Department of Physiology and Biophysics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905
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ABSTRACT |
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This contribution to the centennial commemorative issue of the American Journal of Physiology: Gastrointestinal and Liver Physiology identifies some of the important studies of spontaneous electrical and motor activity in the gastrointestinal tract published in the Journal between 1898 and 1996. Emphasis is given to the contributions made by Walter B. Cannon, Walter C. Alvarez, Emil Bozler, C. Ladd Prosser, and James Christensen.
electrical slow wave; frequency gradient; interdigestive activity
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ARTICLE |
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THE MOTOR APPARATUS of the digestive tract is truly remarkable. It can respond to acute events such as food intake, yet it has tightly organized patterns of motility. The basic patterns of motility are changes in muscle tone, segmenting contractions, and peristalsis. Even when devoid of nutrients, the digestive tract exhibits organized periodic motor and electrical activity. The ion channel currents responsible for generating electrical signals in smooth muscle cells of the digestive tract and the intracellular second messenger systems that modulate the ionic currents are known. The digestive tract has an autonomous intrinsic nerve network to regulate its activities, to receive messages from other cells within and outside the gut wall, and to sense mechanical and chemical stimuli, respond to them, and send messages to neurons located in the spinal cord and supraspinal centers. The intrinsic nerve network is hard-wired and programmed to perform specific tasks. The synapses within the network use a wide variety of neurochemicals to communicate amongst themselves and with other cell types in the gut wall. Organized patterns of motility are generally initiated by the release of 5-hydroxytryptamine in the mucosa, where it acts on the nerve endings of intrinsic primary afferent neurons. Nitric oxide and vasoactive intestinal polypeptide are used as inhibitory neurotransmitters to mediate relaxation of descending inhibition, and acetylcholine and substance P are used as excitatory neurotransmitters to mediate contractions. A number of putative neuromodulators such as somatostatin and the enkephalins are used to set the level of excitability of the intrinsic nerve network, as well as of smooth muscle cells. The digestive tract also has an intrinsic pacemaker system to control the frequency of electrical signals, which in turn engage the contractile proteins of smooth muscle cells. These insights into the physiology of gastrointestinal motility arose from methodological and conceptual leaps, painstaking step-by-step insights and rigorous analyses, concise simplifying assumptions and hypotheses, and alert minds.
This contribution to the centennial commemorative issue of the American Journal of Physiology: Gastrointestinal and Liver Physiology addresses the motility of the digestive tract. If motility can be defined as the ability to move spontaneously, then it is essential to understand the underlying mechanism(s) initiating and regulating gut movement. In this retrospective, I focus on how the current view of motility evolved and on electrical slow waves generated in the wall of the digestive tract. With the exception of the cinefluorographic studies of gastrointestinal motility, I will only review studies published in the Journal from 1898 to 1996 that, in my opinion, continue to have a significant impact on current thinking in this field of physiology. Studies published in the Journal from mid-1996 to the present are not included, as they require confirmation and extension before their significance can be established. Table 1 highlights landmark developments in the history of gastrointestinal motility published in this and other scientific journals.
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Movements and Patterns of Contraction of the Digestive Tract (1898-1903; 1960-1985)
Walter B. Cannon is the founding father of the study of gastrointestinal motility. He took the first steps in researching the motor action of the alimentary canal during digestion; he was a pioneer in this area of physiology. Cannon's first two studies on the movements of the stomach and esophagus in cats were published in the inaugural volume of the American Journal of Physiology (10, 13). These studies are milestones because they describe the application of a powerful new noninvasive method using the X-ray to observe gut wall motion. This method is still in use today. Cannon's results, from these two studies (11, 12) and others, made all previous work obsolete, and they remain the basis of all subsequent knowledge of the subject. The concept of segmenting contractions and peristalsis was understood before Cannon's work. However, Cannon was the first to observe peristalsis propel bismuth-impregnated material through the esophagus and stomach, and he observed segmenting contractions divide loops of intestine into a series of fairly uniform segments and move intestinal contents in both directions. Cannon described two kinds of peristalsis: a swiftly moving contraction that sweeps contents over long distances of the bowel, and a slowly advancing occlusive contraction that creeps a short distance along the intestine. He showed that segmenting contractions, peristalsis, and changes in muscle tone are the basic patterns of motility. Cannon was also the first to show that differences in motor patterns between the fundus and orad body of the stomach and the more distal regions of the stomach are responsible for differences in digestion by these two regions of the stomach.Cannon's acute observation that signs of anxiety, rage, or distress inhibit stomach movements (10) was the beginning of his life-long study of the autonomic nervous system. It also foreshadowed the field referred to today as "brain-gut interactions."
