EXTRACELLULAR SLOW WAVES AND PLATEAU AND ACTION POTENTIALS

The stomach is a sophisticated complex sphere of smooth muscle organized into circular, longitudinal, and oblique muscle layers. Gastric myoelectrical activity, termed pacesetter potentials or slow waves, regulate, control, and pace gastric smooth muscle contractions^1,2 (the term slow waves is used in this chapter). In the normal human stomach the slow waves occur at approximately 3 cycles per minute (cpm) or between 2.5 and 3.7 cpm.^3,4 From the pacemaker region on the greater curvature of the stomach, between the fundus and the proximal corpus, slow waves propagate circumferentially and migrate distally toward the pylorus every 20 seconds at a velocity of approximately 14 mm/second in the distal antrum (Fig. 48-1).^5,6 The gastric slow waves originate from the interstitial cells of Cajal.^7,8

Figure 48-1. Gastric electrical activity recorded from electrodes positioned on the serosa of the stomach from the fundus (A) to the antrum (D). Slow waves originate in the pacemaker region located at the juncture of the fundus and the corpus on the greater curvature. Note the fundus does not have slow wave activity (electrode A). Slow waves propagate circumferentially and migrate distally to the pylorus approximately every 20 seconds, or 3 cycles per minute (cpm) (dotted lines with arrowheads). The myoelectrical activity of the slow wave can be recorded with cutaneous electrodes. The summed gastric myoelectrical activity recorded from electrodes positioned on the abdominal surface in the epigastrium is termed an electrogastrogram (EGG), and the normal rhythm is 3 cpm.

(Modified from Koch KL. Electrogastrography. In: Schuster M, Crowel M, Koch, KL, editors. Atlas of Gastrointestinal Motility. Ontario, Canada: BC Decker; 2002. pp 185-201.)

The depolarization upstroke of the slow wave reduces the threshold for circular smooth muscle contraction; and, in the appropriate situation, the amplitude of the circular smooth muscle contraction increases with the onset of the plateau potentials and action potentials.^9,10 The aborad propagation of slow waves linked to plateau potentials (with or without action potentials) is the electrophysiologic basis of gastric peristaltic waves (Fig. 48-2). Thus, the slow waves linked with plateau or action potentials propagate through the corpus and antrum and create moving “ring contractions” that resolve in the antrum or at the pylorus in a terminal antral contraction. The pylorus provides an electrical barrier between the 3 cpm slow wave of the distal antrum and the 12 to 13 cpm slow wave of the duodenum.

Figure 48-2. Gastric slow waves linked with plateau potentials (or action potentials), the electrophysiological basis of gastric peristaltic waves. The plateau and action potentials occur during circular muscle contractions. Peristaltic waves originate in the pacemaker area. The frequency (3 cycles per minute [cpm]) and propagation velocity (approximately 14 mm/second) of the gastric peristaltic waves are controlled by the slow wave, which leads the contraction from the proximal corpus to the distal antrum, as shown at electrodes A through D. The solid black lines and arrows indicate the circumferential and distal propagation of the peristaltic wave, which forms a ring contraction (small arrow), indicating a moving peristaltic contraction. Peristaltic contractions occur three times per minute, the frequency of the gastric slow wave. The increased myoelectrical activity of the plateau potentials and action potentials linked with the slow wave results in increased amplitude of the EGG signal (thick black lines). The fundus does not participate in the gastric peristaltic contractions.

(Modified from Koch KL. Electrogastrography. In: Schuster M, Crowel M, Koch, KL, editors. Atlas of Gastrointestinal Motility. Ontario, Canada: BC Decker; 2002. pp 185-201.)

INTRACELLULAR ELECTRICAL RECORDINGS FROM GASTRIC SMOOTH MUSCLE CELLS

Intracellular recordings from smooth muscle cells from the different regions of the stomach (fundus to the mid-corpus to the terminal antrum) illustrate the electrophysiologic characteristics that distinguish these regions (Fig. 48-3).¹ Key features are (1) regional differences in resting membrane potential, which range from −48 to −75 millivolts (mV); (2) regional differences in threshold for contraction that vary from −52 to −40 mV; and (3) the occurrence of plateau potentials with or without spike potentials.¹ The fundic smooth muscle cells are unique because their resting membrane potential lies at or above the threshold for contraction (−50 mV), a situation that promotes sustained smooth muscle contraction and ongoing fundic tone. Inhibitory vagal input to the fundus increases during swallowing and results in decreasing muscle tone associated with “receptive relaxation” and the accommodation of swallowed foodstuffs.^11,12 Fundic muscle tone decreases in proportion to the intensity and duration of the inhibitory neural discharge.

