Medical Physiology, 3rd Edition

Gastrointestinal Motility

Tonic and rhythmic contractions of smooth muscle are responsible for churning, peristalsis, and reservoir action

The motor activity of the GI tract performs three primary functions. First, it produces segmental contractions that are associated with nonpropulsive movement of the luminal contents. The result is the increased mixing—or churning—that enhances the digestion and absorption of dietary nutrients. Second, GI motor activity produces peristalsis, a progressive wave of relaxation followed by contraction. The result is propulsion, or the propagated movement of food and its digestive products in a caudal direction, ultimately eliminating nondigested, nonabsorbed material. Third, motor activity allows some hollow organs—particularly the stomach and large intestine—to hold the luminal content, exerting a reservoir function. This reservoir function is made possible by sphincters that separate the organs of the GI tract. All these functions are primarily accomplished by the coordinated activity of smooth muscle (see pp. 243–249).

The electrical and mechanical properties of intestinal smooth muscle needed for these functions include both tonic (i.e., sustained) contractions and rhythmic contractions (i.e., alternating contraction and relaxation) of individual muscle cells. The intrinsic rhythmic contractility is a function of the membrane voltage (V m) of the smooth-muscle cell. V m can either oscillate in a subthreshold range at a low frequency (several cycles per minute), referred to as slow-wave activity, or reach a threshold for initiating a true action potential (see Fig. 9-14). The integrated effect of the slow waves and action potentials determines the smooth-muscle activity of the GI tract. Slow-wave activity apparently occurs as voltage-gated Ca2+ channels depolarize the cell and increase [Ca2+]i, followed by the opening of Ca2+-activated K+ channels, which repolarize the cell (see p. 244).

These activities are regulated, in large part, by both neural and hormonal stimuli. Modulation of intestinal smooth-muscle contraction is largely a function of [Ca2+]i (see pp. 246–247). Several agonists regulate [Ca2+]i by one of two mechanisms: (1) activating G protein–linked receptors, which results in the formation of inositol 1,4,5-trisphosphate (IP3) and the release of Ca2+ from intracellular stores; or (2) opening and closing of plasma-membrane Ca2+ channels. Both excitatory and inhibitory neurotransmitters can modulate smooth-muscle [Ca2+]i and thus contractility. In general, ACh is the predominant neurotransmitter of excitatory motor neurons, whereas VIP and NO are the neurotransmitters of inhibitory motor neurons. Different neural or hormonal inputs probably increase (or decrease) the frequency with which V m exceeds threshold and produces an action potential and thus increases (or decreases) muscle contractility.

An additional, unique factor in the aforementioned regulatory control is that luminal food and digestive products activate mucosal chemoreceptors and mechanoreceptors, as discussed above, thus inducing hormone release or stimulating the ENS and controlling smooth-muscle function. For example, gastric contents with elevated osmolality or a high lipid content entering the duodenum activate mucosal osmoreceptors and chemoreceptors that increase the release of cholecystokinin and thus delay gastric emptying (see p. 878).

Segments of the GI tract have both longitudinal and circular arrays of muscles and are separated by sphincters that consist of specialized circular muscles

The muscle layers of the GI tract consist almost entirely of smooth muscle. Exceptions are the striated muscle of (1) the upper esophageal sphincter (UES), which separates the hypopharynx from the esophagus; (2) the upper third of the esophagus; and (3) the external anal sphincter. As shown above in Figure 41-2, the two smooth-muscle layers are arranged as an inner circular layer and an outer longitudinal layer. The myenteric ganglia of the ENS are located between the two muscle layers.

The segments of the GI tract through which food products pass are hollow, low-pressure organs that are separated by specialized circular muscles or sphincters. These sphincters function as barriers to flow by maintaining a positive resting pressure that serves to separate the two adjacent organs, in which lower pressures prevail. Sphincters thus regulate both antegrade (forward) and retrograde (reverse) movement. For example, the resting pressure of the pyloric sphincter controls, in part, the emptying of gastric contents into the duodenum. On the opposite end of the stomach, the resting pressure of the lower esophageal sphincter (LES) prevents gastric contents from refluxing back into the esophagus and causing gastroesophageal reflux disease (GERD). As a general rule, stimuli proximal to a sphincter cause sphincteric relaxation, whereas stimuli distal to a sphincter induce sphincteric contraction. Changes in sphincter pressure are coordinated with the smooth-muscle contractions in the organs on either side. This coordination depends on both the intrinsic properties of sphincteric smooth muscle and neurohumoral stimuli.

