21.1

Overview

The stomach is perhaps the most paradoxical organ of the gastrointestinal (GI) tract, accomplishing extensive and often rapid expansion to accommodate ingested food at low pressure in the proximal stomach while simultaneously generating propagating contractions in the distal stomach that can generate substantial pressures that breakdown and empty food. These disparate regions of the stomach are continuous with each other; there are no specialized anatomical structures such as sphincters or junctions that divide the two regions. The action and interaction of motor activity in the proximal and distal stomach result in food being progressively broken down to a watery paste (chyme) that is delivered, quite precisely, into the duodenum for further processing in the intestine.

The three main motor functions of the stomach—accommodation, mixing, and emptying—have been observed, described, and investigated for over 130 years. The motor behaviors that alter the contractile properties of the gastric muscular coat to achieve these functions are largely intrinsic to the stomach, but can be modulated by extrinsic neural, humoral factors, and microbes (addressed in subsequent chapters). While the development of tools and techniques to study gastric motor behavior has been ongoing, in the past two decades, significant advances in the tools used to study gastric motility have expanded our understanding of how different intrinsic cell networks interact to produce these gastric motor behaviors. This chapter will primarily focus on how intrinsic networks located within the wall of the stomach generate and modulate gastric motor patterns.

21.2

Anatomy of the Gastric Musculature

The main function of the proximal stomach is to store food. This region is isolated from the esophagus by the lower esophageal sphincter (LES) and is comprised of the fundus and orad corpus. Its structural characteristics are uniquely specialized to accommodate food. It has relatively thin and distensible external smooth muscle layers, lacks a slow wave pacemaker network, and receives substantial inhibitory innervations. In contrast, the main function of the distal stomach, comprising the distal corpus, antrum, and pylorus, is to generate strong pressure waves for the breakdown and mixing of food into chyme and emptying of chime through the pylorus into the duodenum. The distal stomach essentially has the opposite characteristics of the proximal stomach. The thickness of the external smooth muscle layers, particularly the circular muscle, increases distally and is maximal in the distal antrum and pylorus. The longitudinal and oblique muscle layers reinforce the distal stomach, particularly around the greater curvature. Together, these muscle layers can generate powerful contractions and are inherently less distensible to provide substantial resistive forces to contain the high pressures generated.

21.3

Cell Networks Involved in the Control of Gastric Motility

There are three main specialized networks that control the spatial and temporal characteristics of smooth muscle motor behavior in the stomach. First, starting in the mid-corpus, a mesh-like network of interstitial cells of Cajal (ICC) located between the circular and longitudinal muscle layers ICC (ICC-MY) generate propagating bands of depolarization (slow waves) that depolarize surrounding longitudinal and circular smooth muscle cells, resulting, if conditions are favorable, in propagating ring-like contractions called antral peristalsis. Like the muscle layers, the ICC-MY network increases in density and volume towards the pylorus in the distal stomach and can be multiple layers thick in the distal antrum.

Second, the gastric enteric nervous system (ENS), made up of neurons and glial cells arranged in ganglia connected by internodal strands, is almost exclusively involved in modulating smooth muscle activity. It is a comparatively pared down arrangement compared to the ENS in the intestines, lacking plexi involved in control of blood flow and secretion (submucosal/Henle’s plexi) and lacks neurons that have large, smooth cell bodies with multiple axons (Dogiel Type II) that are intrinsic primary afferent neurons in the intestines (~ 30%). Similar to the small intestine, distinct electrophysiological classes of gastric myenteric neurons have been identified. In the antrum, three major types: I, II, and III have been identified, including neurons with AH-type electrophysiology. The synaptic properties of myenteric neurons in the gastric antrum differs from the gastric corpus, which may reflect functional differences in the two regions. In the ENS of the mammalian stomach, acetylcholine appears to be the major enteric neuroneuronal transmitter, similar to the small and large bowel. All intracellular recordings from myenteric neurons in the antrum have revealed fast excitatory synaptic potentials to fiber tract stimulation. Similarly in the gastric corpus, fast EPSPs were readily evoked in every neuron that was mediated by acetylcholine. This is supported by immunohistochemical studies that have shown about 60% of all myenteric neurons in the guinea-pig gastric corpus synthesize choline acetyltransferase, while about 40% synthesize nitric oxide synthase, which are likely to be inhibitory motor neurons that project to the smooth muscle layers. A significant population of myenteric neurons in the antrum also synthesize substance P (37%), vasoactive inhibitory polypeptide (VIP) (22%), and neuropeptide Y (29%) and a small proportion synthesizes 5-HT (3%). Exogenous 5-HT potently activates myenteric neurons in the stomach, but is synthesized in very small populations of enteric neurons in most species (1%–3%).