Figure 48-3. Intracellular electrical recordings from smooth muscle from the fundus to the pylorus (A through I). Resting membrane potential in millivolts (mV) is shown on the vertical axis and time is shown on the horizontal axis. Distinctive electrical characteristics in each region are shown: A, Spontaneous electrical activity in the fundic smooth muscle is absent. B through E, The resting membrane potential is less negative in the smooth muscle in the corpus compared with the antrum (F through H). Spontaneous upstroke depolarization is also recorded in the corpus and antrum, as well as in the pylorus (panel I). The upstroke depolarization in the smooth muscle is initiated by interstitial cells of Cajal (see text). The upstroke depolarization is followed by the plateau potential and repolarization (D through I). The upstroke depolarization and plateau potentials are associated with contraction of the smooth muscle. Action potentials are superimposed on the plateau potentials in the terminal antrum and pylorus (G through I) and are associated with increased amplitude of smooth muscle contraction.

(From Szurszewski JH. Electrophysiological basis of gastrointestinal motility. In: Johnson LR, editor. Physiology of the Gastrointestinal Tract. 2nd ed. New York, NY: Raven Press; 1986. p 383.)

In contrast to the fundus, intracellular recordings from the corpus indicate a lower resting membrane potential of −60 mV. The rapid upstroke depolarization in these cells is followed by a plateau potential that slowly returns to the baseline resting electrical potential (see Fig. 48-3F). The plateau potentials are associated with circular muscle contraction activity in the corpus and antrum.¹ The plateau potential may be accompanied by action potentials in the corpus and antrum (see Fig. 48-3G and H). Extrinsic stimuli such as release of acetylcholine or stretch of the stomach wall increases the amplitude and duration of the plateau potential and the occurrence of action potentials, resulting in contractions of varying force, as seen in the muscle of the terminal antrum. Depending on the excitatory neural stimuli and the amplitude of plateau potentials and the number of action potentials, peristaltic contraction waves of the circular muscle layer vary from very-low-amplitude contractions to high-amplitude lumen-occluding contractions. At the pylorus, the plateau potentials have long durations and superimposed action potentials that result in closure of the pyloric sphincter in conjunction with the terminal antral contraction (see Fig. 48-3H and I).¹

The membrane potential and the force of smooth muscle contraction also distinguish the fundus, corpus, and antrum (Fig. 48-4). The resting membrane potential of the fundus is approximately −50 mV and produces the sustained contraction and the resting tone of the fundus.¹ This fundic tone ensures a sensitive response to excitatory or inhibitory stimuli for relaxation or contraction of the fundus. Receptive relaxation during ingestion of food is accomplished by these electrophysiologic attributes of smooth muscle in the fundus. In contrast, the resting membrane potentials of the corpus and antrum are −60 to −70 mV, respectively. In the presence of plateau potentials or action potentials the membrane potential reaches −45 mV or less and smooth muscle contraction occurs. If the plateau potentials have higher amplitude, then contractions of larger amplitude or force occur. When the plateau potential and action potentials are linked to the propagating slow waves in the antrum, then the moving ring contractions of the gastric peristaltic “waves” are formed (see Fig. 48-2).

Figure 48-4. Relationship between membrane potential in millivolts (mV) and force of contraction in grams (gF) in gastric smooth muscle from the fundus, corpus, and antrum. The resting membrane potential in fundic smooth muscle is approximately −50 mV, a potential that generates muscle contraction and “resting tone” in the fundus. The resting membrane potential in the antrum smooth muscle is −70 mV, almost 30 mV below the threshold for smooth muscle contraction. When the resting membrane potential reaches −40 or −35 mV, the steep slope of the voltage-contraction curve is observed in the corpus and antrum.

(From Szurszewski JH. Electrophysiological basis of gastrointestinal motility. In: Johnson LR, editor. Physiology of the Gastrointestinal Tract. 2nd ed. New York, NY: Raven Press; 1986. p 383.)

In conjunction with terminal antral contractions, the pyloric sphincter contraction prevents emptying of gastric content into the duodenum and results in retention of solid foodstuffs in the stomach. Thus, the peristaltic waves associated with terminal antral and pyloric sphincter contraction produce little or no emptying of the gastric contents from the stomach into the duodenum. In contrast, if the pylorus remains open during the gastric peristaltic wave, then an aliquot of nutrient chyme is emptied into the duodenum.