Sphincters effectively serve as one-way valves. Thus, the act of deglutition (or swallowing) induces relaxation of the UES, whereas the LES remains contracted. Only when the UES returns to its initial pressure does the LES begin to relax, ~3 seconds after the start of deglutition. Disturbances in sphincter activity are often associated with alterations in one or more of these regulatory processes.

Location of a sphincter determines its function

Six sphincters are present in the GI tract (see Fig. 41-1), each with a different resting pressure and different response to various stimuli. An additional sphincter, the sphincter of Oddi, regulates movement of the contents of the common bile duct into the duodenum.

Upper Esophageal Sphincter

Separating the pharynx and the upper part of the esophagus is the UES, which consists of striated muscle and has the highest resting pressure of all the GI sphincters. The swallowing mechanism, which involves the oropharynx and the UES, is largely under the control of the swallowing center in the medulla via cranial nerves V (trigeminal), IX (glossopharyngeal), X (vagus), and XII (hypoglossal). Respiration and deglutition are closely integrated (see p. 720).

The UES is closed during inspiration, thereby diverting atmospheric air to the glottis and away from the esophagus. During swallowing, the situation reverses, with closure of the glottis and inhibition of respiration, but with relaxation of the UES (Fig. 41-4 ). These changes permit the entry of food contents into the esophagus and not into the airways of the respiratory tract.

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FIGURE 41-4 Esophageal pressures during swallowing. The swallowing center in the medulla that initiates deglutition includes the nucleus ambiguus (cranial nerves [CN] IX and X), the dorsal motor nucleus of the vagus (CN X), and others. Shown are recordings of intraluminal pressures at different sites along the esophagus, from the UES (record 1) to the LES (record 6). The left side of the graph shows the pressures at rest. As shown on the right side, after a dry swallow, the pressure wave of a “primary peristalsis” moves sequentially down the esophagus. (Data from Conklin JL, Christensen J: Motor functions of the pharynx and esophagus. In Johnson LR [ed]: Physiology of the Gastrointestinal Tract, 3rd ed. New York, Lippincott-Raven, 1994, pp 903–928.)

Lower Esophageal Sphincter

The esophagus is separated from the stomach by the LES, which is composed of specialized smooth muscle that is both anatomically and physiologically distinct from adjacent smooth muscle in the distal end of the esophagus and proximal portion of the stomach. The primary functions of the LES are (1) to permit coordinated movement of ingested food into the stomach from the esophagus after swallowing or deglutition, and (2) to prevent reflux of gastric contents into the esophagus. Either deglutition or distention of the esophagus results in a reduction in LES pressure (see Fig. 41-4), thereby permitting entry of food into the stomach. Relaxation of the LES occurs after the UES has already returned to its resting pressure. The LES maintains a resting tone that is the result of both intrinsic myogenic properties of the sphincteric muscle and cholinergic regulation. Relaxation of the LES is mediated both by the vagus nerve and by intrinsic properties of the smooth muscle, including important inhibitory effects by VIP and by NO.

Abnormalities of both resting LES pressure and its relaxation in response to deglutition are often associated with significant symptoms. Thus, a reduced resting LES pressure often results in gastroesophageal reflux, which may cause esophagitis (i.e., inflammation of the esophageal mucosa). A defect in LES relaxation is a major component of a condition called achalasia (Box 41-1 ), which often results in dilation of the esophagus (megaesophagus) and is associated with difficulty in swallowing (dysphagia).

Box 41-1

Achalasia

Achalasia is a relatively uncommon condition associated with difficulty swallowing (dysphagia) and a dilated esophagus proximal to a narrowed, tapered area at the gastroesophageal junction. The term achalasia is derived from Greek words meaning “absence of relaxation.” The distal narrowed area of the esophagus suggests the presence of a stricture. However, it is easy to introduce an esophagoscope into the stomach through the narrowed area. Subsequent studies of esophageal motility in which investigators measured intraesophageal pressure demonstrated the presence of two defects in patients with achalasia: (1) failure of the LES to relax, and (2) impaired peristalsis in the distal two thirds of the body of the esophagus (i.e., the portion that consists of smooth muscle). Peristalsis is intact in the proximal third of the esophagus, which consists of striated muscle. In essence, the smooth-muscle portions of the esophagus behave as a denervated structure. The fundamental defect in achalasia is likely related to selective loss of intramural inhibitory neurons that regulate the LES, the neurotransmitters for which are VIP and NO. Treatment is either physical distention (or stretching) of the LES with a pneumatic-bag dilator or surgical cutting of the LES (i.e., an esophageal Heller myotomy via a laparoscopic approach).