Regardless of the absence of neurons that have Dogiel Type II morphology in the stomach, excitatory and inhibitory neural reflexes can be readily elicited in the isolated stomach, activated by a number of physical (stretch) and chemical mediators (acid/enteroendocrine substances). Also, local distension of the antrum in isolated stomachs that are surgically disconnected from extrinsic spinal and vagal afferent pathways still activates excitatory and inhibitory motor neurons to the circular muscle, generating excitatory and inhibitory junction potentials. For a long time, it was thought that the stomach only received a sensory innervation via extrinsic vagal and spinal afferents. This was based largely on the notion that no intrinsic neurons with properties of sensory neurons similar to those found in the intestine could be identified in the stomach. Indeed, in these isolated preparations, axon collaterals from spinal and vagal afferent endings may still influence motor pathways in the stomach.

In 2004, the notion that only myenteric AH neurons in the ENS have sensory properties changed significantly when it was revealed that another distinct population of myenteric neurons was identified, this time in the colon, which also had intrinsic sensory properties in response to maintained circumferential stretch. This population of neurons were electrophysiologically identified as S-neurons, with Dogiel Type 1 morphology. They were morphologically identified as interneurons that received fast synaptic inputs and generated a tonic-firing pattern to intrasomal current injection. But, interestingly this population of neurons could also generate proximal process potentials in their somata, which were activated independently of any synaptic inputs. To date, neurons with these types of characteristics have not been identified in the mammalian stomach, at least with intracellular microelectrodes. However, our understanding of the functional role of the different classes of myenteric neurons in the stomach took a major step forward when voltage sensitive dyes were used to image the activation of multiple classes of myenteric neurons simultaneously, within the same ganglion of the gastric ENS. It was found that 27% of gastric myenteric neurons were mechanically sensitive, responding to intraganglionic volume injection. Most of these neurons were classified as rapidly adapting cells that responded with a rapid burst of action potentials at the onset of the mechanical stimulus, then exhibited a reduced firing rate. Because it was found that a substantial population of myenteric neurons responded to von Frey hair compression, or intraganglionic volume injection, it was proposed that many neurons in the ENS are multifunctional mechanosensitive neurons (MEN). These MENs have now been identified in the guinea-pig ileum, mouse ileum and colon, and human intestine.

The last specialized network of cells in the stomach has only recently been discovered and appreciated, and is comprised of cells that act as intermediaries in neurotransmission located between motor nerve endings and smooth muscle. This “intermediary cell network” contains two distinct cell types: (i) long, spindle-shaped ICCs that are embedded within the circular and longitudinal muscle layer (known as intramuscular ICC: ICC-IM) that are innervated by excitatory and inhibitory motor neurons and (ii) a type of fibroblast, best defined by its expression of platelet-derived growth factor alpha (PDGFR alpha) receptors that are innervated exclusively by inhibitory motor neurons. Both cell types in the “intermediary cell network” are distributed throughout the smooth muscle layers in the stomach.

While each of the control networks can be considered as discrete and separate entities, there is a high degree of interconnectedness within and between them. Studies using dye injection or measuring electrical responses have demonstrated that physical/electrical connections (gap junctions) exist within and between smooth muscle, the pacemaker ICC-MY network, and the “intermediary cell network.” As such, the muscular coat of the stomach can be considered as a multinetwork syncytium consisting of S mooth muscle, I nterstitial Cells (both ICC-MY and ICC-IM), and P DGFR alpha cells—dubbed the SIP syncytium. How currents flow within and between each network during gastric motor activity to produce appropriate motor behaviors is one of the great challenges of the field.

21.4

Gastric Accommodation

Relaxation of the gastric wall in order to store food at low pressure during the initial phases of digestion is an important, unique, and specialized motor behavior of the stomach. If the stomach cannot relax to keep intragastric pressure low, the risk of gastroesophageal reflux increases, particularly immediately after a bolus of food is propelled into the stomach and the LES sphincter has not retained competency. Structural specializations in smooth muscle of the proximal stomach allow for the greatest expansion in this region as explained above. This region is largely under the control of neural reflexes. Intrinsic myogenic mechanisms that relax smooth muscle found in other important storage organs of the body, such as the bladder, play a minor role in the stomach.