INTERSTITIAL CELLS OF CAJAL

ICCs are the “pacemaker cells” for the smooth muscle apparatus of the gastrointestinal tract.^7,8,13,14 ICCs originate from c-Kit–positive mesenchymal cell precursors.¹⁵ ICCs in the stomach are located in submuscular, intramuscular, myenteric, and subserosal layers of the gastric wall.^16,17 Figure 48-5 shows the anatomic relationships between the ICCs in the myenteric plexus (MY-ICCs), the intramuscular ICCs (IM-ICCs), the enteric neurons, and the circular smooth muscle cells. MY-ICCs are located between the circular and longitudinal muscle layers of the stomach and are the ICCs responsible for the generation of the slow waves (see Fig. 48-5). These ICCs spontaneously generate slow waves that are conducted into adjacent smooth muscle cells and cause depolarization and contraction of the smooth muscle by activating voltage-dependent, dihydropyridine-sensitive (l-type) calcium channels (see Fig. 48-5).^18–20 Increased amplitude of the plateau potential correlates with increased amplitude of smooth muscle contraction (Fig. 48-6). The slow waves propagate circumferentially and distally through the ICC network via gap junctions and entrain more distal ICCs with slower intrinsic frequencies to the higher slow wave frequency, the pacemaker frequency.

Figure 48-5. Relationships among interstitial cells of Cajal (ICCs), smooth muscle cells in the circular muscle layer, and motor neurons of the enteric nervous system. ICCs in the region of the myenteric plexus (MY-ICCs) are pacemaker cells and spontaneously generate slow wave depolarizations. Slow waves conduct to adjacent smooth muscle cells via low-resistance junctions (gap junctions) as shown by the curved arrow. Depolarization of smooth muscle cells leads to activation of l-type calcium channels, Ca²⁺ entry, and contraction of the smooth muscle cells. Thus, slow waves naturally organize the contractile pattern of gastric smooth muscles into a series of phasic contractions. Smooth muscle cells do not possess the ionic mechanisms necessary to regenerate slow waves, so the amplitude of slow waves decreases as slow waves conduct from smooth muscle cell to smooth muscle cell in a muscle bundle. Active propagation of slow waves from the dominant (i.e., highest frequency) pacemaker along the greater curvature of the gastric corpus to the pyloric sphincter requires a continuous coupled network of MY-ICCs. SMC, smooth muscle cell.

A second class of ICCs lies within circular layers of smooth muscle bundles and are known as intramuscular ICCs (IM-ICCs). The IM-ICCs appear to be important in mediating neurotransmission because they form very close, synaptic connections with the varicose terminals of enteric motor neurons (short arrows). IM-ICCs are also electrically coupled via gap junctions to smooth muscle cells. Postjunctional neural responses can be conducted from IM-ICCs to muscle bundles. Thus, stimulation of excitatory enteric neurons leads to depolarization of IM-ICCs; and the depolarization, conducting through gap junctions to the MY-ICCs network, causes positive chronotropic effects on the frequency of gastric slow waves. Depolarization of IM-ICCs in response to excitatory nerve stimulation also increases the contractile responses of smooth muscle cells to slow wave depolarizations initiated by MY-ICCs. Stimulation of inhibitory enteric neurons causes hyperpolarization and stabilization of membrane potential and tends to inhibit contractile responses to slow wave depolarization.

(Figure courtesy of KM Sanders.)

Figure 48-6. Relationships between smooth muscle contraction (tension) and membrane potential (MP). In these intracellular recordings from antral smooth muscle, the upstroke potential is the rapid depolarization (upstroke) event, followed by the plateau phase. The plateau potentials are associated with contraction of the smooth muscle cell, as shown in panel A. Note that an increase in the amplitude of the plateau potentials (red line in panel B) is associated with greater contractility (tension). During redepolarization to the resting membrane potential (RMP), the contraction resolves.

(Modified from Sanders KM, Ordog T, Koh SD, Ward SM. Properties of electrical rhythmicity in the stomach. In: Koch KL, Stern RM, editors. Handbook of Electrogastrography. New York, NY: Oxford Press; 2004. pp 13-36.)

ICCs are also located within the layers of the circular smooth muscle (IM-ICCs), where they integrate and coordinate the spread of the slow wave and the smooth muscle contraction initiated by the MY-ICCs.¹⁰ Slow waves are not regenerated in the smooth muscle cells because the ion channels needed to generate and propagate slow waves are not expressed by gastric smooth muscle.

In the corpus and antrum the MY-ICCs form a continuous lattice-like network of interconnections that extend from the pacemaker region circumferentially and aborally to the pylorus. The MY-ICCs establish the dominant pacemaker frequency, and IM-ICCs carry the slow wave into the circular smooth muscle bundles to coordinate circumferential and aboral propagation of the contraction wave.