Swallowing and the function of the UES and LES are closely integrated into the function of the esophagus. Under normal circumstances, esophageal muscle contractions are almost exclusively peristaltic and are initiated by swallowing. Deglutition initiates relaxation of the UES and propagated contractions, first of the UES and then of the muscles along the esophagus (see Fig. 41-4). In the meantime, the LES has already relaxed. The result of the advancing peristaltic wave is the caudad propulsion of a bolus toward the stomach.

Distention of the esophagus (in the absence of swallowing) also initiates propulsive esophageal contractions distal to the site of distention, as well as relaxation of the LES. Reflux of gastric contents into the lower part of the esophagus also produces such a local distention, without a swallow, and elicits the same response: peristaltic contractions that clear the esophagus of refluxed gastric material. Peristalsis that is initiated by swallowing is called primary peristalsis, whereas that elicited by distention of the esophagus is referred to as secondary peristalsis. Esophageal contractions after a swallow are regulated by the medullary swallowing center, intramural esophageal plexuses, the vagus nerve, and intrinsic myogenic processes.

Pyloric Sphincter

The pylorus is the sphincter that separates the stomach from the duodenum. The pressure of the pyloric sphincter regulates, in part, gastric emptying and prevents duodenal-gastric reflux. However, although a specific pyloric sphincter is present, it is quite short and is a relatively poor barrier (i.e., it can resist only a small pressure gradient). The stomach, duodenum, biliary tract, and pancreas—which are closely related embryologically—function as an integrated unit. Indeed, coordinated contraction and relaxation of the antrum, pylorus, and duodenum (which is sometimes referred to as the antroduodenal cluster unit) are probably more important than simply the pressure produced by the pyloric smooth muscle per se. Regulation of gastric emptying is discussed further on pp. 877–878.

Ileocecal Sphincter

The valve-like structure that separates the ileum and cecum is called the ileocecal sphincter. Similar to other GI sphincters, the ileocecal sphincter maintains a positive resting pressure and is under the control of the vagus nerve, sympathetic nerves, and the ENS. Distention of the ileum results in relaxation of the sphincter, whereas distention of the proximal (ascending) colon causes contraction of the ileocecal sphincter. As a consequence, ileal flow into the colon is regulated by luminal contents and pressure, both proximal and distal to the ileocecal sphincter.

Internal and External Anal Sphincters

The “anal sphincter” actually consists of both an internal and an external sphincter. The internal sphincter has both circular and longitudinal smooth muscle and is under involuntary control. The external sphincter, which encircles the rectum, contains only striated muscle but is controlled by both voluntary and involuntary mechanisms. The high resting pressure of the overall anal sphincter predominantly reflects the resting tone of the internal anal sphincter. Distention of the rectum (Fig. 41-5A ), either by colonic contents (i.e., stool) or experimentally by balloon inflation, initiates the rectosphincteric reflex by relaxing the internal sphincter (see Fig. 41-5B ). If defecation is not desired, continence is maintained by an involuntary reflex—orchestrated by the sacral spinal cord—that contracts the external anal sphincter (see Fig. 41-5C ). If defecation is desired, a series of both voluntary and involuntary events occurs that includes relaxation of the external anal sphincter, contraction of abdominal wall muscles, and relaxation of pelvic wall muscles. Flexure of the hips and descent of the pelvic floor then facilitate defecation by minimizing the angle between the rectum and anus. In contrast, if a delay in defecation is needed or desired, voluntary contraction of the external anal sphincter is usually sufficient to override the series of reflexes initiated by rectal distention.

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FIGURE 41-5 Pressure changes initiated by rectal distention. (Data from Schuster MM: Simultaneous manometric recording of internal and external anal sphincteric reflexes. Johns Hopkins Med J 116:70–88, 1965.)