In his experiments, because cats are relaxed by warmth, Cannon rested each cat between his thighs, placed the Crooke's tube beneath the animal, and used transparent toilet paper and pencils with colored lead to trace the outline of the shadows of bismuth cast on the fluorescent screen. The X-ray exposure Cannon received during these experiments burnt his hands and face. He had leukemia when he died. On April 3, 1997, seven months before his own death, Charles Code sent a letter to me recalling a meeting he had had with Cannon approximately 40 years after Cannon's pioneering work:
"Walter Cannon was a friend of Frank Mann and Frank Mann was my mentor when I was a Fellow and his first assistant in Physiology at Mayo Foundation during the mid- and late 1930s. By that time, Doctor Cannon had come to realize he had paid an awful price for his motility accomplishments. He had X-ray burns of the skin of his face, his hands and arms and his thighs and he had become a patient of the Mayo Clinic. When he consulted at the Clinic, he always arranged to have a visit at the Institute of Experimental Medicine with his friend, Frank Mann, and Doctor Mann saw to it that I met him and indeed on one or two occasions had a personal visit alone with him.
"While we visited, 40 years after his first exposure to X-rays, I
saw his face and hands were a brilliant, disfiguring red and his jacket
was sprinkled with the continuous severe desquamation from the affected
skin. He told me that he suffered terribly from itching. He thought the
protective element provided by normal skin against entry of foreign
material had been broken for he had become sensitive to all sorts of
substances, especially to the dander of a number of animals, in
particular, guinea pigs. When he felt an itch on his face, arms or
hands he pressed, but did not scratch, the spot. We had a wonderful
hour together for my work on histamine release during allergic
reactions was just unfolding and he was interested. When we parted, I
felt I had been in the presence of a great man. He treated me kindly.
My heart went out to himhis skin was bothering him terribly and I
wondered what other things might be awry. Later, I learned how severe
his allergic sensitivities had become. Chauncy Leak told me that when
Cannon came to his home for dinner one evening, he had not been there
long when Chauncy noticed Cannon was pressing his face, squeezing spots
on his hand and arms and generally showing discomfort.
"Cannon said `Chauncy, there is something here I am sensitive to, my itch is getting to me. Do you have any guinea pigs in your home?'
`Certainly notnever have had.'
"Then a little later `Chauncy, it's getting me in the chestI can
feel an asthma attack coming on. I am afraid I'll have to leave,' and
with that he rushed from the house.
"Chauncy was terribly upset. Clearly Doctor Cannon was in trouble. A little later Chauncy's son, a boy of 10 to 12, came home and went straight to his father.
`Dad, please come to the basement with me. I have something to show you.'
`What is it son?'
`A couple of guinea pigs, dad.'
"Cannon lived to be 73. His death was related to earlier X-ray exposure. He had requested that an autopsy be done and because knowledge of his condition would be of interest and possible value to others, he also prescribed publication of the findings.
"The price was high, too high we think, although the accomplishments
were grand. The import of his solid block of data from the first decade
of the century is still felt, still influencing progress as we enter
the 21st. He was a true pioneer. He gave leadership to a whole segment
of physiologythe motor action of the alimentary canal. He contributed
greatness to our journal and to our Society. He and others like him are
what make great institutions great! We hope that now, at the close of
the century, there is a cluster of young pioneers ready to launch us
into the 21st century like Cannon did 100 years ago!"
Approximately 70 years after the publication of Cannon's first two studies, Charles Code and his colleagues repeated in dogs and humans many of Cannon's experiments, using new and safer X-ray equipment. The cineradiographic method was established as a routine procedure, and tape recordings of fluoroscopic images were soon to come into use. For the next two decades, Code and his colleagues recorded on film with greater resolution and in real time the motions of the alimentary tract that Cannon saw, and recorded exactly what the alimentary canal does with its contents. Their work revealed better than Cannon's descriptions of static pictures what motions of the alimentary canal do to its contents. Code and his colleagues visualized, documented, and recorded on cineradiographs esophageal and gastric peristalsis, rhythmic segmentation, swiftly moving and slowly advancing peristalsis of the small intestine, and the mass movement contraction that empties the colon of its contents.