The ICCs have innate rhythmicity that is based on their unique metabolism and fluxes in intracellular and extracellular calcium.^19,21 The most active area of depolarization and repolarization of the ICCs is in the pacemaker area of the stomach located between the fundus and the proximal corpus (see Fig. 48-1). The depolarization and repolarization of the ICCs is regenerated and propagated through the network of ICCs in a migrating wave front that moves from the pacemaker region on the greater curve through the corpus and antrum to the pylorus, as shown in Figures 48-1 and 48-2, proscribing the pathway of gastric peristaltic contractions. Excitatory inputs (e.g., cholinergic stimuli, stretch) to the MY-ICC results in opening of calcium channels and depolarization of the smooth muscle cells with IM-ICC activation to coordinate the contractions of the circular muscle cells in time and space. Thus, the ICC networks provide the control of frequency and propagation velocity for the circular muscle contractions that comprise gastric peristalsis waves.

The fundus of the stomach lacks slow waves (see Figs. 48-1 and 48-3A). The IM-ICCs in the fundus have a role in mechanoreception and act as sensory cells with interconnections to the vagal afferent neurons that innervate the fundus.^22,23 Fundic IM-ICCs are also innervated by inhibitory vagal neurons that regulate tone in the fundus.²³ Thus, the ICCs also participate in the relaxation of fundic tone that occurs during accommodation.²⁴

Loss of ICCs in the antrum is associated with gastroparesis in patients with diabetes mellitus.²⁵ Patients with diabetic gastroparesis and severe loss of ICCs have more gastric electrical dysrhythmias (tachygastria), more upper gastrointestinal symptoms, and poorer response to gastric electrical stimulation compared with patients with normal numbers of ICCs.²⁶ Electrical dysrhythmias and gastroparesis were recorded in rodents with experimental diabetes.²⁷ Interruption of ICC pathways from nondiabetic mechanisms also results in gastric dysrhythmias and ectopic pacemakers that are similar to gastric dysrhythmias found in patients with diabetes.^28,29

NERVOUS SYSTEM INNERVATION

As reviewed earlier in Chapter 47, neurons of the ENS populate the stomach wall from the fundus to the pylorus.³⁰ These neurons are located in the myenteric plexuses between the circular muscle and the longitudinal muscle layers (see Fig. 48-5). Neurons of the ENS are also located in submucosal and subserosal plexuses. The ENS provides local reflex circuits within the gastric wall: (a) sensory afferent neurons located in the mucosa linked to (b) interneurons in the myenteric plexus that are linked to (c) efferent neurons that innervate the smooth muscle and glands to perform the gastric secretomuscular functions.^31,32 Release of excitatory neurotransmitters such as acetylcholine and substance P stimulates smooth muscle contractions, whereas inhibitory neurotransmitters such as nitric oxide and vasoactive intestinal polypeptide inhibit contractions. These enteric neural circuits within the gastric wall are programmed to modulate peristaltic contractions (in conjunction with ICC activity described earlier) by sequential inhibition of the distal smooth muscle segment and contraction at the immediate proximal segment of the stomach wall.^33,34 Serotonin in the bowel wall has a primary role in initiating and controlling peristaltic events.³²

Neurons of the ENS are located in proximity to the MY-ICCs and IM-ICCs (see Fig. 48-5).³⁵ The ENS neurons provide additional control and modulation of contraction and relaxation of the gastric smooth muscle via cholinergic excitation and nitrergic inhibitory neurotransmission. Neurons of the ENS form gap junctions with MY-ICCs and IM-ICCs and provide an additional layer of neural control that integrates slow wave activity and smooth muscle activity. Thus, postganglionic excitatory and inhibitory neurons innervate MY-ICCs to modulate gastric neuromuscular contraction and relaxation and provide chronotropic effects on the slow waves.

The PNS and SNS modulate gastric neuromuscular activity. The vagus nerve provides the PNS input for the stomach, although approximately 80% of vagal fibers are afferent neurons. The afferent neurons are responsive to moment-to-moment contraction and relaxation (tone) of the stomach wall.³⁶ Efferent activity of the vagus nerve increases the release of acetylcholine, which increases the amplitude of gastric contractions and stimulates secretion of gastric acid and pepsin. The SNS innervates gastric smooth muscle with neurons that travel with the splanchnic vasculature. SNS activity generally elicits inhibitory action on the smooth muscle via effects on the myenteric neurons of the ENS.³⁷

The release of various hormones, ranging from cholecystokinin (CCK) to gastrin, affects the neuromuscular activity of the stomach. Gut hormones produce their effect on smooth muscle, ICCs, ENS as well as vagal efferent or afferent functions. These effects will be characterized under fasted and fed conditions and discussed in more detail following.

