary (no pressure waves within 0.25 s on consecutive channels). Gated time windows, determined individually for each dog, were used to identify the spread of SPW. Time windows in the duodenum and in the jejunum for each dog were determined under fasting conditions with no intestinal perfusion by analyzing the "best fit" velocity of SPW in the duodenum and jejunum during a 2-min portion of phase III of the MMC, as described in depth previously (4). The time windows were gated as the mean best fit velocity plus or minus 1 s. The duodenal time windows allowed duodenal contractions with velocities ranging from 4.6 to 32 cm/s, whereas in the jejunum the time windows admitted single pressure wave velocities ranging from 2.7 to 32 cm/s.

The mean minimum distance that pressure waves spread was determined. Pressure waves occurring at only one recording site were included in the analysis and considered to spread 0 cm, whereas those that occurred at two recording sites spread at least 8 cm, at three recording sites spread at least 16 cm, and at all four recording sites spread a minimum of 24 cm. The mean minimum length of spread and the mean antegrade and retrograde velocity of spread of pressure waves were determined. The spread of SPW was analyzed in 30-min periods throughout each experiment.

Clustered contractions. The occurrence of clustered contractions, defined as a group of at least three pressure waves occurring at the maximum estimated frequency of the slow wave (18-24/min duodenum and 10-16/min jejunum) and preceded by a 10-s quiescent period, was determined in both the duodenum and the jejunum as described before (4). Each individual contraction within a cluster had a minimum amplitude of 6 mmHg, whereas the mean amplitude for all SPW in a cluster of contractions was >10 mmHg. The duration of a clustered contraction was limited to 4 min so it would not be confused with phase III of the MMC. Clustered contractions were evaluated for the frequency of occurrence and the distance, direction, and velocity of migration. The clustered contractions were considered to migrate in either an antegrade or retrograde direction, or if clustered contractions occurred within 3 s on consecutive channels, the clusters were considered to be simultaneous. Isolated clustered contractions were not accompanied by clusters on consecutive channels within 3 s of the index cluster.

For consistency, the direction of movement of SPW will be referred to as spread, whereas the movement of clustered contractions and of phase III of the MMC will be called migration.

Statistical Methods

Comparisons of response values were analyzed using several complimentary methods. First, the observed values in groups 1 and 2 were compared separately under each condition between groups using an independent samples t-test. Second, the within-dog change in values between different experimental conditions was compared within each group using a paired t-test in the following ways: conditions 2-5 were compared with condition 1 (i.e., we determined if the change in values between condition 2 and condition 1 was different from zero, and similarly for each specific condition); and conditions 6-7 were compared with condition 4. Third, to determine if the changes within dogs under the various conditions were different between groups, the change in values (vs. conditions 1 or 4) within each dog were compared between groups using an independent sample t-test. Alternatively, the groups were compared separately under conditions 2-5 after adjusting for the corresponding values under condition 1 (no duodenal or jejunal infusions) and for conditions 6 and 7 after adjusting for the values under condition 4 (duodenal Meritene and no jejunal infusion). This final analysis was based on analysis of covariance.

Data within the text are expressed as means ± SE. A two-sided alpha level of 0.05 was used to assess the statistical significance of the results, although actual P values in the range of 0 to 0.1 are listed as well.

    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

Motility Data Analysis

Motor patterns. In group 1 the MMC cycled invariably in the duodenum and jejunum during the no- infusion and nonnutrient infusion experiments. During the duodenal and jejunal nutrient infusions, the MMC was consistently inhibited for the duration of the infusions except for one experiment (duodenal infusion) when a single phase III occurred in the duodenum and in the jejunum during the infusion.

In group 2, cycling of the MMC was less consistent, and temporal coordination of phase III activity between the duodenum and jejunum was completely disrupted as described previously (3). Phase III of the MMC was not present in the duodenum or in the jejunum in 7 and 13% of noninfusion experiments, respectively. In these experiments the motor pattern consisted of intermittent contractions resembling subjectively phase II or a fed-like pattern. With nonnutrient infusions, 40% of experiments in group 2 exhibited disruption of the MMC in either the duodenum or jejunum. Again, the motor pattern resembled a phase II or fed-like pattern of motility. During the nutrient infusions, the MMC was reliably and consistently inhibited in both duodenum and jejunum in all experiments.