Arguably the most remarkable pattern Code and his colleague Harley
Carlson filmed is the terminal antral contraction, a pattern of
motility seen during digestion in which a nonocclusive peristaltic contraction moves content out of the body of the stomach and into the
antrum and then moves a fraction of it through the pylorus. Transit
through the pylorus abruptly ends when it and the terminal antrum
contract simultaneously. Thereafter, the pyloric canal is fully patent
until the next terminal antral contraction. Their cineradiographs show
that nonocclusive peristalsis creates two currents of chyme movement in
the antrum: a superficial current along the surface of the stomach wall
in the direction of the advancing peristaltic contraction, and an axial
or centric current moving in the reverse direction. As the peristaltic
wave approaches the fully opened pylorus, small-sized particles caught
in the superficial current are squirted through the pylorus. When the terminal antrum and pylorus contract, larger particles caught in the
axial current are retropelled backward to be caught by the next
advancing peristaltic contraction. The shearing forces acting on the
retropelled particles reduce the size of the particles until they move
in response to the superficial current. Code's experiments visualized
the physiological function of the pylorus that J. Earl Thomas and Paul
Quigley identified with pressure-sensing balloon catheters (26, 34, 35,
49, 50). Years after Code's experiments, James Meyer would show that
the size of the particles emptied into the duodenum ranged from 0.5 to
3 mm (25).
Although Code's cinefluorographic studies are now preserved on videotape, none of the results of his studies were ever published. They are nevertheless included here because they were integral to many meetings of the American Physiological Society and have significantly influenced thinking in this field of physiology. His observations are made daily in the practice of endoscopy and radiology. Looking back, one cannot help but be impressed with the elegance of the methods Cannon and Code used, with their simple but brilliantly executed experiments, and with the impact their conclusions have on current thinking.
Frequency Gradients (1914-1970)
Walter Alvarez (1) recognized the rhythmic characteristics of segmenting contractions of the small intestine and was the first to find that the frequency of rhythmic segmenting contractions decreases in more caudad regions of the intestine. This aborally decreasing gradient in the frequency of rhythmic segmenting contractions establishes a pressure gradient favorable for forward movement of content. Alvarez's findings were significant for another reason. Alvarez also observed the gradient in isolated pieces of intestine, albeit at frequencies lower than those found in corresponding intact segments in vivo, which meant the gradient was independent of external nerves.Alvarez and Mahoney (2) were the first to record spontaneously occurring electrical slow waves from the wall of the stomach and small intestine and the first to suggest that the slow wave frequency gradient and the maximal frequency of rhythmic segmenting contractions were identical. The concept that emerged from Alvarez's work was that the electrical slow wave provides a mechanism through which motility of the digestive tract can be regulated (5, 20-22, 29, 42). Since Alvarez and Mahoney's report, it has been shown that electrical slow waves in all regions of the digestive tract propagate as a sleeve along the bowel wall, with all points on the circumference in the same phase (4). In the small bowel (5, 20, 42), electrical slow waves are propagated in a caudad direction with diminishing velocity and frequency. In the stomach, the frequency of the electrical slow wave is uniform, and the velocity increases as the wave approaches the pylorus (23, 24). In the large bowel, propagation distance of the slow wave is limited (14), most likely because deep septa divide the circular muscle layer (47).
The design of the motor pattern superimposed on the electrical slow waves resides within the intrinsic plexuses. The plexuses program the patterns, using the electrical slow wave. As Jackie Wood (51, 52) has argued since his early studies on the electrical activity of single myenteric neurons, published in the Journal in the 1970s, there is a "little brain" with intelligent networks in the gut wall. The integrative and program circuits of the little brain are assembled from synaptic connections and the vast array of neurochemicals released at the synapses.
