Gastrointestinal Physiology PDF

SECTION 6 Gastrointestinal Physiology KIM E. BARRETT AND HELEN E. RAYBOULD Chapter 27 Chapter 30 Functional Anatomy and General The Small Intestinal Phase of the Principles of Reg...

SECTION 6 Gastrointestinal Physiology KIM E. BARRETT AND HELEN E. RAYBOULD Chapter 27 Chapter 30 Functional Anatomy and General The Small Intestinal Phase of the Principles of Regulation in the Integrated Response to a Meal Gastrointestinal Tract Chapter 31 Chapter 28 The Colonic Phase of the Integrated The Cephalic, Oral, and Esophageal Response to a Meal Phases of the Integrated Response to a Meal Chapter 32 Transport and Metabolic Functions of Chapter 29 the Liver The Gastric Phase of the Integrated Response to a Meal 510 27 Functional Anatomy and General Principles of Regulation in the Gastrointestinal Tract LEARNING OBJECTIVES Upon completion of this chapter the student should be able to When considering the physiology of the GI tract, it answer the following questions: is important to remember that it is a long tube that is in 1. What is the neural innervation of the GI tract, and how is contact with the body’s external environment. As such, it is GI function regulated? vulnerable to infectious microorganisms that can enter along 2. What are some examples of neural, paracrine, and with food and water. To protect itself the GI tract possesses humoral regulation of GI function? a complex system of defenses consisting of immune cells and other nonspecific defense mechanisms. In fact the GI tract represents the largest immune organ of the body. This chapter provides an overview of the functional anatomy and general principles of regulation in the GI system. T he gastrointestinal (GI) tract consists of the alimen- tary tract from the mouth to the anus and includes Functional Anatomy the associated glandular organs that empty their contents into the tract. The overall function of the GI tract The structure of the GI tract varies greatly from region is to absorb nutrients and water into the circulation and to region, but there are common features in the overall eliminate waste products. The major physiological processes organization of the tissue. Essentially the GI tract is a that occur in the GI tract are motility, secretion, diges- hollow tube divided into major functional segments; the tion, and absorption. Most of the nutrients in the diet major structures along the tube are the mouth, pharynx, of mammals are taken in as solids and as macromolecules esophagus, stomach, duodenum, jejunum, ileum, colon, that are not readily transported across cell membranes to rectum, and anus (Fig. 27.1). Together the duodenum, enter the circulation. Thus digestion consists of physical jejunum, and ileum make up the small intestine, and the and chemical modification of food such that absorption can colon is sometimes referred to as the large intestine. Associ- occur across intestinal epithelial cells. Digestion and absorp- ated with the tube are blind-ending glandular structures tion require motility of the muscular wall of the GI tract that are invaginations of the lining of the tube; these glands to move the contents along the tract and to mix the food empty their secretions into the gut lumen (e.g., Brunner’s with secretions. Secretions from the GI tract and associated glands in the duodenum, which secrete copious amounts of organs consist of enzymes, biological detergents, and ions HCO3−). Additionally there are glandular organs attached to that provide an intraluminal environment optimized for the tube via ducts through which secretions empty into the digestion and absorption. These physiological processes are gut lumen—for example, the salivary glands and pancreas. highly regulated to maximize digestion and absorption, and The major structures along the GI tract have many the GI tract is endowed with complex regulatory systems to functions. One important function is storage; the stomach ensure this occurs. In addition the GI tract absorbs drugs and colon are important storage organs for processed food administered by the oral or rectal routes. (also referred to as chyme) and exhibit specialization in The GI tract also serves as an important organ for excre- terms of both their functional anatomy (e.g., shape and tion of substances. It stores and excretes waste substances size) and control mechanisms (characteristics of smooth from ingested food materials and excretes products from muscle to produce tonic contractions) that enable them to the liver such as cholesterol, steroids, and drug metabolites perform this function efficiently. The predominant function (all sharing the common property of being lipid-soluble of the small intestine is digestion and absorption; the major molecules). specialization of this region of the GI tract is a large surface 511 512 S E C T I O N 6 â … Berne & Levy Physiology area over which absorption can occur. The colon reabsorbs the portal circulation leading to the liver. Thus the liver is water and ions to ensure they do not get eliminated from unusual in receiving a considerable part of its blood supply the body. Ingested food is moved along the GI tract by from other than the arterial circulation. GI blood flow is the action of muscle in its walls. Separating the regions also notable for its dynamic regulation. Splanchnic blood of the GI tract are also specialized muscle structures called flow receives about 25% of cardiac output, an amount sphincters. These function to isolate one region from the disproportionate to the mass of the GI tract it supplies. next and provide selective retention of contents or prevent After a meal, blood can also be diverted from muscle to the backflow, or both. GI tract to subserve the metabolic needs of the gut wall and The blood supply to the intestine is important for carry- also to remove absorbed nutrients. ing absorbed nutrients to the rest of the body. Unlike other The lymphatic drainage of the GI tract is important for organ systems of the body, venous drainage from the GI the transport of lipid-soluble substances that are absorbed tract does not return directly to the heart but first enters across the GI tract wall. As we will see later, lipids and other lipid-soluble molecules (including