Laboratoire de Physiologie Digestive, Département de Gastro-entérologie, Hôpital Laënnec, F-75007 Paris, France
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ABSTRACT |
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Intestinal wall motions are not easily studied and are frequently deduced from manometric and electromyographic measurements. This study aimed to establish a method of wall movement analysis based on an automatic technique of image processing. Segments of rat jejunum were fixed in an organ bath under isometric conditions. A real-time edge-detection algorithm was used to find the contours of the intestine using video imaging. After the measurement, a mapping of intestinal wall movements was performed based on diameter variations. In the 260 experiments without stimulation, intestinal wall activity was always detected. Propagated activity was found in 40% of the experiments and periodic wall motion in 60%, with 0.5-Hz activity found more frequently (41%) than 0.24-Hz activity (19%). These cyclic activities, related to intestinal slow waves, had their amplitude decreased by acetylcholine and were modified by vapreotide. Analysis of a propagated wave after cholinergic stimulation showed that it is characterized by an increase of the diameter of the intestine followed by a decrease. Moreover, this methodology allows analysis of the initiation of a propagated wave.
automated video analysis; electromyography; acetylcholine; atropine; vapreotide
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INTRODUCTION |
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DIGESTION REQUIRES the mechanical propulsion of the fluid mixture (food and secretions) and progress of this fluid within the intestinal lumen. This movement of luminal contents is induced by propulsive forces that are generated primarily by the musculature of the intestine. This intestinal activity, generating wall movements, is the consequence of contractions of the two layers of smooth musculature of the alimentary canal. A network of interconnecting nerve fibers and ganglion cells is present between the two smooth muscle layers, i.e., the myenteric plexus (19). Nevertheless, there are few data concerning the relationship between intestinal motility and the flow of luminal contents (18). This lack of data is the result of the absence of a simple method to analyze the dynamics of intestinal wall motions, the modifications of their kinetics by neurotransmitters and drugs, the modifications of fluid flow induced by wall motions, and the interactions between the central nervous system, the enteric system, and myogenic and hormonal factors.
Analysis of in vitro intestinal motility has most often used nonimaging techniques such as manometry and electromyography (1). Furthermore, other techniques have also been proposed based on impedance, displacement transducers, ultrasound, strain gauges, and magnetic resonance imaging. Nevertheless, for the analysis of wall motion in in vitro studies, imaging techniques were chosen in early (15) and in more recent (2, 11, 16) studies, mainly because intestinal activity is evident when a jejunal segment is immersed in an organ bath. The earliest studies used a sequence of photographs from either a movie camera or, more recently, a video system (11). These studies established the correlation between wall motion and either fluid propulsion (11) or the manometric pattern (2). However, these techniques involve manual image analysis; movements of the intestine, monitored by a camera, were stored on videotape (2, 16), and the shape of the intestine was analyzed image by image, mainly by maximizing the contrast to yield a binary black and white image. This methodology, although effective for measurement of the length of a fiber (4), is inadequate when morphological information is required and even more so for kinetic studies of intestinal wall motions.
The present study demonstrates a new method of computerized video analysis of intestinal wall movements by applying it in two situations, at rest and during a cholinergic-induced propagated wave. We then illustrate the application of this technique in pharmacological studies by testing the action of vapreotide, an analog of somatostatin.
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MATERIALS AND METHODS |
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Materials
Ninety Wistar rats weighing 150-250 g were decapitated after an overnight fast. The abdomen was opened via a midline incision, and a 10-cm jejunal segment was quickly removed. Dissection and experimentation were performed in a Krebs solution buffer gassed with 95% O2-5% CO2 at 37°C with the following composition (in mmol/l): 110 NaCl, 33.3 NaHCO3, 1.1 MgCl2, 0.8 Na2HPO4, 4.7 KCl,, 2.56 CaCl2, and 13.9 D-glucose.Methods
The jejunal segment was then suspended in a 500-ml organ bath at 37°C. The organ bath was on a drip perfused with Krebs solution, directly bubbled with 95% O2-5% CO2 at a constant rate of 1 ml/min. Each intestinal segment was adjusted to a resting tension by fixing it to the bottom of the recording chamber using a 4.1-g weight attached to the distal end and attaching a 1.4-g weight to the upper end (Fig. 1). Once the segment reached a stable length at this tension, the position of the upper weight was fixed, maintaining a constant length for the remainder of the experiment. Video imaging was performed directly by recording the intestinal wall movements. The bathing fluid was free to enter and leave the segment because the ligatures did not occlude the ends.