A problem developed when Alvarez referred to electrical slow waves as action currents (2). Electrical slow waves could be recorded from the stomach wall, which showed no sign of contraction. The problem was resolved in part by Curt Richter (36) and later by Emil Bozler (8) when they recorded fast spike-shaped potentials, using recording instruments with faster response times. It was known at the time that the voltage transient that triggered skeletal muscle contraction was rapid and spike shaped. These investigators' recordings of spike potentials seemed to resolve the problem for gut smooth muscle, because it was widely believed that spike potentials were an essential determinant for triggering muscle contraction. However, when contraction and intracellular voltage of gut smooth muscle were later recorded simultaneously, it became clear that the electrical slow wave can engage the contractile machinery directly when its peak voltage crosses the mechanical threshold, and indirectly by voltage regulation of ion channels that regulate the passage of ions causing spike-shaped potentials (6, 38).
Emil Bozler's (7) methodical and quantitative analyses showed that smooth muscle cells of the digestive tract are electrically interconnected to form a functional syncytium and that electrical slow waves are propagated through bundles of smooth muscle cells. Bozler (9, 23) also mathematically resolved the electrical slow wave recorded from the surface of the stomach wall to show that it is a derivative of the fundamental electrical change that can be recorded intracellularly (9, 23).
Interdigestive Activity (1969)
While studying the frequency gradient of slow waves of the small bowel of unanesthetized fasting dogs, each equipped with 20 electrodes spaced evenly from the mid-duodenum to the terminal ileum, J. H. Szurszewski (41) identified a caudad-moving band of large-amplitude spike potentials starting in the duodenum and traversing the small bowel. When the band of spikes reaches the ileum, another develops in the duodenum and proximal jejunum. The complexes were found only in fasting dogs as food interrupted the complex. As expected, and as shown by others, the burst of spikes is accompanied by powerful contractions. This interdigestive electrical and motor complex is common to many mammals. The stimulus for its occurrence resides in the bowel wall. It is the basic pattern of the digestive tract proximal to the colon, and it is a distinctive characteristic of the digestive tract in the absence of intraluminal nutrients. William Beaumont (1820s) by chance may have heard the borborygmus of the gastric phase of the interdigestive motor complex. William Boldyreff (1902) recorded in a conscious dog bursts of periodic gastric contractions similar to those that occur during the interdigestive complex. And Cannon and Washburn (1912) and others also recorded bursts of periodic contractile activity. But none of these scientists realized its progression and recurrence.Site of Origin of the Electrical Slow Wave (1960-1996)
If the spontaneously occurring electrical slow wave was a puzzle, the site of its origin was an enigma wrapped in that puzzle. C. Ladd Prosser, his colleague Alex Bortoff, and others attacked the problem. Their studies on the site of origin of spontaneously occurring slow waves enriched the pages of the Journal for nearly 30 years (18, 19, 27, 28, 30-32, 40, 43). Although much of the work of these scientists forms the basis of the present understanding of synchronization and propagation of electrical slow waves and spike potentials, the original hypothesis that electrical slow waves originate in longitudinal muscle cells is no longer tenable. A number of factors led to the questioning of this hypothesis. It was observed that fewer than 20% of all preparations of "isolated" longitudinal muscle generated spontaneous electrical slow waves. In those that did, only localized regions generated slow waves, and in these regions attached bits and pieces of the myenteric plexus were found. Although Bortoff and Prosser's hypothesis may have seemed reasonable for the stomach and small intestine, it was not for the large intestine. Using isolated pieces of colonic circular smooth muscle, James Christensen and colleagues (14-17) presented definitive evidence showing that spontaneously occurring electrical slow waves are dependent on the integrity of the junction between the submucosal and the innermost circular muscle layer. They put forward the hypothesis that the circular smooth muscle layer was the site of origin of electrical slow waves in the large bowel. The site of origin of the electrical slow wave in the small intestine was called into question when Prosser and his colleagues found, using microfine steel needles as recording electrodes, that the magnitude of the slow wave was maximum at the boundary between the longitudinal and circular muscle layers. Nevertheless, Prosser continued to promote the hypothesis that the longitudinal muscle layer was the site of origin of the electrical slow wave and suggested that the slow wave was conducted passively through fibroblasts and interstitial cells to the circular muscle layer, where it was amplified. This seemed reasonable; it was known that connective tissue can serve as an electrical conductor between cultured heart cells. Prosser's views were clearly stated in a letter to Charles Code on April 16, 1976:"I am enjoying the opportunity to be in the laboratory nearly full time. I was put back on a light teaching load for this semester to fill a vacancy but this will not continue. We are making real progress on several topics dealing with intestinal muscle. Most interesting to you is the interaction between the two muscle layers and the requirement of the circular layer to provide for longitudinal conduction. The nature of the interaction is not entirely clear but slow potentials which originate in the longitudinal layer are clearly amplified and made faster in rise time by passing through circular muscle. The coupling is passive electrically and we have evidence that fibroblasts may serve as the conducting elements. We find fibroblasts in abundance and they make nexal contacts with longitudinal and circular muscle fibers as well as with each other."