Number of contractions. The mean number of SPW per 30-min interval of the 5-h experiments is shown in Fig. 1. Under fasting conditions with no infusions in both duodenum and jejunum, neural isolation of the jejunoileum (group 2) resulted in an increase in the number of jejunal SPW compared with neurally intact animals (221 ± 42 vs. 344 ± 32, P < 0.05). No difference in the number of SPW was apparent in the duodenum between the two groups.


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Fig. 1.   Mean ± SE number of single pressure waves (SPW) per 30-min interval in duodenum (A) and jejunum (B) in groups 1 (open bars) and 2 (solid bars) during enteric infusion. Conditions 2-5 vs. condition 1 and conditions 6 and 7 vs. condition 4. SS, salt solution; N, no infusion; M, mixed nutrient solution; C, chyme exiting proximal diverting jejunal cannula. * P < 0.05, group 1 vs. group 2 (ANCOVA). dagger  P < 0.05, within group comparisons.

Infusions of the noncaloric salt solution (SS) and the mixed nutrient solution (M) altered the number of duodenal SPW under certain conditions. Duodenal infusion of M increased the number of duodenal SPW within group 2 (P < 0.05) only, but duodenal infusions of SS and jejunal infusions of SS had no consistent or significant effect on the number of SPW in the duodenum in either group. In contrast, infusions of M into the jejunum markedly decreased the number of duodenal SPW in both groups 1 and 2 compared with no infusion (N; 320 ± 34 to 87 ± 27 and 284 ± 43 to 61 ± 22, respectively; P < 0.05 each). When the duodenal chyme (C) but not SS was concomitantly reinfused into the proximal jejunum during duodenal infusion of M, the number of duodenal SPW decreased in both groups compared with experiments with duodenal M and no jejunal reinfusion (N; P < 0.05 for each).

Changes were also noted in jejunal SPW with infusions. Duodenal and jejunal infusions of SS had no significant effects on the number of jejunal SPW in either group, but both duodenal and jejunal infusions of M increased the number of jejunal SPW in both groups. Jejunal reinfusion of C during duodenal infusion of M had no significant effects on jejunal SPW compared with no jejunal reinfusion, but jejunal reinfusion of SS increased the number of jejunal SPW in group 2; this effect was not seen in group 1.

Motility index. Changes in the motility index during the various infusion conditions tended to follow trends similar to the changes observed in the number of SPW (Table 2). In the absence of duodenal and jejunal infusions, no significant differences were noted in the duodenal motility indexes of groups 1 and 2. In contrast, the jejunal motility index was greater in group 2 (11.1 ± 0.5 vs. 12.9 ± 0.3, P < 0.005).

                              
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Table 2.   Duodenal and jejunal motility indexes in dogs with neurally intact (group 1) and neurally isolated (group 2) small bowel during nutrient infusion

Within group 1, duodenal infusions of SS increased the duodenal and jejunal motility indexes, but duodenal nutrients increased only the duodenal motility index. These differences were not apparent within group 2, nor were between-group differences noted during duodenal infusion. Jejunal infusions of SS increased the jejunal motility index in group 2 compared with group 1, but this difference was not present when the condition was corrected for the basal condition. Jejunal M increased the jejunal motility index within group 2 compared with no infusion (N). When C or SS was reinfused into the jejunum in group 1 (while M was infused into the duodenum), there was no significant effect on the duodenal motility index compared with the state of duodenal M and no infusion into the jejunum. In contrast, within group 2 jejunal reinfusion of C decreased the motility index in the duodenum, while reinfusion of SS increased the motility index slightly in both the duodenum and jejunum.

Adjusted between-group analyses showed that jejunal infusion of SS with duodenal M decreased the duodenal motility index in group 1 compared with group 2 (P = 0.004).