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Electromyographic recording. In 10 other rats, electromyographic (EMG) recording was performed using unipolar muscle electrodes (sample rate 50 Hz, amplification ALVAR analog-to-digital converter EuroSmart MES-EXT) simultaneously with a video recording (6 Hz). Spectral analysis was performed on the two signals (intestinal diameter and EMG recordings) recorded at the same level.
Video recording. Recording was done using a video card (Matrox PIP-1024A, Dorval, Quebec, Canada) included in a 486 personal computer linked to a Panasonic WV-CD50 camera (power source WV-CD52; Matsuchita, Osaka, Japan). All records were visualized on a video monitor (Sony KX-14 CP1). The camera captured the images, which were archived in the computer memory. During capture, a custom real-time edge-detection algorithm was used. To obtain the best contrast, the experiments were performed in a darkened room, with only indirect lighting from a halogen lamp.
A zone of interest (5-8 cm of jejunum) was delimited in a "window" and a specific software program, written in C language (Microsoft C, version 6; Borland C++, version 4.5), allowed edge detection at frequencies of up to six images per second (Fig. 2). Edge detection was based on analysis of gray levels in the image and computed using a previously described technique (3). By this technique, continuous recording (40 min) was performed and the diameter, expressed as length in pixels of each video line, was computed.
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Display of data. Animated display of the images could be done either on-line or at some subsequent time; the kinetics of wall movements were viewed in a window or plotted as a function of time. The diameter of each "slice" was expressed as a pseudocolor, relative to the median diameter of the entire file (Fig. 3). For each experiment, the software calculated the scale of the image, thus permitting the conversion of diameters from pixels to millimeters.
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Spectral analysis.
We studied the variations of diameter relative to the mean diameter
D, i.e.,
(dt D)/D,
where dt is the
diameter at time t. To
analyze the frequency of diameter variations in a given slice (i.e.,
one video line), a spectral analysis was computed using fast Fourier
transform (FFT) methodology on a rectangular window of 256 points
representing 256 successive measurements of the same slice (8). This
analysis gave 128 bands of frequency characterized by two parameters,
frequency (Hz) and amplitude of diameter variation, expressed as a
percentage of variation of the mean diameter. To summarize spectral
activity of an entire image, we calculated a mean spectrum by
calculating the mean at each frequency (Fig.
4).
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Experimental procedure. Video recordings of jejunal wall movements were performed in 140 different jejunal segments. The duration of each experiment varied from 2 to 40 min. In some records, acetylcholine and/or atropine was added to the Krebs solution. A total of 273 measurements were performed at rest, and 205 measurements were performed after chemical stimulation, including 163 after acetylcholine (acetylcholine chloride, AP-PCH, Paris, France) and 42 after atropine (atropine sulfate, Laboratoires Aguettant, Lyon, France).
Pharmacological study. In 30 other jejunal segments, the action of vapreotide (RC-160, Octastatin; Debiopharm, Lausanne, Switzerland) was studied to find a possible use of this methodology in pharmacological studies. This octapeptide (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2), an analog of somatostatin, was added to the bath at two concentrations, 0.88 and 2.65 µmol/l.
Statistical analysis. Comparisons of data were carried out using analysis of variance (ANOVA) with repeated measures. The design of ANOVA included one subject factor and one within factor (drug concentration). Post hoc comparisons were made using the Student-Newman-Keuls test. The analysis was done using SAS software (SAS Institute, Cary, NC). Division of the main frequency into three subgroups was performed using a K-means cluster analysis (10).
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RESULTS |
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In all rats studied, the detection of wall movements gave information that could be analyzed.
Analysis of Wall Motion in Unstimulated Conditions
In all 273 experiments, spontaneous activity was found in all segments. After spectral analysis, a principal frequency was found and was used for classification (Fig. 5). Preparations with three different types of spontaneous activity could be distinguished, with main frequencies of <0.13 Hz, between 0.13 and 0.39 Hz, and >0.39 Hz (Table 1). These rhythms were in fact present in all segments, independent of the sampling rate used (from 2 to 6 Hz), even if the main peak of frequency was <0.13 Hz. Nevertheless, experiments showing a very low peak frequency (n = 109) also showed propagated waves. Therefore, experiments with cyclic patterns are described separately from experiments with propagated activity.