some vitamins and drugs) are packaged into particles that are too large to pass Esophagus Upper and into the capillaries and instead pass into lymph vessels in the lower esophageal intestinal wall. These lymph vessels drain into larger lymph Liver sphincters ducts, which finally drain into the thoracic duct and thus into the systemic circulation on the arterial side. This has Stomach major physiological implications in lipid metabolism and Gallbladder Pylorus also in the ability of drugs to be delivered straight into the Pancreas systemic circulation. Sphincter of Oddi Cellular Specialization Colon The wall of the tubular gut is made up of layers consisting of specialized cells (Fig. 27.2). Small intestine Mucosa The mucosa is the innermost layer of the GI tract. It consists of the epithelium, the lamina propria, and the muscularis Ileocecal Internal and external anal mucosae. The epithelium is a single layer of specialized cells valve sphincters that line the lumen of the GI tract. It forms a continuous Fig. 27.1 General anatomy of the GI system and its division into layer along the tube and with the glands and organs that functional segments. drain into the lumen of the tube. Within this cell layer are Lymph node Villus Epithelium Lamina propria Muscularis mucosae Submucosa Circular muscle Longitudinal muscle Serosa Myenteric Muscularis externa plexus Submucosal plexus Gland in submucosa Fig. 27.2 General organization of the layers composing the wall of the GI tract.  CHAPTER 27â … Functional Anatomy and General Principles of Regulation in the Gastrointestinal Tract 513 a number of specialized epithelial cells; the most abundant The lamina propria immediately below the epithelium are cells termed absorptive enterocytes, which express consists largely of loose connective tissue that contains col- many proteins important for digestion and absorption of lagen and elastin fibrils (see Fig. 27.2). The lamina propria macronutrients. Enteroendocrine cells contain secretory is rich in several types of glands and contains lymph vessels granules that release regulatory peptides and amines to and nodules, capillaries, and nerve fibers. The muscularis help regulate GI function. In addition, cells in the gastric mucosae is the thin innermost layer of intestinal smooth mucosa are specialized for production of protons, and muscle. When seen through an endoscope, the mucosa mucin-producing cells throughout the GI tract produce a has folds and ridges that are caused by contractions of the glycoprotein (mucin) that helps protect the GI tract and muscularis mucosae. lubricate the luminal contents. The columnar epithelial cells are linked together by Submucosa intercellular connections called tight junctions. These The next layer is the submucosa (see Fig. 27.2), which junctions are complexes of intracellular and transmembrane consists largely of loose connective tissue with collagen proteins, and the tightness of these junctions is regulated and elastin fibrils. In some regions of the GI tract, glands throughout the postprandial period. The nature of the (invaginations or folds of the mucosa) are present in the epithelium varies greatly from one part of the digestive submucosa. The larger nerve trunks, blood vessels, and tract to another, depending on the predominant function lymph vessels of the intestinal wall lie in the submucosa, of that region. For example, the intestinal epithelium is together with one of the plexuses of the enteric nervous designed for absorption; these cells mediate selective uptake system (ENS), the submucosal plexus. of nutrients, ions, and water. In contrast, the esophagus has a squamous epithelium that has no absorptive role. Muscle Layers It is a conduit for transportation of swallowed food and The muscularis externa, or muscularis propria, typically thus needs some protection, provided by the squamous consists of two substantial layers of smooth muscle cells: epithelium, from rough food such as fiber. an inner circular layer and an outer longitudinal layer (see The surface area of the epithelium is arranged into villi Fig. 27.2). Muscle fibers in the circular muscle layer are and crypts (Fig. 27.3). Villi are finger-like projections that oriented circumferentially, whereas muscle fibers in the serve to increase the surface area of the mucosa. Crypts are longitudinal muscle layer are oriented along the longitu- invaginations or folds in the epithelium. The epithelium dinal axis of the tube. In humans and most mammals, the lining the GI tract is continuously renewed and replaced by circular muscle layer of the small intestine is subdivided dividing cells; in humans this process takes about 3 days. into an inner dense circular layer that consists of smaller, These proliferating cells are localized to the crypts, where more closely packed cells, and an outer circular layer. there is a proliferative zone of intestinal stem cells. Between the circular and longitudinal layers of muscle lies the other plexus of the ENS, the myenteric plexus. SMALL INTESTINE Contractions of the muscularis externa mix and circulate the contents of the lumen and propel them along the Lumen GI tract. The wall of the GI tract contains many interconnected neurons. The submucosa contains a dense network of nerve Villus cells called the submucosal plexus (also referred to as Meiss- ner’s plexus). The prominent myenteric plexus (Auerbach’s plexus) is located between the circular and longitudinal smooth muscle layers. These intramural plexuses constitute the ENS. The ENS helps integrate the motor and secre- Crypt tory activities of the GI system. If the sympathetic and parasympathetic nerves to the gut are cut, many motor and secretory activities continue because the ENS directly COLON controls these processes. Lumen Serosa Surface The serosa, or adventitia, is the outermost layer of the GI tract and consists of a layer of squamous mesothelial cells (see Fig. 27.2). It is part of the mesentery that lines Crypt the surface of the abdominal wall and suspends the organs within the abdominal cavity. The mesenteric membranes secrete a thin viscous fluid that helps lubricate the abdomi- Fig. 27.3 Comparison of the morphology of the epithelium of the nal organs so movement of the organs can occur as the small intestine and colon. muscle layers contract and relax. 