Single Pressure Wave Analysis

Direction of spread. The percentage of enteric SPW spreading in the antegrade (aborad) direction is shown in Table 3. Under basal conditions without duodenal or jejunal infusions, the antegrade spread of jejunal SPW was greater in group 2 (17 ± 3 vs. 27 ± 2, P = 0.018). Infusion of SS or M into the duodenum had no significant effect on direction of spread of SPW in group 1 either in the duodenum or in the jejunum. In contrast, duodenal M but not SS markedly increased the percentage of SPW spreading antegrade in both the duodenum and the jejunum within group 2. During jejunal infusion of SS, the percentage of jejunal antegrade spread of SPW was greater in group 2, but there were no significant effects in either group when corrected for basal conditions. Jejunal M decreased the percentage of SPW spreading antegrade in the duodenum within both groups but increased the percentage in the jejunum. Compared with duodenal infusion of M alone, reinfusion of C into the jejunum had no significant effect in either group, but reinfusion of SS increased the percentage of duodenal aborad spread within group 1 only. In addition, adjusted between-group analysis showed that duodenal aborad spread was greater in group 1 in this condition.

                              
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Table 3.   Antegrade direction of spread of single pressure waves in duodenum and jejunum during enteric infusions

Although infrequent, on occasion small differences were noted in the direction of spread of retrograde SPW. These differences were small and not related consistently to the location of infusion or content of the infusate (data not shown).

Distance of spread. The mean distance of antegrade, retrograde, and stationary spread of SPW was determined, and the results of antegrade spread are shown in Table 4. With no duodenal or jejunal infusion, group 1 had a decreased jejunal distance of spread compared with group 2 (P = 0.014). Duodenal infusion of SS had no effect within or between groups, but duodenal nutrients increased the distance of jejunal SPW spread in group 2 (compared with group 1). Group 2 also demonstrated within-group differences in the distance of spread of duodenal and jejunal SPW with duodenal nutrient infusion. Jejunal infusion of either SS or M increased the jejunal distance of spread of group 2 compared with group 1, but these differences disappeared when values were adjusted for basal conditions within groups. In addition, jejunal M resulted in within-group differences in groups 1 and 2 by decreasing the duodenal (but increasing the jejunal) distance of spread of SPW.

                              
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Table 4.   Distance of antegrade spread of duodenal and jejunal single pressure waves during enteric infusions

Jejunal reinfusion of C or SS had little consistent effect on the distance of spread, but within group 1 the duodenal distance decreased compared with condition 4 (M, N) during SS reinfusion. The duodenal distance of spread in group 2 was increased compared with group 1 when analyzed by adjusted methods (P = 0.008) during SS reinfusion.

The mean distance of spread of antegrade SPW and retrograde SPW averaged 3-5 cm and <1 cm, respectively, in both groups, and few SPW spread 16 or 24 cm. No consistent differences were noted depending on location of infusion or content of perfusate (data not shown).

Velocity of spread. The mean velocity of spread of SPW in duodenum and in jejunum differed little between or within groups under basal conditions and during the infusion experiments (Table 5). Duodenal infusion of SS had no effect on the velocity of spread, but duodenal M increased the duodenal velocity within group 1 (P = 0.001). Jejunal SS infusion increased the velocity of spread of duodenal SPW in group 1 and jejunal SPW in group 2. Adjusted between-group analysis also demonstrated differences in the jejunal velocity of spread during jejunal SS infusion. Jejunal nutrient infusion increased only duodenal velocity of spread within group 1. No differences were noted with jejunal C or SS reinfusion.

                              
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Table 5.   Velocity of antegrade spread of duodenal and jejunal single pressure waves during enteric infusions

The mean velocities of spread of antegrade SPW in the duodenum and jejunum were 12-15 and 6-9 cm/s, respectively, in both groups. Although infrequent, differences in the velocity of spread of retrograde SPW were noted. These were generally small and were not consistently related to the location or content of infusion (data not shown).

Clustered Contractions

Number of clustered contractions. During baseline conditions of no duodenal or jejunal infusions, there were no differences noted between groups either in duodenum or jejunum (Fig. 2). Infusion of SS into the duodenum increased the number of clustered contractions in the duodenum but not in the jejunum in group 1 but had no significant effects in either the duodenum or jejunum compared with the basal condition in group 2. Duodenal infusions of M increased the number of clustered contractions only in the duodenum in group 2 (328 ± 41 to 623 ± 111, P < 0.05). In contrast, although jejunal SS infusions had no significant effects in either group, jejunal infusion of M markedly decreased the number of duodenal clustered contractions in group 2 but increased the number of jejunal clustered contractions in group 1 only. Compared with the condition of duodenal infusion of M alone, reinfusion of C into the jejunum decreased the number of duodenal clustered contractions in group 2 but not in group 1, and had no effects on the number of jejunal clustered contractions. Reinfusion of SS into the jejunum had no significant effects on the number of duodenal or jejunal clustered contractions compared with duodenal infusion of M alone.