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Cyclic Variations of Diameter
The study of the variation of jejunum diameter without stimulation shows cyclic variations in 60% of the experiments. These cyclic variations of diameter were called high-frequency cyclic activity when frequency was >0.40 Hz and low-frequency cyclic activity when frequency was between 0.13 and 0.40 Hz.High-frequency cyclic activity. In 41% of the experiments, the cyclic variations had a frequency of ~30 cycles per minute (cpm) = 0.5 Hz (Fig. 3C). To best characterize this resting jejunal wall motion, a spectral analysis of the image was performed (Fig. 4C). Results of the FFT confirm this information; peaks vary from 0.39 to 0.62 Hz (median 0.51 Hz). The diameter variations resulting from this high-frequency cyclic activity were ~3.9% (median value). Using simultaneous recording of EMG signal and variation of diameter at a given level, we demonstrated that these two signals have similar frequencies (Fig. 6).
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Low-frequency cyclic activity. Another very common spontaneous jejunal activity, ~0.22 Hz (median value), was found in 19% of the measurements (Fig. 3B). Variation of diameter related to this low-frequency cyclic activity (Fig. 4B), amounting to ~4.3% (median value), was greater than the diameter variation related to high-frequency cyclic activity (P < 0.05, Student's t-test).
Propagated Contractions
All propagated waves, spontaneous or stimulated, were directed toward the anal end in their initial part. No specific focus was found to originate the propagated wave.Spontaneous propagated waves. The main frequency was <0.13 Hz in 109 experiments (median 0.032 Hz, range 0.024-0.126 Hz). All segments of this group presented propagated activity (Fig. 3A). This spontaneous propagated activity was always associated with the presence of cyclic variation of diameter (Fig. 4A). Furthermore, no propagated diameter variation occurred in segments with a principal frequency >0.13 Hz.
Cholinergic-induced propagated wave. The methodology used gives information about the initiation and the propagation of a wave of contraction. As shown in Fig. 7, after adding acetylcholine we can easily see a propagated wave and the events at the origin of the contraction. The study of wall movements during a propagated contraction (Fig. 8) shows, in any given slice, two different steps, a small increase of the diameter followed by a strong decrease of the diameter. Thus propagated activity begins by a distension at one point lasting 6 s, followed by a contraction over 11 s. During the subsequent propagated wave, these two events are propagated along the intestine. The analysis of the propagated wave along the axis of the intestine showed first a decrease of diameter in the oral end of the segment where a propagated wave occurred and then an increase of diameter in the anal end of this segment (Fig. 7).
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Pharmacological Studies
Modification of 0.5-Hz activity by acetylcholine and atropine. Acetylcholine decreased the 0.5-Hz activity (Fig. 9). Atropine reversed the effect of acetylcholine and completely restored the initial high-frequency cyclic activity within minutes. This restoration was accompanied by a lengthening of the intestinal segment (Fig. 10).
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Action of vapreotide. At high concentrations, vapreotide increased the amplitude of low-frequency cyclic activity (0.2 Hz) and decreased the amplitude of high-frequency cyclic activity (0.5 Hz). In contrast, at lower concentrations, only the decrease of the amplitude of high-frequency cyclic activity (0.5 Hz) was seen. These results can be summarized by analysis of the variation of the ratio of low- to high-frequency cyclic activity (Fig. 11). This ratio increases significantly with the concentration of vapreotide (P < 0.001). In addition, the methodology used permits measurement of the mean diameter of the jejunal segment. There was a significant decrease of 2 ± 2% (SD) of the diameter with the low dose (P < 0.05) and a nonsignificant decrease of 6 ± 19% of the diameter with the high dose.
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DISCUSSION |
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In vivo analysis of intraluminal pressure waves of the small intestine has limited value for explaining physiological changes that occur in the smooth muscle. The limitations of such methods derive from the lack of knowledge about the forces that generate the pressure patterns and about the morphological characteristics of the site of application of these forces. In contrast to other techniques of motility measurement, the methodology developed in the present paper is based only on the analysis of wall movement. It permits the description of jejunal wall motion at rest and the description of propagated activity as a two-phase event at a given point, distension and then contraction.
To study longitudinal and transverse movements of the jejunum in dogs, Tasaka and Farrar (14) used a Mann-Bollman fistula and cineradiography of radiopaque markers attached to the serosa. More recently, Bercik et al. (2) used a simultaneous video and manometric record to describe the relationship between small intestinal motility and the flow of luminal contents. Our technique, based on an original, entirely automated, real-time image analysis technique, describes only the variations of the intestinal diameter. Moreover, we propose a new visual representation of wall motion that makes possible a temporal and lengthwise analysis of the resting and propagated activity of the jejunum.