514 S E C T I O N 6 â … Berne & Levy Physiology Regulatory Mechanisms in the ENDOCRINE Gastrointestinal Tract Sensor cell Target cell Unlike the cardiovascular or respiratory systems, the GI Microvilli tract undergoes periods of relative quiescence (intermeal period) and periods of intense activity after the intake of food (postprandial period). Consequently the GI tract has to detect and respond appropriately to food intake. Hormone In addition the macronutrient content of a meal can vary considerably, and there have to be mechanisms that can Circulation detect this and mount appropriate physiological responses. Thus the GI tract has to communicate with associated organs such as the pancreas. Finally, because the GI tract is essentially a long tube, there have to be mechanisms by NEUROCRINE which events occurring in the proximal portion of the GI Interneuron tract are signaled to the more distal parts, and vice versa. Sensory neuron Secretomotor There are three principal control mechanisms involved in neuron the regulation of GI function: endocrine, paracrine, and neurocrine (Fig. 27.4). Neurotransmitter Endocrine Regulation Endocrine regulation describes the process whereby the Target cells sensing cell in the GI tract, an enteroendocrine cell (EEC), responds to a stimulus by secreting a regulatory peptide or hormone that travels via the bloodstream to target cells removed from the point of secretion. Cells responding to a GI hormone express specific receptors for the hormone. PARACRINE Hormones released from the GI tract have effects on cells Target cell Target cell located in other regions of the GI tract and also on glandular structures associated with the GI tract, such as the pancreas. In addition, GI hormones have effects on other tissues that have no direct role in digestion and absorption, including endocrine cells in liver and brain. EECs are packed with secretory granules, the products of which are released from the cell in response to chemical and mechanical stimuli to the wall of the GI tract (Fig. Paracrine mediator 27.5). In addition, EECs can be stimulated by neural input or other factors not associated with a meal. The most Fig. 27.4 The three mechanisms by which function in the GI tract is regulated in the integrated response to a meal. common EECs in the gut wall are referred to as the “open” type; these cells have an apical membrane that is in contact with the lumen of the GI tract (generally regarded as the Paracrine Regulation location where sensing occurs) and a basolateral membrane through which secretion occurs. There are also “closed”-type Paracrine regulation describes the process whereby a chemi- EECs that do not have part of their membrane in contact cal messenger or regulatory peptide is released from a sensing with the luminal surface of the gut; an example is the cell (often an EEC) in the intestinal wall that acts on a enterochromaffin-like (ECL) cell in the gastric epithelium, nearby target cell by diffusion through the interstitial space. which secretes histamine. Paracrine agents exert their actions on several different cell There are many examples of hormones secreted by the types in the wall of the GI tract, including smooth muscle GI tract (see Table 27.1); it is worth remembering that cells, absorptive enterocytes, secretory cells in glands, and the first hormone ever identified was the GI hormone even on other EECs. There are several important paracrine secretin. One of the most well-characterized GI hormones agents, and they are listed in Table 27.1 along with their site is gastrin, which is released from endocrine cells located in of production, site of action, and function. An important the wall of the distal part of the stomach. Release of gastrin paracrine mediator in the gut wall is histamine. In the is stimulated by activation of parasympathetic outflow to stomach, histamine is stored and released by ECL cells the GI tract, and gastrin potently stimulates gastric acid located in the gastric glands. Histamine diffuses through secretion in the postprandial period. the interstitial space in the lamina propria to neighboring  CHAPTER 27â … Functional Anatomy and General Principles of Regulation in the Gastrointestinal Tract 515 is released from a nerve terminal located in the GI tract and the neurotransmitter has an effect on the cell that is innervated. However, in some cases there are no syn- apses between motor nerves and effector cells in the GI tract. Neural regulation of GI function is very important within an organ, as well as between distant parts of the GI tract. AT THE CELLULAR LEVEL There are multiple receptor subtypes for the regulatory peptide hormones released from endocrine cells in the wall of the gut. The selectivity of receptors to peptide hormones is determined by posttranslational modifications, which then confers receptor selectivity. An example of this is peptide YY (PYY). There are multiple receptor subtypes for PYY, classified as Y1 to Y7. PYY is released from endocrine cells in the wall of the gut, mainly in response to fatty acids. It is released as a 36–amino acid peptide and binds to the Y1, Y2, and Y5 receptors; however, it can be cleaved to PYY3-36 by the enzyme dipeptidyl peptidase IV, a membrane peptidase. This form of the peptide is more selective for the Y2 receptor. Thus the presence of the enzyme that cleaves the peptide can alter the biological response to PYY secretion. IN THE CLINIC Fig. 27.5 Electron micrograph of an open-type endocrine cell in the GI tract. Note the microvilli at the apical projection and the Glucagon-like peptide 1 (GLP-1) is a regulatory peptide secretory granules in the basolateral portion of the cell. (From Barrett released from EECs cells in the gut wall in response to the K. Gastrointestinal Physiology [Lange Physiology Series]. New York: presence of luminal carbohydrate and lipids. GLP-1 arises McGraw-Hill; 2005.) (Courtesy of Leonard R. Johnson, Ph.D.) from differential processing of the glucagon gene, the same gene that is expressed in the pancreas and that gives rise to glucagon. GLP-1 is involved in regulation of the blood glucose level via stimulation of insulin secretion