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Fig. 2.   Number of clustered contractions in duodenum (A) and jejunum (B) in groups 1 (open bars) and 2 (solid bars) during enteric infusion. See legend for Fig. 1 for conditions, P values, and abbreviations.

Direction of migration. The percentage of clustered contractions that migrated in the antegrade direction is shown in Table 6. During conditions of no duodenal or jejunal infusions (N), the percentage of clustered contractions migrating in any direction was not different between groups. During duodenal infusion of SS, no significant changes were demonstrated; however, duodenal M increased the percentage of antegrade migration within group 2. Similarly, jejunal infusion of SS resulted in no changes, whereas jejunal infusion of M led to an increased percentage of duodenal antegrade migration in group 1 compared with group 2, but when this comparison was made after adjustment for baseline conditions, the difference between groups disappeared. Within group 1, jejunal M decreased duodenal and increased jejunal migration of spread. Also, duodenal antegrade spread of clustered contractions was decreased in group 2 under this condition.

                              
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Table 6.   Antegrade direction of migration of duodenal and jejunal clustered contractions during enteric nutrient infusions

Compared with duodenal infusions of M alone, reinfusion of C into the jejunum had little effect on the direction of migration of clustered contractions except for a small (but statistically significant) decrease in the duodenum of group 2. During reinfusion of SS into the jejunum, the only difference noted between groups when adjusted for the percentage of antegrade migration in condition 4 was a decrease in duodenal antegrade migration in group 1.

Only small differences were evident in the percentages of retrograde, simultaneous, or isolated migration of clustered contractions, and no consistent trends were evident according to location or content of infusion (data not shown).

Distance of migration. Overall, the changes in the mean distance of migration of clustered contractions as analyzed both by mean distance of spread and by the percentage of clustered contractions that spread at least 8, 16, or 24 cm were small (data not shown). Less than 20% of clustered contractions spread 16 cm and very few spread 24 cm. Under conditions of no duodenal or jejunal infusion no differences in the distance of migration were apparent between groups (Table 7). Duodenal infusion of SS had no effect, but duodenal M increased the distance of migration within group 2. Jejunal infusion of M resulted in decreased jejunal distance of migration of group 2 compared with group 1, but this difference disappeared when the changes were adjusted for baseline conditions. Within group 2, jejunal M decreased duodenal distance of migration.

                              
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Table 7.   Distance of antegrade migration of duodenal and jejunal clustered contractions during enteric nutrient infusions

Jejunal reinfusion of C decreased the distance of jejunal migration between groups but this difference disappeared after adjustment for baseline conditions. Jejunal M did decrease the distance of duodenal migration within group 2. Jejunal reinfusion of SS had no effect on the distance of migration.

Only small differences were noted in the distance of retrograde migration of clustered contractions under the different conditions, and no consistent trends were evident according to location or content of infusion (data not shown).

Velocity of migration. The velocity of antegrade migration of clustered contractions is shown in Table 8. Overall, only small differences were noted during nutrient and nonnutrient experiments in the velocity of migration of clustered contractions. Under basal conditions, no change in the velocity was apparent between groups. Duodenal infusion of M increased the velocity of jejunal clustered contraction within group 2. Within group 1, jejunal SS increased the velocity of antegrade migration of jejunal clustered contractions. During jejunal M, a difference was noted between groups, but this difference was not apparent when corrected for basal conditions. Neither C nor SS reinfused into the jejunum altered the velocity of migration.

                              
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Table 8.   Velocity of antegrade migration of duodenal and jejunal clustered contractions during enteric nutrient infusions

Only small differences in the velocity of retrograde migration of clustered contractions were present and these were not consistently related to the location or content of infusion (data not shown).