GASTRIC NEUROMUSCULAR ACTIVITY DURING FASTING

In the fasting state, electrical and contractile events of the corpus or antrum occur in a highly regular pattern termed the migrating myoelectrical (or “motor”) complex, or MMC.^38,39 The three phases of the MMC, as described by changes in intraluminal contractions, recur approximately every 90 to 120 minutes. Phase 1 is a period of quiescence wherein little or no contractile activity is recorded. Phase 1 is followed by phase 2 during which random, irregular contractions occur. Phase 3 of the MMC is a burst of regular, high-amplitude phasic contractions that last from 5 to 10 minutes (Fig. 48-7A). Phase 3 contractions are also termed the “activity front.” The activity front migrates from the antrum to the ileum, a journey of 90 to 120 minutes’ duration. The three phases of the MMC occur regularly in the small intestine, whereas approximately 50% of the phase 3 activity fronts originate in the stomach and then migrate through the small intestine.⁴⁰ The MMCs that originate in the stomach or duodenum travel through the small intestine and terminate in the distal ileum. If fasting continues, then another phase 3 activity front reappears in the antrum or duodenum at the 90- to 120-minute interval. The high-amplitude, three-per-minute contractions of phase 3 that develop in the distal antrum empty nondigestible, fibrous foodstuffs that remain in the stomach after a meal.

Figure 48-7. Antroduodenal motor activity in a healthy subject. A, Fasted state: Phase 3 contractions in the antrum (antral) and duodenum (Duo). Intraluminal contractions in the antrum (channels 1, 3, and 5) and the duodenum (channels 2, 4, and 6) are shown. A phase 3 activity front with three-minute antral peristaltic contractions lasting almost six minutes is noted in channels 1, 3 and 5. The phase 3 activity front propagates distally and migrates past the duodenal recording ports. The frequency of contractions in the duodenum is approximately 11 or 12 per minute, the same as the frequency of the duodenal slow wave. After completion of the phase 3 contractions, the quiescence of phase 1 and lack of contractions are seen in the antrum. B, Fed state: The subject ingested a standard liquid meal (Ensure). Contractions of variable amplitude are seen in the antrum and a series of relatively low-amplitude, irregular contractions are noted in the duodenum, all of which represent the fed state and are in marked contrast to phase 3 activity during fasting shown in panel A.

(Modified from Koch KL. The stomach. Manometry. In: Schuster M, Crowell M, Koch KL, editors. Atlas of Gastrointestinal Motility. Ontario, Canada: BC Decker; 2002. pp 135-150.)

Cyclic contractile activity associated with the onset of phase 3 also has been identified in the lower esophageal sphincter, the sphincter of Oddi, and the gallbladder. The phase 3 contractions correlate with rapid eye movement (REM) sleep and are related to a larger system of biological clocks.^38,41 MMCs develop after vagotomy, indicating that nonvagal mechanisms initiate and sustain MMC neuromuscular activity. Motilin is released during the intense phase 3 contractions that occur in the proximal duodenum.⁴² Motilin appears to be important for phase 3 activity of the MMC because administration of a motilin-neutralizing antibody abolishes the phase 3 contractions.

GASTRIC NEUROMUSCULAR ACTIVITY AFTER A MEAL

Three basic gastric neuromuscular activities occur during and after ingestion of solid foods: (1) receptive relaxation to accommodate the ingested food; (2) trituration of the ingested solid food by recurrent corpus-antral peristaltic waves to produce chyme; and (3) antral peristalsis with antropyloroduodenal coordination to empty chyme in small aliquots into the duodenum in a controlled manner for optimal digestion and absorption of the nutrients.

Gastric Neuromuscular Response to the Ingestion of Solid Foods

The neuromuscular work of the stomach in mixing, milling, and emptying food depends upon the physical characteristics, volume, and the fat, protein, and carbohydrate content of the ingested food. For example, almost 240 minutes of neuromuscular work is required to empty approximately 95% of a 255-kcal low-fat, egg substitute sandwich.⁴³ In contrast, 35 minutes of gastric neuromuscular work is required to empty almost 70% of a 20-kcal 500-mL soup broth meal that was consumed in four minutes.⁴⁴ Each meal requires its own specific time to be emptied, an emptying time achieved by the distinct gastric neuromuscular “work” elicited by the specific food. Figure 48-8 illustrates gastric neuromuscular activity required to receive, mix, and empty a solid meal. The spectrum of gastric work extends from fundic relaxation to gastric peristalsis to antropyloroduodenal coordination, the work that is needed to produce chyme and empty it into the duodenum. Ingestion of food abolishes the fasted state as regular three per minute gastric peristalsis begins in the corpus and antrum to mix the food; and in the fed state, a pattern of continuous small bowel contractions with short runs of peristalsis over distances of 2 to 4 cm optimize digestion and absorption of nutrients (see Fig. 48-7B).