and also insulin biosynthesis. Agonists of the GLP-1 receptor improve parietal cells and stimulates production of acid. Serotonin insulin sensitivity in diabetic animal models and human (5-hydroxytryptamine [5-HT]), released from enteric subjects. Administration of GLP-1 also reduces appetite and neurons, mucosal mast cells, and specialized EECs called food intake and delays gastric emptying, responses that enterochromaffin cells, regulates smooth muscle function may contribute to improving glucose tolerance. Long-acting agonists for the GLP-1 receptor (e.g., exenatide) have been and water absorption across the intestinal wall. There are approved for the treatment of type 2 diabetes. other paracrine mediators in the gut wall, including prosta- glandins, adenosine, and nitric oxide (NO); the functions of these mediators are not well described, but they are capable of producing changes in GI function. Neural regulation of the GI tract is surprisingly complex. Many substances can be both paracrine and endocrine The gut is innervated by two sets of nerves, the extrinsic regulators of GI function. For example, cholecystokinin, and intrinsic nervous systems. The extrinsic nervous which is released from the duodenum in response to dietary system is defined as nerves that innervate the gut, with cell protein and lipid, acts locally on nerve terminals in a para- bodies located outside the gut wall; these extrinsic nerves crine fashion and also affects the pancreas. This will be are part of the autonomic nervous system (ANS). The discussed in more detail in Chapter 30. intrinsic nervous system, also referred to as the enteric nervous system, has cell bodies that are contained within Neural Regulation of the wall of the gut (submucosal and myenteric plexuses). Gastrointestinal Function Some GI functions are highly dependent on the extrinsic nervous system, yet others can take place independently of Nerves and neurotransmitters play an important role in the extrinsic nervous system and are mediated entirely by regulating the function of the GI tract. In its simplest the ENS. However, extrinsic nerves can often modulate form, neural regulation occurs when a neurotransmitter intrinsic nervous system function (Fig. 27.6). 516 S E C T I O N 6 â … Berne & Levy Physiology TABLE 27.1â … Hormonal and Paracrine Mediators in the GI Tract Stimulus for Pathway of GI Hormone Source Release Action Targets Effect Gastrin Gastric Oligopeptides Endocrine ECL cells and Stimulation of parietal cells to antrum parietal cells secrete H+ and ECL cells to (G cells) of the gastric secrete histamine corpus Cholecystokinin Duodenum Fatty acids, Paracrine, Vagal afferent Inhibition of gastric emptying and (I cells) hydrolyzed endocrine terminals, H+ secretion; stimulation of protein pancreatic pancreatic enzyme secretion, acinar cells gallbladder contraction, inhibition of food intake Secretin Duodenum Protons Paracrine, Vagal afferent Stimulation of pancreatic duct (S cells) endocrine terminals, secretion (H2O and HCO3−) pancreatic duct cell Gluco- Intestine Fatty acids, glucose Endocrine Beta cells of the Stimulation of insulin secretion insulinotropic (K cells) pancreas peptide (GIP) Peptide YY (PYY) Intestine Fatty acids, glucose, Endocrine, Neurons, smooth Inhibition of gastric emptying, (L cells) hydrolyzed paracrine muscle pancreatic secretion, gastric protein acid secretion, intestinal motility, food intake Proglucagon- Intestine Fatty acids, glucose, Endocrine, Neurons, epithelial Glucose homeostasis, epithelial derived peptides (L cells) hydrolyzed paracrine cells cell proliferation 1/2 (GLP-1/2) protein the gut (vagus and pelvic nerves, respectively), where they BRAIN AND synapse with postganglionic neurons in the wall of the SPINAL CORD organ, which in this case are enteric neurons in the gut wall. There is no direct innervation of these efferent nerves SENSORS ENTERIC EFFECTORS to effector cells within the wall of the gut; the transmission motility STIMULI mechanical NERVOUS secretion pathway is always via a neuron in the ENS. and chemical SYSTEM blood flow Consistent with transmission in the ANS, the synapse between preganglionic and postganglionic neurons is an Fig. 27.6 Hierarchical neural control of GI function. Stimuli to the obligatory nicotinic synapse. That is, the synapse between GI tract from a meal (e.g., chemical, mechanical, osmotic) will activate preganglionic and postganglionic neurons is mediated via both the intrinsic and extrinsic sensory (afferent) pathways, which in turn will activate the extrinsic and intrinsic neural reflex pathways. acetylcholine released from the nerve terminal and acting at nicotinic receptors localized on the postganglionic neuron, which in this case is an intrinsic neuron. Sympathetic innervation is supplied by cell bodies in Extrinsic Neural Innervation the spinal cord and fibers that terminate in the prever- Extrinsic neural innervation to the gut is via the two major tebral ganglia (celiac, superior, and inferior mesenteric subdivisions of the ANS, namely, parasympathetic and ganglia); these are the preganglionic neurons. These nerve sympathetic innervation (Fig. 27.7). Parasympathetic fibers synapse with postganglionic neurons in the ganglia, innervation to the gut is via the vagus and pelvic nerves. and the fibers leave the ganglia and reach the end organ The vagus nerve, the 10th cranial nerve, innervates the along the major blood vessels and their branches. Rarely esophagus, stomach, gallbladder, pancreas, first part of there is a synapse in the paravertebral (chain) ganglia, as the intestine, cecum, and the proximal part of the colon. seen with sympathetic innervation of other organ systems. The pelvic nerves innervate the distal part of the colon Some vasoconstrictor sympathetic fibers directly innervate and the anorectal region, in addition to the other pelvic blood vessels of the GI tract, and other sympathetic fibers organs that are not part of the GI tract. innervate glandular structures in the wall of the gut. Consistent with the typical organization of the para- The ANS, both parasympathetic and sympathetic, also sympathetic nervous system, the preganglionic nerve cell carries the fibers of afferent (toward the central nervous