Inhibitory motor output to the proximal stomach can be activated from regions proximal to the stomach (receptive relaxation: esophageal peristalsis, cephalic vagal reflexes), within the stomach (adaptive relaxation/accommodation, stretch) and in regions distal to the stomach (duodenal nutrient reflexes; interorgan reflexes; ileogastric and colonogastric reflexes). Regardless of the region and mode of activation of inhibitory reflexes/pathways, the end result is the activation of inhibitory motor neurons that innervate ICC-IM and PDGFR alpha cells in the “intermediary cell network.” Neural inhibition of the proximal stomach is mediated by the release of a number of inhibitory neurotransmitters from the endings of inhibitory motor neurons including nitric oxide (NO), purines, and VIP. These inhibitory neurotransmitters hyperpolarize cells in the “intermediary cell network,” and this hyperpolarization is transmitted to couple adjacent smooth cells, causing a reduction in their cytoplasmic Ca ^{2 +} and subsequent relaxation. The inhibitory electrical event recorded in smooth muscle (the inhibitory junction potential or IJP) has different characteristics depending on the proportion and type of inhibitory neurotransmitter being released. IJPs mediated by NO acting on cGMP in cells in the “intermediary network” are relatively long lasting (~ 1–2 s) while IJPs evoked by the release of purines acting via P2Y receptors on primarily PDGFR alpha cells give rise to a faster hyperpolarization event, but have a shorter duration (< 1). The peptide neurotransmitter, VIP, is also released from inhibitory neurons only at higher stimulation intensities (> 10 Hz) although it has been difficult to quantify to what degree VIP is involved directly involved due to the lack of specific antagonists.

The role of the “intermediary cell network” in gastric accommodation has not been fully appreciated until relatively recently. Before the 1990s, the general consensus was that these inhibitory transmitters acted directly on smooth muscle to evoke relaxation. However, the use of W / W ^v mice that are heterozygous for a mutation in the protooncogene, c-Kit, or antibodies targeted against the kit receptor (ACK2) to disrupt the development of, or target the destruction of ICC, respectively, revealed disordered gastric motor responses. In these animals, inhibitory and excitatory responses to neural stimulation were reduced or abolished. Pathophysiological disruptions in which reduced kit-positive cells/staining is observed has been associated with compromised inhibitory transmission.

An important, but underappreciated, characteristic of gastric accommodation that is unique compared to other reservoir/storage organs in the body is the speed at which the proximal stomach can relax. To put gastric accommodation into context, filling of the bladder is comparatively slow (0.02–0.15 mL s ^{− 1} ) and normal emptying of contents from the ileum into the proximal colon is in the order of 0.01–0.02 mL s ^{− 1} . However, in extreme situations, the human stomach can relax to accommodate solid volumes at a rate of ~ 6 mL s ^{− 1} [350 mL min ^{− 1} ] to a final volume of ~ 3.5 L [70 hotdogs (~ 7 kg), in 10 min ] or liquid volumes at a rate of ~ 130 mL s ^{− 1} [7600 mL min ^{− 1} ] to a final volume of ~ 1.4 L (Australian Prime Minister, Bob Hawke, 1963). This relaxation not only slows the pressure increase incurred by increasing volumes, but can be so effective as to create a relative vacuum (negative resistivity, or a reduction in pressure with increasing volumes), to ensure low intragastric pressure is maintained ( Fig. 21.1 ).

During distension of isolated stomachs in which extrinsic pathways have been severed, there is activation of excitatory motor pathways predominantly in the distal stomach at small volumes resulting in an increase in intraluminal pressure ( red area in trace and image with red border), followed by a pronounced activation of inhibitory motor pathways in the proximal stomach resulting in a noticeable drop in intraluminal pressure ( blue area in trace and image with blue border) at medium to large volumes. These excitatory and inhibitory responses are coordinated by the gastric enteric nervous system and are blocked by TTX.

(Adapted from Hennig GW, Brookes SJ, Costa M. Excitatory and inhibitory motor reflexes in the isolated guinea-pig stomach. J Physiol 1997; 501 (Pt. 1):197–212.)