Figure 48-8. Spectrum of gastric neuromuscular work after ingestion of a solid meal. To receive the ingested solid foods and accommodate the volume of food without increasing intragastric pressure, the fundic smooth muscle relaxes (receptive relaxation). The fundus then contracts to empty the ingested food into the corpus and antrum for trituration and emptying. Recurrent corpus-antral peristaltic waves mill the solids into chyme, which is composed of 1- to 2-mm solid particles suspended in gastric juice. Antral peristaltic waves, indicated by the ring-like indentation in the antrum, empty 2 to 4 mL of the chyme through the pylorus and into the duodenal bulb at the slow wave frequency of three peristaltic contractions per minute. Antropyloroduodenal coordination indicates efficient emptying of chyme through the pylorus, which modulates flow of the chyme by varying sphincter resistance. Contractions in the duodenum also provide resistance to emptying.

(Modified from Koch KL. Physiological basis of electrogastrography. In: Koch KL, Stern RM, editors. Handbook of Electrogastrography. New York, NY: Oxford Press; 2004. pp 37-67.)

Solid food delivered from the esophagus into the fundus is associated with receptive relaxation of the fundus, the “work” of fundic muscle relaxation. As the fundic smooth muscle relaxes, larger amounts of solid or liquid food are accommodated in the fundus and proximal corpus with little or no increase in intraluminal pressure. Liquids, in contrast, are immediately distributed throughout the antrum and corpus (emptying of liquids is discussed in the next section). Relaxation of the fundus occurs before the work of trituration in the corpus-antrum and is a vagal nerve–mediated event that requires nitric oxide.^45,46 Figure 48-9 shows an example of the changes in intragastric volume during relaxation of the fundus and proximal corpus in response to a caloric meal.⁴⁷ Relaxation of the fundus and the stimulation of mechanoreceptors (stretch), mediated through IM-ICCs in the fundic wall, activate vagal afferent neurons and vagovagal reflexes. These reflexes involve the nucleus of the tractus solitarius and efferent neurons from the dorsal motor nucleus of the vagus. Vagal excitatory neurons are inhibited and the vagal inhibitory neural transmitters nitric oxide and vasoactive intestinal peptide (VIP) are released to accomplish receptive relaxation.

Figure 48-9. Gastric accommodation of the fundus and proximal stomach in a healthy volunteer after a test meal. The intragastric volume, measured with a barostat balloon, increases from approximately 200 mL to approximately 450 mL during the 20 minutes after the meal is ingested. As the meal is emptied, the volume within the stomach slowly decreases over the two-hour postprandial period. Relaxation of the proximal stomach and accommodation of the meal volume reflect vagal-mediated receptive relaxation.

(From Tack J, Piessevuax H, Coulie B, et al. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 1998; 115:1346-52.)

Other factors influence the muscle tone of the fundus. Antral distention, duodenal distention, duodenal acidification,⁴⁸ intraluminal perfusion of the duodenum with lipid or protein, and colonic distention all decrease fundic tone through various reflexes. The gastric reflex is mediated through an arc initiated by capsaicin-sensitive afferent vagal nerves and is mediated by 5-hydroxytryptamine-3 (5-HT₃), gastrin-releasing peptide (GRP) and CCK_A receptors.⁴⁹

Solid foods labeled with technetium are accommodated initially in the fundus and proximal corpus, and by obtaining frequent scintigraphic images, the distribution of the labeled solid meal can be followed over four hours using scintigraphic methods.⁴³ Figure 48-10 shows that immediately after ingestion of this solid meal, the food is accommodated and the majority of the meal is retained in the fundus and proximal corpus. Subsequently, contractions of the fundus press portions of the food into the corpus and antrum for trituration. This early postprandial period of accommodation and trituration, that occurs before gastric emptying of the nutrients, is termed the lag phase. The lag phase may last from 45 to 60 minutes for solid foods, but the duration of the lag depends on the components of the meal, the thoroughness of chewing the food, and the time required to ingest the meal. For the 255-kcal egg substitute test meal that is ingested in a 10-minute period, the lag phase is 30 to 45 minutes.

Figure 48-10. Gastric emptying of an egg sandwich. One-minute scintigraphic images of a radiolabeled 255-kcal substitute egg meal in the stomach at time 0, 30, 60, 120, 180, and 240 minutes after ingestion are shown. The yellow and pink areas indicate regions of the stomach with higher isotope counts and more food than the other regions. Note the persistence of portions of the meal in the fundus at 120 minutes after ingestion. The meal is slowly redistributed from the fundus to the antrum for trituration and emptying. Only a small amount of the meal remains in the stomach by 240 minutes, and most of the labeled eggs are in the small intestine.