bodies lie in the brainstem (vagus) or the sacral spinal cord system [CNS]) neurons; these are sensory in nature. (pelvic). Axons from these neurons run in the nerves to The cell bodies for the vagal afferents are in the nodose  CHAPTER 27â … Functional Anatomy and General Principles of Regulation in the Gastrointestinal Tract 517 Medulla Vagal nerves innervation to the GI tract. These reflexes can be mediated oblongata entirely via the vagus nerve (termed a vagovagal reflex), (dorsal which has both afferent and efferent fibers. The vagal vagal complex) afferents send sensory information to the CNS, where they synapse with an interneuron, which then drives activity in the efferent motor neuron. These extrinsic reflexes are very important in regulating GI function after ingestion of a meal. An example of an important vagovagal reflex is the gastric receptive relaxation reflex, in which distention of the stomach results in relaxation of the smooth muscle in Sacral the stomach; this allows filling of the stomach to occur spinal cord without an increase in intraluminal pressure. In general, as with other visceral organ systems, the Pelvic parasympathetic and sympathetic nervous systems tend nerves to work in opposition. However, this is not as simple as in the cardiovascular system, for example. Activation of A the parasympathetic nervous system is important in the integrative response to a meal and is discussed in the following chapters. The parasympathetic nervous system Medulla generally results in activation of physiological processes oblongata in the gut wall, although there are notable exceptions. Superior In contrast, the sympathetic nervous system tends to be cervical inhibitory to GI function and is more frequently activated ganglion in pathophysiological circumstances. Overall, sympathetic Thoraco- activation inhibits smooth muscle function. The exception lumbar to this is the sympathetic innervation of GI sphincters, in region 1 which sympathetic activation tends to induce contraction of 2 smooth muscle. Moreover, the sympathetic nervous system is notably important in regulation of blood flow in the GI 3 tract. Intrinsic Neural Innervation Prevertebral ganglia 1. Celiac The ENS is made up of two major plexuses, which are 2. Superior mesenteric collections of nerve cell bodies (ganglia) and their fibers, all 3. Inferior mesenteric originating in the wall of the gut (Fig. 27.8). The myenteric B plexus lies between the longitudinal and circular muscle Fig. 27.7 Extrinsic innervation of the GI tract, consisting of the layers, and the submucosal plexus lies in the submucosa. parasympathetic (A) and sympathetic (B) subdivisions of the autonomic Interganglionic strands link neurons in the two plexuses. nervous system. Neurons in the ENS are characterized functionally as afferent neurons, interneurons, or efferent neurons, similar to neurons in the extrinsic part of the ANS. Thus all ganglion. These neurons have a central projection terminat- components of a reflex pathway can be contained within ing in the nucleus of the tractus solitarius in the brainstem the ENS. Stimuli in the wall of the gut are detected by and the other terminal in the gut wall. The cell bodies of afferent neurons, which activate interneurons and then the spinal afferent neurons that run with the sympathetic efferent neurons to alter function. In this way the ENS pathway are segmentally organized and are found in the can act autonomously from extrinsic innervation. However, dorsal root ganglia. Peripheral terminals of the spinal and neurons in the ENS, as we have already seen, are innervated vagal afferents are located in all layers of the gut wall, where by extrinsic neurons, and thus the function of these reflex they detect information about the state of the gut. Afferent pathways can be modulated by the extrinsic nervous system. neurons send this information to the CNS. Information Because the ENS is capable of performing its own integra- sent to the CNS relays the nature of the luminal contents tive functions and complex reflex pathways, it is sometimes (e.g., acidity, nutrient content, osmolality of the luminal referred to as the “little brain in the gut” as a result of its contents), as well as the degree of stretch or contraction in importance and complexity. It is estimated that there are as smooth muscle. Afferent innervation is also responsible for many neurons in the ENS as in the spinal cord. In addition, transmitting painful stimuli to the CNS. many GI hormones also act as neurotransmitters in the The components of a reflex pathway—afferents, inter- ENS and in the brain in regions involved in autonomic neurons, and efferent neurons—exist within the extrinsic outflow. These mediators and regulatory peptides are thus 518 S E C T I O N 6 â … Berne & Levy Physiology Myenteric plexus Tertiary plexus Circular muscle Deep muscular plexus Submucosal plexus Longitudinal muscle Submucosal Mucosa Muscularis artery muscle Mucosal plexus Paravascular nerve Perivascular nerves Subserous Mesentery nerve Myenteric plexus Submucosal plexus Deep muscular Mucosal plexus plexus Fig. 27.8 The enteric nervous system in the wall of the GI tract. referred to as brain-gut peptides, and the extrinsic and cephalic, oral, esophageal, gastric, duodenal, and intestinal. intrinsic components innervating the gut are sometimes In each phase the meal presents certain stimuli (e.g., referred to as the brain-gut axis. chemical, mechanical, and osmotic) that activate different pathways (e.g., neural, paracrine, and humoral reflexes) Response of the GI Tract to a Meal that result in changes in effector function (e.g., secretion and motility). There is considerable crosstalk between the This introductory chapter provides a broad overview of the regulatory mechanisms that have been outlined, and this anatomy and regulatory mechanisms in the GI tract. In the will be discussed in the next chapters. As with maintenance following chapters there will be discussion of the integrated of homeostasis in other systems of the body, control of GI response to a meal to provide the details of GI physiology. function requires complex regulatory mechanisms to sense The response to a meal is classically divided into phases: and act in a dynamic fashion.  