    DISCUSSION
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Abstract
Introduction
Methods
Results
Discussion
References

The aims of this study were to determine if neural mechanisms mediate the effects of isolated duodenal and jejunal nutrient infusion on local and distant motor patterns and on the characteristics of individual and grouped (clustered) intestinal contractions. These outcomes were assessed in neurally intact dogs and in dogs with neurally isolated jejunoileum (i.e., after extrinsic denervation and disruption of enteric neural continuity of jejunoileum with duodenum). We hypothesized that duodenal and jejunal nutrient infusions would disrupt the MMC, increase the quantity of motor activity, and decrease the proportion and distance of spread of individual intestinal contractions and clustered contractions in the duodenum and jejunum, irrespective of the site of infusion, in both groups of dogs. This study demonstrated that isolated duodenal and jejunal nutrient infusion consistently inhibited the fasting motor pattern in dogs with neurally intact and neurally isolated jejunoileum and increased the quantity of motor activity within groups in the segment in contact with the nutrients, but did not alter markedly the direction, distance, or velocity of spread of SPW or clustered contractions. The absence of extrinsic innervation to the jejunum and intrinsic neural continuity between duodenum and jejunum had little effect on the response to nutrient infusion either in the duodenum or in the jejunum.

Disruption of the MMC by intestinal nutrients has been shown by numerous previous investigators (8, 11, 26). This inhibition is not dependent on local mucosal nutrient contact (11) but may be related to nutrient content and composition (23). Hakim et al. (10) demonstrated previously that jejunoileal nutrient infusion disrupted duodenal fasting motor activity through a mechanism independent of extrinsic innervation and intrinsic neural continuity. Likewise, in a separate study we showed that isolated duodenal nutrient infusion inhibited duodenal and jejunal fasting motor patterns in neurally intact and neurally isolated jejunoileum (2). The current work further corroborates the findings of the previous studies and shows that extrinsic neural input and intrinsic neural continuity between the duodenum and the jejunum do not mediate changes in nutrient-induced motor patterns. Several peptides (13, 14, 17, 27) have been implicated as potential hormonal mediators of interruption of the MMC, yet no single peptide governs postprandial motor changes; indeed, postprandial disruption of the MMC is likely the result of multifactorial changes in neural and hormonal input to the intestinal smooth muscle and enteric nerves.

We hypothesized that intestinal nutrient infusion would increase the quantity of motor activity as quantitated by a motility index (independent of patterns of contractions like the MMC) by increasing the number and amplitude of contractions participating in a segmenting motor pattern. This study showed, however, that overall duodenal and jejunal contractile activity was not increased consistently; although significant changes did occur, they tended to be small within-group increases in motor activity. In the remainder of the nutrient experiments, the motility index was not increased uniformly, suggesting that the presence of nutrients in the intestine does not markedly increase the frequency or amplitude of contractions regardless of motor patterns. These findings are in agreement in principle with previous work (10), which demonstrated that jejunal nutrient infusion had no marked effect on the frequency of the duodenal slow wave. Others (24, 25) have also shown that the motility index is either unchanged or decreased during enteric nutrient infusion experiments. Changes in motor activity may be a function of the duration of infusion, the caloric load, or the type of the nutrient infusion (25); nutrient contact with the absorptive mucosal surface appears to be important in these models of liquid enteric nutrient infusion.

Analysis of individual intestinal contractions in this study demonstrated that duodenal nutrient infusion increased the percentage of duodenal and jejunal SPW spreading in the antegrade direction in group 2 only. Conversely, jejunal nutrient infusion decreased the percentage of antegrade SPW in the duodenum in both groups. In addition, duodenal nutrients increased the distance of antegrade spread of duodenal and jejunal SPW in group 2, whereas jejunal nutrients decreased duodenal but increased jejunal SPW distance of antegrade spread. Others have described a decreased frequency of contractions and a decrease in distance of spread during intestinal nutrient infusion (5). The divergence of these findings may be related to meal composition. The latter study tested contraction parameters with various nutrients, all of which were accompanied by a noncaloric cellulose component. In our study, the nutrients consisted of a liquid mixed nutrient solution. Additionally, Buhner and Ehrlein (5) showed that characteristics of individual intestinal contractions may be site specific, which may also account for divergent results. Interestingly, our work showed that the increased proportion and length of antegrade spread were not limited to the region of the intestine infused with the nutrients but were also present in the nonperfused segment. These findings suggest that alterations in intestinal contractions can occur in the absence of extrinsic innervation and intrinsic neural continuity between the jejunum and the duodenum and that nutrient-laden intestinal segments may signal distant intestinal regions to alter local contractile patterns.