The first main result found using our method was evidence of a high-frequency cyclic activity (i.e., >0.40 Hz). This frequency was described in a previous study in mouse jejunum (12); in Ussing chambers, intact tissues exhibited oscillations of basal transmural potential differences and short-circuit current that found their origin in muscle activity. These authors showed that in contrast to intact tissues, mucosal preparations failed to exhibit this activity, and manometric recording of these tissues also showed this activity. Bercik et al. (2), in an isolated, arterially perfused ileal segment of rat intestine, also recorded such manometric activity (26-28 cpm) at the two ends of the tissue. Our analysis of the diameter of the intestinal segment shows that this component is present along the whole length of the intestinal wall. The small amplitude of the waves reported by Bercik et al. could be related to the small variations of diameter found in our present work. However, we found that the wall cyclic activity was decreased by acetylcholine, whereas they found an increase (2). This high-frequency cyclic activity of wall motion could be interpreted in the light of results obtained by Sheldon et al. (12), in which this activity was attributed to spontaneous contractions and was suppressed by a Ca2+ channel antagonist, nifedipine, indicating that this activity was related to a myogenic process. In agreement with their study, we observed a strong decrease of the high-frequency cyclic activity by adding diltiazem to the bath (unpublished data). Ca2+ channel antagonists block muscle action potentials and then antagonize excitation and contraction. Nevertheless, we found similar results using acetylcholine, which is expected to increase excitability and contractility (but we found an increase of very low frequency activity). This apparent contradiction could be due to the significant shortening induced by acetylcholine that limits the variation of diameter. High-frequency cyclic activity, found in the majority of experiments exhibiting cyclic activity (67%), as well as low-frequency cyclic activity reflect the jejunal slow wave frequency (0.50 Hz in the rat) as demonstrated when simultaneous video and EMG recordings were performed (Fig. 6). Wall motion occurred only at frequencies authorized by the slow waves [i.e., (0.50 Hz)/N (N = integer)]. In fact, we frequently found cyclic activity around 0.25 Hz, i.e., one-half of 0.50 Hz, and more rarely around 0.17 Hz. Nevertheless, the great variability of the low-frequency cyclic activity (from 0.13 to 0.39 Hz) and the absence of such a direct relationship in some experiments in which high- and low-frequency cyclic activity are present support the possibility of another type of contraction.
Our analysis gives information about propagating waves (temporal variation of diameter at a given level, length variation of the diameter along the intestine) and gives an indication of the events initiating this propagated activity. Two types of propagated waves were found, spontaneous (Fig. 3A) and cholinergic-induced (Fig. 7) propagated waves.
The analysis of propagated waves shows clearly that in regard to the wall movement with time, it is composed of two main events: first, an increase of the diameter (i.e., a distension), and second, a decrease of the diameter (i.e., a contraction). These two events are propagated along the length of the intestine. This temporal organization at a given level can be understood as a consequence of the spatially propagated organization; as seen in Fig. 8, distension is followed immediately by contraction, with no delay. Each segment is consecutively a receiving segment (i.e., a distension) and a propulsive segment (i.e., a contraction). The methodology used here allowed us to conclude that the length of these functional segments (receiving, then propulsive) is <200 µm, the distance between two video lines (Fig. 7). Therefore, the propagated wave must be understood as a biphasic event that is propagated. The possibility that the distension phase was only passive, resulting from the propulsion of the fluid from more oral regions, could be raised. Nevertheless, Fig. 7 clearly shows that only distension was continuously propagated and that contraction stopped 42 mm from the oral end. Thus the interpretation of propagating waves we propose accords equal importance to the temporal and spatial relationships.
The present study shows clearly that, at a given point, distension and contraction occur successively. The contractile wave would appear to occur after the inhibition at a point, because intraluminal fluid displacement in an anal direction would tend to reinitiate a local propagated reflex by stimulating the mucosa and distending the bowel to threshold for a contraction (13). In fact, this phenomenon appears to occur in Fig. 7, which shows a propagating wave. At time = 65 s, a wave is initiated that appears to consist of a contraction (green to blue) moving down the bowel in time, associated with a distal dilation (yellow to purple) that follows the contraction. We can also see that distension has less variation of duration than does contraction, which varied in both duration and length (Fig. 7). Nevertheless, at the 35-mm level, distension lasted longer than in other segments (14 vs. 2 s usually). Thus there is a great variation of the response of the propulsive and receiving segments to the same stimulus. The origin of the distension that precedes the contraction remains an open question. Is it a simple, passive response to fluid being propelled from more oral regions, which then depends on the passive mechanical properties of the jejunum, or is it a real relaxation? What are the mechanisms (neurons, chemical transmitters) implicated in this event (5-7, 17)?