CHAPTER 27â … Functional Anatomy and General Principles of Regulation in the Gastrointestinal Tract 519 IN THE CLINIC Hirschsprung’s disease is a congenital disorder of the neurons in the distal part of the colon and rectum. It is enteric nervous system characterized by failure to pass a polygenic disorder with characteristic mutations in at meconium at birth or severe chronic constipation in infancy. least three different classes of genes involved in neuronal The typical features are absence of myenteric and submucosal development and differentiation. Key Concepts 1. The GI tract is a tube subdivided into regions that ANS: parasympathetic and sympathetic. Both have an subserve different functions associated with digestion important sensory (afferent) component. and absorption. 6. The intrinsic or enteric nervous system (cell bodies 2. The lining of the GI tract is subdivided into layers— in the wall of the GI tract) can act independently of the mucosal, submucosal, and muscle layers. extrinsic neural innervation. 3. There are three major control mechanisms: hormonal, 7. When a meal is in different regions of the tract, paracrine, and neurocrine. sensory mechanisms detect the presence of the 4. The innervation of the GI tract is particularly nutrients and mount appropriate physiological interesting because it consists of two interacting responses in that region of the tract, as well components, extrinsic and intrinsic. as in more distal regions. These responses are 5. Extrinsic innervation (cell bodies outside the wall of mediated by endocrine, paracrine, and neurocrine the GI tract) consists of the two subdivisions of the pathways. Additional Reading Physiology of the GI Tract. 5th ed. Waltham, MA: Academic Press; 2012. Baldwin GS. Posttranslational modification of gastrointestinal Furness JB. The enteric nervous system and neurogastroenterology. peptides. In: Johnson LR, ed. Physiology of the GI Tract. 5th ed. Nat Rev Gastroenterol Hepatol. 2012;9:286-294. Waltham, MA: Academic Press; 2012. Gomez GA, etâ ¯al. Postpyloric gastrointestinal peptides. In: Johnson Brierley SM, etâ ¯al. Innervation of the gastrointestinal tract by spinal LR, ed. Physiology of the GI Tract. 5th ed. Waltham, MA: Academic and vagal afferent nerves. In: Johnson LR, ed. Physiology of the GI Press; 2012. Tract. 5th ed. Waltham, MA: Academic Press; 2012. Parker HE, etâ ¯al. The role of gut endocrine cells in control of metabo- Brookes SJ, etâ ¯al. Extrinsic primary afferent signalling in the gut. Nat lism and appetite. Exp Physiol. 2014;99:1116-1120. Rev Gastroenterol Hepatol. 2013;10:286-296. Sandoval DA, D’Alessio DA. Physiology of proglucagon peptides: Chao C, Hellmich MR. Gastrointestinal peptides: gastrin, cho- role of glucagon and GLP-1 in health and disease. Physiol Rev. lecystokinin, somatostatin and ghrelin. In: Johnson LR, ed. 2015;95:513-548. 28 The Cephalic, Oral, and Esophageal Phases of the Integrated Response to a Meal LEARNING OBJECTIVES Upon completion of this chapter the student should be able to are cognitive and include anticipation or thinking about answer the following questions: the consumption of food, olfactory input, visual input 1. What are the structures of the functional anatomy of (seeing or smelling appetizing food when hungry), and salivary glands, including their secretory elements? auditory input. The latter may be an unexpected link 2. What are the cephalic and oral phases (what, why, how but was clearly demonstrated in the classic conditioning it happens) of the response to a meal? experiments of Pavlov, in which he paired an auditory 3. What are the general principles of secretion along the stimulus to the presentation of food to dogs; eventually gastrointestinal (GI) tract (where do secretions come the auditory stimulus alone could stimulate secretion. A from, what are the components)? real-life analogy is presumably being told that dinner is 4. How do the components of secretion vary with the ready. All these stimuli result in an increase in excitatory gland or region of the GI tract? 5. What is the correlation between the composition and parasympathetic neural outflow to the gut. Sensory input functions of salivary secretion? (e.g., smell) stimulates sensory nerves that activate para- 6. How are primary and secondary secretion within salivary sympathetic outflow from the brainstem. Higher brain sites glands generated and regulated? (e.g., limbic system, hypothalamus, cortex) are also involved 7. What is the sequence of events in swallowing? in the cognitive components of this response. The response 8. What are the stimulus and neural pathways generating can be both positive and negative; thus anticipation of primary and secondary esophageal peristalsis? food and a person’s psychological status, such as anxiety, 9. What changes in gastric motility take place during can alter the cognitive response to a meal. However, the swallowing, and what is the significance? final common pathway is activation of the dorsal motor 10. What are the major functions of the esophagus and nucleus in the brainstem, the region where the cell bodies associated structures in terms of protection and of the vagal preganglionic neurons arise. Activation of the propulsion? nucleus leads to increased activity in efferent fibers passing to the GI tract in the vagus nerve. In turn the efferent fibers activate the postganglionic motor neurons (referred to as motor because their activation results in change of T his chapter will describe the processes that occur in function of an effector cell). Increased parasympathetic the gastrointestinal (GI) tract in the early stages of the outflow enhances salivary secretion, gastric acid secretion, integrated response to a meal. There are changes in pancreatic enzyme secretion, gallbladder contraction, and GI tract physiology (1) before food is ingested (the cephalic relaxation of the sphincter of Oddi (the sphincter between phase), (2) when ingested food is in the mouth (the oral the common bile duct and duodenum). All these responses phase), and (3) when food is transferred from the mouth enhance the ability of the GI tract to receive and digest the to the esophagus (the esophageal phase). The responses of incoming