Another crucial function to allow prompt and responsive relaxation of the proximal stomach is the shutdown of ongoing excitatory activity to smooth muscle in the proximal stomach. Migrating motor complexes (migrating myoelectric complex (MMC)—see Section 21.7 for more detail) occur in the fasted state and consist of a repeated pattern of quiescence, followed by irregular contractions culminating in a burst of strong, repetitive contractions. The moment food is consumed, the MMC ceases, thereby disabling the often intense excitation produced by the MMC, allowing more effective inhibition and accommodation of contents. While irregular contractions (pressure events) are observed during and after a meal, it takes ~ 20 min for solid contents to begin to be emptied into the duodenum. During this period, mixing motor behaviors in the distal stomach apparently coexist with sustained inhibition of smooth muscle in the proximal stomach.

21.5

Gastric Mixing

The motor behavior of the distal stomach that underlies both mixing and emptying is essentially the same and consists of ring-like contractions that constrict the circumference of the stomach that originate in the orad corpus and propagate towards the antrum (antral peristalsis). These contractions are most immediate and noticeable movements of the stomach, observed in Egyptian times and documented in detail as early as 1838. Unlike the intestines that have dedicated mixing and emptying motor patterns, the degree of mixing and emptying in the stomach is ultimately determined by the pressure differential between the stomach and the duodenum and the degree of constriction or relaxation of the pylorus. The aperture of the pylorus is exquisitely controlled by a number of intrinsic and extrinsic neural pathways. The presence of nutrients in the duodenum activates numerous intrinsic and extrinsic (vagal) feedback pathways that regulate pyloric tone. These can be fats, carbohydrates, protein, acidity, and osmolarity, but generally they have the effect of increasing the tone (constricting) of the pylorus if nutrients are other than isotonic saline. Increasing the resistance to flow across the pylorus delays gastric emptying with smaller volumes passing through for any given peristaltic contraction, but it also increases mixing and trituration via a process called retropulsion. As an advancing peristaltic contraction propagates towards a closed pylorus, the contents begin to get pressurized, accentuated by the funnel shape of the distal antrum. Eventually, the pressure reaches a point where the antral peristaltic contraction ring cannot contain the pressure build-up in the distal antrum, and contents are forcefully propelled back through the narrow peristaltic contraction into the proximal antrum and corpus. The shearing forces during retropulsion are sufficient to break apart and shear even the most durable of substances, and, with enough time, food is broken down into particles of < 1 mm (chyme), which can pass into the duodenum. For retropulsion to occur effectively, antral peristaltic contractions need to advance towards the pylorus in a continuous fashion to generate the sustained pressure build-up.

The propagating ring-like contractions were originally thought to be generated by the gastric smooth muscle layer itself, as electrical depolarizations (slow waves) with the same frequency as antral peristaltic contractions could be recorded from smooth muscle in whole thickness preparations. Speculation that another dedicated cell network, the ICC network, was involved in the generation and propagation of slow waves was proposed in the 1970s; however, it was not until reliable and effective methods to largely eliminate ICC using W / W ^v mutants or antibodies directed to ACK2 were used, that this mechanism was validated. Interestingly, in the W / W ^v mouse small intestine, the loss of pacemaker-type ICC at the level of the myenteric plexus (ICC-MY) causes loss of slow waves and electrical rhythmicity, but does not block propagating neurogenic migrating motor complexes. Also, while W / W ^v mice have shed light onto the roles of ICC in neurotransmission and pacemaking, the mutation is not lethal. Hence, other mechanisms may adequately compensate for the loss of slow waves and reduced neurotransmission in W / W ^v mutant mice.

To appreciate the importance of gastric slow waves, an understanding of how they are generated and propagated is necessary. This has been carefully worked out by a number of laboratories over the last two decades. As the spatiotemporal characteristics of antral peristaltic contractions are intimately controlled by the pacemaker ICC-MY network in concert with neural output to the muscle, an understanding of how slow waves are generated and organized is crucial to understanding how gastric mixing and emptying occur.