Motility of the small intestine achieves both churning and propulsive movement, and its temporal pattern differs in the fed and fasted states

Digestion and absorption of dietary nutrients are the primary functions of the small intestine, and the motor activity of the small intestine is closely integrated with its digestive and absorptive roles. The two classes of small-intestinal motor activity are churning (or mixing) and propulsion of the bolus of luminal contents. Churning—which is accomplished by segmental, nonpropulsive contractions—mixes the luminal contents with pancreatic, biliary, and small-intestinal secretions, thus enhancing the digestion of dietary nutrients in the lumen. These segmental contractions also decrease the unstirred water layer that is adjacent to the apical membranes of the small-intestine cells, thus promoting absorption. Churning or mixing movements occur following eating and are the result of contractions of circular muscle in segments flanked at either end by receiving segments that relax. Churning, however, does not advance the luminal contents along the small intestine. In contrast, propulsion—which is accomplished by propagated, peristaltic contractions—results in caudad movement of the intestinal luminal contents, either for absorption at more distal sites of the small or large intestine or for elimination in stool. Peristaltic propulsion occurs as a result of contraction of the circular muscle and relaxation of the longitudinal muscle in the propulsive or upstream segment, together with relaxation of the circular muscle and contraction of the longitudinal muscle in the downstream receiving segment. Thus, circular smooth muscle in the small intestine participates in both churning and propulsion.

The V m changes of intestinal smooth-muscle cells consist of both action potentials (see p. 244) and slow-wave activity (see p. 244). The patterns of electrical and mechanical activity differ in the fasting and fed states. In the fasting state, the small intestine is relatively quiescent but exhibits synchronized, rhythmic changes in both electrical and motor activity (Fig. 41-6 ). The interdigestive myoelectric or migrating motor complex (MMC) is the term used to describe these rhythmic contractions of the small intestine that are observed in the fasting state. MMCs in humans occur at intervals of 90 to 120 minutes and consist of four distinct phases: (1) a prolonged quiescent period, (2) a period of increasing action potential frequency and contractility, (3) a period of peak electrical and mechanical activity that lasts a few minutes, and (4) a period of declining activity that merges into the next quiescent period. During the interdigestive period, particles >2 mm in diameter can pass from the stomach into the duodenum, which permits emptying of ingested material from the stomach (e.g., bones, coins) that could not be reduced in size to <2 mm. The slow propulsive contractions that characterize phases 2 to 4 of the MMCs clear the small intestine of its residual content, including undigested food, bacteria, desquamated cells, and intestinal and pancreatic biliary secretions. MMCs usually originate in the stomach and often travel to the distal end of the ileum, but ~25% are initiated in the duodenum and proximal part of the jejunum.

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FIGURE 41-6 Mechanical activity in the fasting and fed states. Shown are records of intraluminal pressure along the small intestine of a conscious dog. Before feeding (left side), the pattern is one of MMCs. Feeding triggers a switch to a different pattern, characterized by both segmental contractions that churn the contents and peristaltic contractions that propel the contents along the small intestine. (Data from Itoh Z, Sekiguchi T: Interdigestive motor activity in health and disease. Scand J Gastroenterol Suppl 82:121–134, 1983.)

Feeding terminates MMCs and initiates the appearance of the fed motor pattern (see Fig. 41-6). The latter is less well characterized than MMCs but, as noted above, consists of both segmental contractions (churning), which enhance digestion and absorption, and peristaltic contractions (propulsion).

Determination of the primary factors that regulate both MMCs and transition to the fed pattern has been hampered by both species differences and complex interactions among the multiple probable mediators. Nonetheless, clear evidence has been presented for a role of the ENS, one or more humoral factors, and extrinsic innervation. A major determinant of the MMC pattern is the hormone motilin, a 22–amino-acid peptide that is synthesized in the duodenal mucosa and released just before the initiation of phase 3 of the MMC cycle. Motilin does not appear to have a role in the motor pattern that is observed in the fed state. Factors important in induction of the fed pattern include the activity of the vagus nerve (because sham feeding also both terminates MMCs and initiates a fed pattern) as well as the caloric content and type of food (e.g., fat more than protein) in the meal.

Motility of the large intestine achieves both propulsive movement and a reservoir function

The human large intestine has four primary functions. First, the colon absorbs large quantities of fluid and electrolytes and converts the liquid content of ileocecal material to solid or semisolid stool. Second, the colon avidly absorbs the short-chain fatty acids formed by the catabolism (or fermentation) of dietary carbohydrates that are not absorbed in the small intestine. The abundant colonic microflora accomplish this fermentation. Third, the storage of colonic content represents a reservoir function of the large intestine. Fourth, the colon eliminates its contents in a regulated and controlled fashion, largely under voluntary control. To accomplish these important activities, the large intestine functionally acts as two distinct organs. The proximal (or ascending and transverse) part of the colon is the site where most of the fluid and electrolyte absorption occurs and where bacterial fermentation takes place. The distal (or descending and rectosigmoid) portion of the colon provides final desiccation, as well as reservoir function, and serves as a storage organ for colonic material before defecation.