food. The salivary response is mediated via the the GI tract to the presence of food are mainly associated ninth cranial nerve; the remaining responses are mediated with preparing the GI tract for digestion and absorption. via the vagus nerve. Many of the features of the oral phase are indistinguish- Cephalic and Oral Phases able from the cephalic phase. The only difference is that food is in contact with the surface of the GI tract. Thus The main feature of the cephalic phase is activation of the there are additional stimuli generated from the mouth, GI tract in readiness for the meal. The stimuli involved both mechanical and chemical (taste). However, many of 520  CHAPTER 28â … The Cephalic, Oral, and Esophageal Phases of the Integrated Response to a Meal  521 the responses initiated by the presence of food in the oral optimal conditions for the action of digestive enzymes in cavity are identical to those initiated in the cephalic phase, the small intestine. because the efferent pathway is the same. The responses Organic secretory components are also gland or organ specifically initiated in the mouth, which consist mainly of specific and depend on the function of that region of the the stimulation of salivary secretion, will be discussed next. gut. The organic constituents are enzymes (for digestion), The mouth is important for the mechanical disruption mucin (for lubrication and mucosal protection), and other of food and for initiation of digestion. Chewing subdivides factors such as growth factors, immunoglobulins, bile acids, and mixes the food with the enzymes salivary amylase and and absorptive factors. lingual lipase and with the glycoprotein mucin, which lubricates food for chewing and swallowing. Minimal Salivary Secretion absorption occurs in the mouth, although alcohol and some drugs are absorbed from the oral cavity, and this can be During the cephalic and oral phases of the meal, consider- clinically important. However, as with the cephalic phase, able stimulation of salivary secretion takes place. Saliva has it is important to realize that stimulation of the oral cavity a variety of functions, including those important for the initiates responses in the more distal GI tract, including integrative responses to a meal and for other physiologi- increased gastric acid secretion, increased pancreatic enzyme cal processes (Box 28.1). The main functions of saliva in secretion, gallbladder contraction, and relaxation of the digestion include lubrication and moistening of food for sphincter of Oddi, mediated via the efferent vagal pathway. swallowing, solubilization of material for taste, initiation of carbohydrate digestion, and clearance and neutralization of refluxed gastric secretions in the esophagus. Saliva also has Properties of Secretion antibacterial actions that are important for overall health of General Considerations the oral cavity and teeth. Secretions in the GI tract come from glands associated with the tract (salivary glands, pancreas, and liver), from glands Functional Anatomy of the Salivary Glands formed by the gut wall itself (e.g., submucosal glands in There are three pairs of major salivary glands: parotid, esophagus and duodenum), and from the intestinal mucosa submandibular, and sublingual. In addition, many smaller itself. The exact nature of the secretory products can vary glands are found on the tongue, lips, and palate. These tremendously, depending on the function of that region glands are the typical tubuloalveolar structures of glands of the GI tract. However, these secretions have several located in the GI tract (Fig. 28.1). The acinar portion of the characteristics in common. Secretions from the GI tract gland is classified according to its major secretion: serous and associated glands include water, electrolytes, protein, (“watery”), mucous, or mixed. The parotid gland produces and humoral agents. Water is essential for generating an mainly serous secretion, the sublingual gland secretes aqueous environment for efficient enzyme action. Secretion mainly mucus, and the submandibular gland produces a of electrolytes is important for generation of osmotic gradi- mixed secretion. ents to drive the movement of water. Digestive enzymes in Cells in the secretory end pieces, or acini, are called secreted fluid catalyze the breakdown of macronutrients in acinar cells and are characterized by basally located nuclei, ingested food. Moreover, many additional proteins secreted abundant rough endoplasmic reticulum, and apically along the GI tract have specialized functions, some of which located secretory granules that contain the enzyme amylase are fairly well understood, such as those of mucin and and other secreted proteins. There are also mucous cells in immunoglobulins, and others that are only just beginning the acinus; the granules in these cells are larger and contain to be understood, such as those of trefoil peptides. the specialized glycoprotein mucin. There are three kinds Secretion is initiated by multiple signals associated with of ducts in the gland that transport secretions from the the meal, including chemical, osmotic, and mechanical acinus to the opening in the mouth and also modify the components. Secretion is elicited by the action of specific secretion: intercalated ducts drain acinar fluid into larger effector substances called secretagogues acting on secretory cells. Secretagogues work in one of the three ways that have already been described in Chapter 27—endocrine, BOX 28.1 Functions of Saliva and Chewing paracrine, and neurocrine. Disruption of food to produce smaller particles Formation of a bolus for swallowing Constituents of Secretions Initiation of starch and lipid digestion Facilitation of taste Inorganic secretory components are region or gland specific, Production of intraluminal stimuli in the stomach depending on the particular conditions required in that part Regulation of food intake and ingestive behavior of the GI tract. The inorganic components are electrolytes, Cleansing of the mouth and selective antibacterial action including H+ and HCO3−. Two examples of different secre- Neutralization of refluxed gastric contents tions include acid (HCl) in the stomach, which is important Mucosal growth