Clustered contractions are a grouped collection of individual intestinal contractions that occur at the frequency of the slow wave and migrate with a velocity much slower than single intestinal contractions. This motor pattern is found commonly in the ileum and may be responsible for transit of solids into the colon. This and our previous study (4) showed that the number or selected characteristics of clustered contractions are not altered significantly by in vivo neural isolation of the jejunoileum. However, in the dogs with neurally isolated jejunoileum, duodenal nutrient infusion increased the number of clustered contractions locally in the duodenum but not in the jejunum, whereas jejunal nutrient infusion decreased the number of clustered contractions in the duodenum despite the lack of neural or enteric continuity with the duodenum. Neurally intact dogs responded to jejunal nutrient infusion with an increased number of clustered contractions in the jejunum, whereas the response of the neurally isolated jejunum was unchanged compared with nonnutrient infusion. In addition, changes in the direction and distance of migration, although not profound, were apparent during nutrient infusion in the neurally isolated jejunum. Collectively, these findings suggest that extrinsic neural input and intrinsic neural continuity between duodenum and jejunum may modify the motor response to the intestinal nutrient infusion; however, the physiological importance of these motor changes on transit are unknown. Ehrlein et al. (9) and Miedema et al. (12) showed that clustered contractions may be responsible for some element of nutrient transit in neurally intact intestine, but this is the first study to demonstrate that characteristics of clustered contractions during nutrient infusion may be altered by neural isolation.

Previous work (16, 21) has established that the response of the neurally isolated small intestine to intraluminal nutrients is altered by a delayed onset and shortened duration of the fed pattern, which is presumably mediated by extrinsic nerves (16). The response of individual intestinal contractions and groups of contractions to nutrient infusion was modified in part by neural isolation, but consistent site-specific or infusion-specific changes in SPW and clustered contractions were not observed in this study. These findings suggest that the motor responses of the duodenum and jejunum, as determined by careful, computer-assisted analysis of individual and grouped contractions, are not regulated to a significant degree by extrinsic innervation and intrinsic neural continuity between the duodenum and jejunum.

Potential limitations of this investigation merit discussion. In this model of neural isolation, nerve fibers within the walls of the superior mesenteric artery and vein are undisturbed and potentially able to innervate the jejunoileum. In previous work (20), however, we demonstrated that tissue catecholamine levels are undetectable and therefore functional innervation of the gut by these nerves is unlikely. Furthermore, the computer-assisted methods of analysis used to determine the spread and migration of SPW and especially clustered contractions are complex and make two assumptions: 1) that the velocity of spread of SPW is similar in phases II and III of the MMC and during the nutrient infusions that disrupt the MMC pattern and 2) that the velocity of spread over a region of recording is uniform. In an attempt to limit inter-dog variables, we determined time windows for spread of SPW individually for each dog. Finally, others (9) have recommended a shorter (4 cm) distance as optimal for the spread of SPW in the jejunum, but the 8-cm spread in our study produced results that largely agree with their results.

In summary, extrinsic innervation and intrinsic neural continuity between duodenum and jejunum do not control in large part the response of SPW or clustered contractions to infused nutrients. Infused intestinal nutrients inhibit fasting motor activity in neurally isolated small bowel and increase motor activity slightly, but do not alter consistently either the characteristics of SPW or clustered contractions. Although the changes that do occur in characteristics of SPW and clustered contractions locally and distantly during nutrient infusion appear inconsistent and of little probable physiological significance, the effect on nutrient transit and absorption were not addressed by this experimental design. Further investigation of the interactions of motor activity with nutrient transit and absorption are required to clarify the physiological importance of extrinsic innervation and intrinsic neural continuity.

    ACKNOWLEDGEMENTS

The authors thank Deborah Frank for excellent assistance in the preparation of the manuscript.

    FOOTNOTES

This work was supported in part by National Institutes of Health Grant DK-39337 and the Mayo Foundation.

Address for reprint requests: M. G. Sarr, Gastroenterology Research Unit, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.

Received 2 December 1996; accepted in final form 12 January 1998.

    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

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