To which Code replied in a letter to Prosser on May 6, 1976:
"How exciting to receive news of your interesting studies in which
you feel you're definitely collecting evidence that the fibroblasts
play a role in the propagation or conduction process between the
longitudinal and circular layers of the alimentary canal. I am
fascinated by the report, but I would put up the `red flag of danger'
be careful, I wonder if these are really fibroblasts? They may be
specialized conduction cellslike Purkinje fibers in the
heart."
After Lars Thunenberg obtained the first functional evidence that the electrical slow wave originates in and is conducted through the network of the interstitial cells of Cajal between the two muscle layers of the small intestine, Prosser's final article in the Journal on the site of origin of the electrical slow wave concluded: "The interstitial cells of Cajal (ICC-I) are most likely the boundary elements essential for slow waves in either layer of intestinal muscle (40)."
Kenton Sander's work and that of his colleagues on the electrophysiology of smooth muscle, published in the Journal in the mid-1980s, provides the basis for a unifying hypothesis regarding the site of origin of spontaneous electrical slow waves. Although Sander's studies establishing the whole cell and single ion channel currents underlying the basis of electrical slow waves should not be neglected, in the context of this review, Sander's work on the site of origin of the electrical slow wave deserves greater emphasis (6, 37, 39, 46, 47). Using the standard intracellular recording technique to obtain precise information, Sanders and colleagues found that slow wave pacemaker regions were located throughout the digestive tract in regions lined with interstitial cells. Their work also shows that active propagation of slow waves occurs along the borders of the muscle layer where the interstitial cells are located. Beyond these regions, slow waves propagate passively through the muscle layers. Electrical slow waves recorded intracellularly in putative interstitial cells of intact strips of colonic smooth muscle (3) and in dispersed and cultured interstitial cells from the canine colon (33) provide direct evidence essential for the hypothesis. Recent studies published in the Journal show that spontaneously, rhythmically occurring contractions develop in parallel with the appearance of interstitial cells (44), and spontaneously occurring electrical slow waves are absent in mice with mutations in steel factor, the natural ligand for the c-Kit receptor tyrosine kinase (45). c-Kit receptor tyrosine kinase is essential for the development of interstitial cells.
Epilogue
Presently there is great excitement in the field of gastrointestinal motility. The finding that the interstitial cells are essential for electrical and mechanical rhythmicity suggests that this cell system is the long-sought pacemaker system of the digestive tract. The challenges for the future are to characterize the electrical currents in these cells, the messenger systems that modulate the ion channels that carry the currents, and the genes that manufacture the ion channel proteins. It is known that the c-Kit receptor tyrosine kinase is essential for the normal development of the interstitial cells found in the myenteric region of the small intestine. A critical future step will be to understand its physiological function in interstitial cells. Other challenges include better definition of the cellular and molecular mechanisms by which the immune system signals the enteric nervous system to change the program of the effector system to adapt to perturbations in the gut lumen, and the identification of the growth factors essential for the normal development of the interstitial cell networks and the enteric nervous system. Molecular biological methods applied to the interstitial cells, smooth muscle cells, and intrinsic ganglion neurons will serve as an essential link between the single cell and the function of the organ system only if the results are applied along with the findings made by Cannon, Code, Alvarez, Bozler, Prosser, and Christensen. The studies published in the American Journal of Physiology over the past 100 years should serve as key tools in unlocking the functional meaning of the present reductionist and molecular approach. ![]() |
ACKNOWLEDGEMENTS |
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I thank Dr. Gianrico Farrugia and Dr. Steven Miller for helpful comments and suggestions and Jan Applequist for technical assistance.
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FOOTNOTES |
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Address reprint requests to Dept. of Physiology and Biophysics, Mayo Clinic and Mayo Foundation, 200 First St. SW, Rochester, MN 55905.
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