The methodology used here also gives information concerning the initiation of propagating waves (Fig. 7). The first part of the sequence (time 2 s, level 10 mm) is characterized by a dilation simultaneous to a contraction at a lower level (time 2 s, level 17 mm). This could be interpreted as a longitudinal contraction; because the segment was under tension, any contraction of the longitudinal muscle may appear as a dilation of the circular muscle as the intestine adjusts its diameter to conserve muscle volume (20). This phenomenon was seen to be isolated, without propagated contraction, at 2 s and was followed by a propagated wave in the second part of the sequence (time 65 s). The difference of response of the same segment at two different times could be related to a difference of the magnitude of the distension at the origin of the phenomenon. In Fig. 7, we see that the first two bands (violet and red) show no variation. In contrast, the subsequent bands change during the initiation of the propagated wave. In the first contraction, increase of the diameter occurs only in the violet band (3.3-mm length), but in the propagated wave it increases in the yellow, red, and violet bands (6.5-mm length). Thus the size of the segment that distends at the beginning of contraction could be an important factor in the initiation of the propagating activity. The initiation of the propagating activity could thus be described as a sufficient initial dilation at the oral end and a simultaneous contraction at the anal end. Thus a propagated wave is characterized at a given level by a temporal succession of distension followed by a contraction and along the intestine by a contracted segment followed by a dilated segment.
In 109 experiments, spontaneous propagated waves were found. These propagated waves happen without disappearance of the intestinal cyclic activity, as shown by Fig. 3A or by spectral analysis (Fig. 4A). However, these propagated waves have specific patterns: 1) they have a limited distance of propagation (2-4 cm); 2) conduction velocity is slow and nonuniform along the propagated wave; and 3) low levels of diameter variation are recorded. Nevertheless, the analysis of the initiation of these waves revealed no specific pattern, and during the propagation dilation and contraction were successively found at a given level. Spontaneous and cholinergic-induced propagating waves could be similar events; some slowly jejunal-migrating contractions/relaxations could propagate faster and more completely when the smooth muscle is excited by acetylcholine. Nevertheless, when we increased acetylcholine concentration in the organ bath we did not observe a variation of activity.
A pharmacological application of this technique was shown by the analysis of the action of vapreotide on jejunal segments of rats. Because the clinical use of somatostatin is limited by its short half-life (3 min), a large number of analogs of this hormone were produced by amino acid substitution at various sites along the peptide chain (e.g., octreotide, somatuline). Vapreotide has pharmacological properties comparable to native somatostatin but with a much longer duration of action (9). The effects of somatostatin on gastrointestinal motility are still unclear, but it is known to induce a relaxation of longitudinal muscle of the intestine (21). Our results show that vapreotide and probably somatostatin reduced the high-frequency cyclic activity and increased the low-frequency cyclic activity of the rat jejunum in a dose-related manner. Moreover, the decrease of diameter is in accord with the relaxant action of vapreotide on longitudinal fibers. The elongation of the intestine and the need to conserve the intestinal volume explain the decrease of the mean diameter. For high doses, the increased activity resulted in a wide variation of the diameter, reducing the statistical significance of the decrease of diameter.
The use of automated image analysis of captured video frames could be useful for pharmacological and physiological studies of in vitro preparations. The results of this first study are mainly limited to a description of diameter variation along the intestine and raise several questions: Do high- and low-frequency cyclic activity migrate? Do separate regions beat entirely independently? Are high- and low-frequency cyclic activity neuronally mediated? Is there some zone where propagated waves originate? The answers to these questions will probably require more experiments using the simultaneous measurement of other parameters such as EMG and manometric recordings.
To conclude, video recording of the intestinal diameter is a simple method for in vitro intestinal motility analysis. This novel approach could be used to investigate motor events in isolated segments of bowel. Video analysis of wall movement showed, at rest, a wall activity certainly related to intestinal slow waves. The analysis of propagated contractions showed that these waves are biphasic both temporally and spatially. In vitro analysis of wall movement is shown to be useful for extending our knowledge of the physiological and pharmacological events of intestinal wall motion. Furthermore, quantitative analysis (length, duration) of the segments involved in or originating intestinal propagation is possible.
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ACKNOWLEDGEMENTS |
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The authors thank Prof. Jacques Prado, Ecole Nationale Supérieure des Télécommunications, Paris, for the verification of routines used in spectral analysis and for valuable comments.
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FOOTNOTES |
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Address for reprint requests: M. Bouchoucha, Université Paris V, Hôpital Laënnec, Laboratoire de physiologie digestive, 42 rue de Sèvres, F-75007 Paris, France.
Received 20 February 1996; accepted in final form 28 May 1997.
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