Physiology of Gastric Motility Patterns

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 ).

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