In contrast to the motor pattern in the small intestine, no distinct fasting and fed patterns of contractions are seen in the colon. Similarly to small-intestinal motor activity, colonic contractions are regulated by myogenic, neurogenic, and hormonal factors. Parasympathetic control of the proximal two thirds of the colon is mediated by the vagus nerve, whereas parasympathetic control of the descending and rectosigmoid colon is mediated by pelvic nerves originating from the sacral spinal cord.

The proximal colon has two types of motor activity, nonpropulsive segmentation and mass peristalsis. Nonpropulsive “segmentation” is generated by slow-wave activity that produces circular-muscle contractions that churn the colonic contents and move them in an orad direction (i.e., toward the cecum). The segmental contractions that produce the churning give the colon its typical appearance of segments or haustra (see Fig. 41-1). During this mixing phase, material is retained in the proximal portion of the large intestine for relatively long periods, and fluid and electrolyte absorption continues. One to three times a day, a so-called mass peristalsis occurs in which a portion of the colonic contents is propelled distally 20 cm or more. Such mass peristaltic contractions are the primary form of propulsive motility in the colon and may be initiated by eating. During mass peristalsis, the haustra disappear; they reappear after the completion of mass peristalsis.

In the distal colon, the primary motor activity is nonpropulsive segmentation that is produced by annular or segmental contractions. It is in the distal part of the colon that the final desiccation of colonic contents occurs. It is also here that these contents are stored before an occasional mass peristalsis that propels them into the rectum. The rectum itself is kept nearly empty by nonpropulsive segmentation until it is filled by mass peristalsis of the distal end of the colon. As described in Figure 41-5, filling of the rectum triggers a series of reflexes in the internal and external anal sphincters that lead to defecation (Box 41-2 ).

Box 41-2

Hirschsprung Disease

The anal sphincter controls defecation and consists of a smooth-muscle internal sphincter and a striated-muscle external sphincter. Distention of the rectum by inflation of a balloon—which simulates the effect of the presence of solid feces in the rectum—results in relaxation of the internal sphincter and contraction of the external sphincter (see Fig. 41-5). Voluntary control of the external sphincter regulates the timing of defecation.

Hirschsprung disease is a congenital polygenic disorder. At least 11 genes image N41-3  have been associated with Hirschsprung disease (http://www.emedicine.com/radio/topic343.htm. Accessed Sept 2014), including mutations in the RET receptor (a receptor tyrosine kinase) and its ligand. Variable penetrance leads to variable manifestations of the disease. At the cellular level, the fundamental defect is arrest of the caudad migration of neural crest cells, which are the precursors of ganglion cells. Symptoms include constipation, megacolon, and a narrowed segment of colon in the rectum. Histological examination of this narrowed segment reveals an absence of ganglion cells from both the submucosal and myenteric plexuses (see Fig. 41-3A ). The patient's constipation and resulting megacolon are secondary to failure of this “aganglionic” segment to relax in response to proximal distention. Manometric assessment of the internal and external anal sphincters reveals that the smooth-muscle internal sphincter does not relax after rectal distention (see Fig. 41-5) but that the external anal sphincter functions normally. Treatment of this condition is usually surgical, with removal of the narrowed segment that is missing the ganglia that normally regulate relaxation of the smooth muscle of the internal anal sphincter.

N41-3

Mutations in Hirschsprung Disease

Contributed by Emile Boulpaep, and Walter Boron

At least 11 mutations are associated with Hirschsprung disease, including mutations in the following proteins:

• RET, an acronym for rearranged during transfection, is a receptor tyrosine kinase (RTK; see p. 66)

• Glial-cell derived neurotrophic factor (GDNF), which is the ligand for RET

• The endothelin-B receptor (EBNRB)

• Endothelin 3 (ET-3), which is the ligand for EBNRB

Reference

Parisi MA. Hirschsprung disease overview. [Last revised November 10, 2011]  http://www.ncbi.nlm.nih.gov/books/NBK1439/ [Accessed November 2015].