Once portions of the meal have been triturated into 1- to 2-mm particles suspended in gastric juice, the linear phase of gastric emptying of the chyme begins. Recurrent gastric peristaltic waves mix saliva, acid, and pepsin with the chewed food and then mill the food to produce chyme. The normal peristaltic waves occur every 20 seconds, generated by 3 cpm slow waves linked to plateau and action potentials. In healthy subjects approximately 60% of the egg substitute meal is emptied in two hours and more than 95% is emptied at four hours (Fig. 48-11).⁴³

Figure 48-11. Solid phase gastric emptying curve for 123 subjects after ingestion of a 255-kcal substitute egg meal, the same meal shown in Figure 48-10. Note that only approximately 15% of the eggs are emptied in the first 45 minutes, the lag phase of gastric emptying of this meal. At 90 minutes approximately 50% of the meal has been emptied and 50% is retained. By 240 minutes more than 95% of the meal has been emptied.

(Modified from Tougas G, Eaker EY, Abell TL, et al. Assessment of gastric emptying using a low fat meal: Establishment of international control values. Am J Gastroenterol 2000; 95:1456-62.)

During the linear phase of gastric emptying, each peristaltic wave empties from 3 to 4 mL of chyme into the duodenum.^50,51 Movement of chyme into the duodenum is usually, but not always, pulsatile due to the systole-like effect of antral peristaltic waves.⁵¹ The volume of chyme delivered into the duodenum by each peristaltic wave is modulated by the configuration of the peristaltic wave (e.g., depth of contraction, length of the peristaltic wave) pressure within the stomach, and resistance to flow provided by the pyloric sphincter and duodenal contractions.^52,53 The gastric peristaltic wave delivers a larger stroke volume when the pylorus and the duodenum are relaxed to receive the aliquot of chyme, but the overall rate of calories delivered each minute to the duodenum is consistent at approximately 3 to 4 kcal/min.⁵⁴

As time elapses after ingestion of the meal, the chewed food is continually redistributed from the fundus to the antrum for trituration (see Figs. 48-8 and 48-10). Some gastric peristaltic waves end at various points in the antrum and others end with a terminal antral contraction associated with closure of the pylorus that prevents the emptying of larger food particles or indigestible solids. These terminal antral and pyloric contractions result in retention of the solid particles in the corpus and antrum. In this manner, solid food particles that require further trituration are retained and subjected further to the milling effects of the recurrent peristaltic waves (see Figs. 48-7B and 48-8).

The intragastric pressure and gastric intraluminal pH values recorded after a healthy subject ingested an egg substitute meal are shown in Figure 48-12. During the first 2 hours after the meal the amplitude of intraluminal contractions varies from 10 to 40 mm Hg. Approximately three and a half hours after the solid meal was ingested, high amplitude contractions (>65 mm Hg) occur just before the pH increases from 1 to 6 as the motility/pH capsule is emptied from the acidic antrum into the alkaline environment of the duodenum. After the digestible components of the meal are emptied, strong antral contractions (phase 3–like contractions) empty the capsule from the stomach into the duodenum.⁵⁵ Thus, fibrous and indigestible materials are emptied by high-amplitude, antral contractions, whereas the digestible nutrients in the chyme are emptied earlier by the lower-amplitude peristaltic waves during the linear phase of emptying.⁵⁶

Figure 48-12. Gastric contractions and intraluminal gastric pH recordings during the emptying of a 255-kcal egg substitute meal, the same meal shown in Figure 48-10, recorded with an ambulatory capsule pH and motility device. pH is shown on the right vertical axis and pressure in mm Hg is shown on the left vertical axis. The pH increases to approximately 3 for the first 45 minutes as gastric acid is buffered by the meal. The pH then gradually decreases to 1 and remains near 1 at about 3 hours after ingestion of the meal. Stomach contractions are generally of low amplitude, less than 10 mm Hg after ingestion of the meal. At approximately 3 hours and 40 minutes after the meal, the recorded pH increases abruptly to 7 and then decreases and remains stable at around 6. Prior to the abrupt increase in pH, there is a series of clustered, high-amplitude antral contractions (pressure). These antral contractions empty the capsule from the antrum (pH 1) into the duodenum, where the pH is 6 or more. The contractions that occurred during the 3 hours and 50 minutes required to empty the meal document the neuromuscular work required to triturate and empty this meal in a healthy subject.

The pylorus modulates the rate of gastric emptying by several mechanisms. Increased pyloric tone and isolated pyloric pressure waves prevent gastric emptying and promote retention of food for further milling. Pyloric contractions associated with terminal antral contractions are common during the lag phase when trituration is occurring. Once the linear phase of emptying begins, the numbers of isolated pyloric contraction waves diminish as chyme is available for emptying via the gastric peristaltic waves.