21.5.4

Phasic Contractions in the Fundus

The fundus has long been defined by its absence of rhythmic contractions, as it lacks an ICC-MY network and does not display phasic oscillations in membrane potential (slow waves) in electrophysiological recordings. This pervading notion of an absence of phasic activity in the fundus is somewhat perplexing, as secretions from the gastric mucosa such as hydrochloric acid and pepsinogen presumably have their maximal effect on food located close to the mucosa. Without mechanical perturbation of contents, food located more centrally is unlikely to be exposed to these secretions. Small phasic contractions have been observed in the fundus using video recordings, but appear to lack the force or coordination to provide any substantial mixing effect. Similarly, electrophysiological recordings in the isolated human fundus have shown that there are rhythmic undulations in membrane potential, reminiscent of slow waves in the corpus, and rhythmic biopotentials have been recorded in the fundus using extracellular recordings, but their role in generating contractions capable of mixing contents is unknown.

Use of conditionally expressible Ca ^{2 +} indicators in ICC using the kit promoter (kit ⁺ /GCaMP3 ⁺ ) confirm that slow waves generated in the orad corpus do not spread into the fundus; however, Ca ^{2 +} imaging of smooth muscle cells that express a Ca ^{2 +} -indicator (smHC ⁺ /GCaMP3 ⁺ ) has revealed that the fundus is far from being mechanically quiescent. Rhythmic, isolated, and propagating Ca ^{2 +} transients in smooth muscle syncytium associated with strong propagating contractions ( Fig. 21.2 ) have been observed to occur throughout the fundus in intact isolated stomachs. These Ca ^{2 +} transients and associated contractions appear to be generated and propagated within the smooth muscle syncytium itself. This activity appears to be quite sensitive to the manipulation of tissue and is not observed in tissue strips. These contractions in the fundus may explain how secretions from the gastric mucosa are mixed throughout the cross-section of food in the fundus, and may act similar to ripple contractions in the proximal colon.

Frames from a recording of Ca ^{2 +} waves in smooth muscle of the fundus in a mouse expressing the Ca ^{2 +} indicator GCaMP3 on an smHC promoter (A). Propagating bands of Ca ^{2 +} activity (see orange arrows ) summarized in an ST map (Ca ^{2 +} : B) are associated with propagating constrictions after a short delay as shown by the red areas on the lower ST map (diameter: C) and are likely to be involved in mixing of contents in the fundus (the author is grateful to S. Ro, M. Shonnard, & K. Sanders, Dept. Physiology & Cell Biology, Reno, NV, USA, for the use of this example).

21.5.5

Spiral and Unstable Slow Waves

Another hitherto unobserved behavior revealed by low-power Ca ^{2 +} imaging of ICC activity in the entire stomach is that the majority of slow waves emanate out from their site of initiation as spirals ( Fig. 21.3 ); that is, most slow wave initiation sites appear as rotors, similar to cardiac action potentials in the heart. As the shape of the slow wave front that propagates through the ICC-MY network is ultimately responsible for shaping smooth muscle contractions and their propagation, the spiral slow wave adds a degree of complexity to how longitudinal and circular muscle layers are activated.

In isolated stomachs (A) from mice expressing the Ca ^{2 +} indicator GCaMP3 in ICC on the kit promoter (kit ⁺ /GCaMP3 ⁺ ), the majority of slow waves emanate out from initiation sites in the shape of a spiral (B and C).

Due to the high degree of coupling in the circular muscle layer and the long length-to-diameter ratio (~ 200 μm long, 7–9 μm wide), depolarization of a small region of circular smooth muscle anywhere around the circumference of the stomach will spread rapidly and circumferentially within the circular muscle layer resulting in a uniform ring/band of constriction. The spread perpendicular to the long axis of circular smooth muscle cells (i.e., longitudinal) is much slower (~ 1/6th), and more importantly, is slower than the speed of propagation of slow waves through the ICC-MY network. This speed difference allows the slow wave to “outpace” circular smooth muscle activity in the longitudinal direction, thereby dictating where rings of contraction will occur. However, as slow waves propagate through the ICC-MY network in an isotropic fashion (the same speed in all directions), smooth muscle cells located away from the greater curvature are potentially exposed to current injection from slow waves in the ICC-MY for much longer (see Fig. 21.3 ).

Similarly, Ca ^{2 +} imaging experiments of slow wave activity in the ICC-MY network show that slow wave initiation sites are unstable as previously reported. Initiation sites located distal to the orad corpus always result in the part of the expanding slow wave propagating proximally towards the fundus. There also appear to be instances of retrograde slow wave propagation in seemingly normal initiation sites, akin to the reentry phenomenon in the heart ( Fig. 21.4 ).

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