Gastric Neuromuscular Response to the Ingestion of Liquids

The gastric neuromuscular activity required to mix and empty liquids from the stomach is distinctly different compared with the emptying of solid foods.^55–59 Figure 48-13 shows three-dimensional (3-D) ultrasound images of the stomach in a healthy subject during the fasting state and 10 minutes after the subject ingested 500 mL of soup.⁵⁸ The intragastric volume was approximately 40 mL during fasting and increased almost nine-fold to 350 mL 10 minutes after ingestion of the meal, indicating the remarkable relaxation of the smooth muscle of the antrum and corpus (in addition to the fundic relaxation) that was required to accommodate this liquid volume. (In contrast, solid meals are initially accommodated and retained primarily in the fundus and proximal stomach, as shown in Figs. 48-9 and 48-10.) Once accommodated, nutrient liquids are emptied into the duodenum in a controlled but more rapid rate compared with solid foods, which require trituration. Noncaloric liquid meals empty without the lag phase in a curve described as monoexponential emptying (Fig. 48-14).⁶⁰ Caloric-dense liquids on the other hand are retained for longer periods in the antrum and are emptied slower than noncaloric liquids. Liquids are emptied from the stomach by a combination of (a) pressure gradients between the stomach and the duodenum that produce flow of liquid into the duodenum; (b) antral peristaltic contractions that produce a pulsatile pattern of emptying of liquids from the antrum into the duodenum; and (c) duodenogastric reflux events that modify gastric emptying results.^51,52 From a gastric myoelectrical activity viewpoint, ingestion of water until the point of fullness induces a brief “frequency dip” followed by normal 3 cpm activity on the electrogastrogram (EGG) (Fig. 48-15).⁶¹ The rate of gastric emptying of liquids is influenced by the volume, nutrient content, viscosity, and osmolarity of the ingested liquid.^53,54,59,62 These factors affect the neuromuscular activity of the stomach, which ultimately produces the rate of emptying. These factors are discussed below.

Figure 48-13. Three-dimensional ultrasound images from the stomach before and after a healthy subject ingested a 500-mL soup meal. A, In the fasted state, intragastric volume is approximately 38 mL. B, Ten minutes after ingestion of the meal the stomach volume is 350 mL. Note that the antrum, corpus, and fundus are now distended, indicating the marked relaxation of the smooth muscle required to accommodate this volume of liquid.

(Modified from Gilja OH, Detmer PR, Jong JM, et al. Intragastric distribution and gastric emptying assessed by three-dimensional ultrasonography. Gastroenterology 1997; 113:38-49.)

Figure 48-14. Emptying of a mixed liquid and solid meal in healthy subjects, who ingested 300 mL of radiolabeled water with two radiolabeled eggs and toast. A, Emptying rate for the solid phase of the meal. A short lag phase is noted before the linear phase of emptying, and by 60 minutes approximately 55% of the meal is emptied (45% is retained). The lag phase may be shortened if the subject has taken a relatively long time to eat the meal or the solids require little trituration. B, Empyting rate for the liquid phase of the meal. Approximately 80% of the water is emptied (20% is retained) at 60 minutes, as the liquid is rapidly distributed throughout the antrum and corpus. This is considered a monoexponential liquid emptying curve.

(Modified from Maurer AH, Parkman HP, Knight LC, Fisher RS. Scintigraphy. In: Schuster M, Crowel M, Koch, KL, editors. Atlas of Gastrointestinal Motility. Ontario, Canada: BC Decker; 2002. pp 171-184.)

Figure 48-15. Running spectral analysis of the electrogastrogram (EGG) signal and EGG rhythm strips before and after ingestion of a water-load in a healthy subject. The X-axis shows the frequencies in the EGG signal in cycles per minute (cpm). The Y-axis indicates time, and the peaks (or Z-axis) indicate the power of the frequencies contained in the EGG signal. The baseline EGG rhythm strip (A) shows 3 cpm activity. The regularity and the amplitude of the 3 cpm EGG signal is increased (B) after the subject ingested 750 mL of water (water-load arrow) over a 5-minute period. The running spectral analysis shows relatively low power 3 cpm peaks at baseline (A1). After ingestion of the water load the peaks initially disappear (the frequency “dip”) and then 3 cpm peaks emerge and are prominent until the end of the 30-minute recording (B1). This is a normal gastric myoelectrical response to the filling of the stomach with water and the subsequent emptying of the water. The four graphs in the red insert show the percentage distribution of EGG power in the four relevant frequency ranges during baseline (BL) and the 10, 20, and 30 minutes after ingestion of the water by the subject (green lines). Normal ranges are shown by blue lines. Note the initial decrease in the percentage of normal EGG activity (2.5-3.75 cpm) 10 minutes after ingestion of the water (the frequency dip), followed by increased percentages in the 3 cpm normal range 20 and 30 minutes after ingestion of the water. Resp., respiratory activity.

(Modified from Koch KL. Physiological basis of electrogastrography. In: Koch KL, Stern RM, editors. Handbook of Electrogastrography. New York, NY: Oxford Press; 2004. pp. 37-67.)