and protection in the rest of the GI tract Aid in speech to activate pepsin and start protein digestion, and HCO3− in the duodenum, which neutralizes gastric acid and provides 522 S E C T I O N 6 â … Berne & Levy Physiology Serous cell Demilune of serous cells Basement membrane Mucous cell Intercalated duct Salivary duct (secretory) Fig. 28.1â … General structure of tubuloalveolar secretory glands (e.g., salivary glands, pancreas) associ- ated with the digestive tract. ducts, the striated ducts, which then empty into even larger lumen and establishes an osmotic and electrical gradient. excretory ducts. In addition, a single large duct from each Because the epithelium of the acinus is relatively leaky, Na+ gland drains saliva to the mouth. The ductal cells lining the and water then follow across the epithelium via the tight striated ducts, in particular, modify the ionic composition junctions (i.e., via paracellular transport). Transcellular and osmolarity of saliva. water movement may also occur, mediated by aquaporin 5 water channels. The amylase content and rate of fluid Composition of Saliva secretion vary with the type and level of stimulus. As the The important properties of saliva are a large flow rate fluid passes along the ducts, the excretory and striated duct relative to the mass of gland, low osmolarity, high K+ cells modify the ionic composition of the primary secretion concentration, and organic constituents, including enzymes to produce the secondary secretion. The duct cells reabsorb (amylase, lipase), mucin, and growth factors. The latter are Na+ and Cl−, and secrete K+ and HCO3− into the lumen. not important in the integrated response to a meal but are Na+ is exchanged for protons, but some of the secreted essential for long-term maintenance of the lining of the protons are then reabsorbed in exchange for K+. HCO3− on GI tract. the other hand is secreted only in exchange for Cl−, thereby The inorganic composition is entirely dependent on the alkalinizing salivary secretion. stimulus and the rate of salivary flow. In humans, salivary At rest, final salivary secretion is hypotonic and slightly secretion is always hypotonic. The major components are alkaline. The alkalinity of saliva is important in restricting Na+, K+, HCO3−, Ca++, Mg++, and Cl−. Fluoride can be microbial growth in the mouth, as well as in neutralizing secreted in saliva, and fluoride secretion forms the basis refluxed gastric acid once the saliva is swallowed. When of oral fluoride treatment for prevention of dental caries. salivary secretion is stimulated, there is a small decrease The concentration of ions varies with the rate of secretion; in the K+ concentration (but it always remains above the flow rate of salivary secretion is stimulated during the plasma concentrations), the Na+ concentration increases postprandial period. toward plasma levels, and Cl− and HCO3− concentrations The primary secretion is produced by acinar cells in the increase, thus the secreted fluid becomes even more alkaline secretory end pieces (or acini) and is modified by duct cells (Fig. 28.2). Note that HCO3− secretion can be directly as saliva passes through the ducts. The primary secretion is stimulated by the action of secretagogues on duct cells. isotonic, and the concentration of the major ions is similar The duct epithelium is relatively tight and lacks expression to that in plasma. Secretion is driven predominantly by of aquaporin, and therefore water cannot follow the ions Ca++-dependent signaling, which opens apical Cl− channels rapidly enough to maintain isotonicity at moderate or high in the acinar cells. Cl− therefore flows out into the duct flow rates during stimulated salivary secretion. Thus with  CHAPTER 28â … The Cephalic, Oral, and Esophageal Phases of the Integrated Response to a Meal  523 160 160 Saliva Plasma 140 Na+ 140 120 120 Concentration (mEq/L) Concentration (mEq/L) Cl– 100 100 Na+ 80 80 60 HCO3– 60 40 Cl– 40 HCO3– 20 K+ 20 K+ 0 0 1.0 2.0 3.0 4.0 Flow of saliva (mL/min) A Endpieces Amylase-containing PRIMARY SECRETION (nearly isotonic; levels of Na+, K+, Cl –, and probably HCO3– similar to plasma) Na+ K+ Modification Striated and of ionic excretory ducts Fig. 28.2 â … A, The composition of salivary secretion as a function of the Cl– content salivary flow rate compared with the concentration of ions in plasma. Saliva is hypotonic to plasma at all flow rates. [HCO3−] in saliva exceeds that in plasma HCO3– except at very low flow rates. B, Schematic representation of the two-stage model of salivary secretion. The primary secretion containing amylase and electrolytes is produced in the acinar cell. The concentration of electrolytes in plasma is similar to that in the primary secretion, but it is modified as it passes B through ducts that absorb Na+ and Cl− and secrete K+ and HCO3−. an increase in secretion rate, there is less time for ionic of pancreatic amylase. Similarly the importance of lingual modification by the duct cells, and the resulting saliva lipase is unclear. more closely resembles the primary secretion and therefore plasma. However, [HCO3−] remains high because secretion Metabolism and Blood Flow of Salivary Glands from duct cells and possibly acinar cells is stimulated (see The salivary glands produce a prodigious flow of saliva. The Fig. 28.2). maximal rate of saliva production in humans is about 1â ¯mL/ The organic constituents of saliva—proteins and min/g of gland; thus at this rate, the glands are producing glycoproteins—are synthesized, stored, and secreted by the their own weight in saliva each minute. Salivary glands acinar cells. The major products are amylase (an enzyme have a high rate of metabolism and high blood flow; both that initiates starch digestion), lipase (important for lipid are proportional to the rate of saliva formation. Blood flow digestion), glycoprotein (mucin, which forms mucus when to maximally secreting salivary glands is approximately 10 hydrated), and lysozyme (attacks bacterial cell walls to limit times that of an equal mass of actively contracting skeletal colonization of bacteria in the mouth). Although salivary muscle. Stimulation of the parasympathetic nerves to sali- amylase begins the process of digestion of carbohydrates, vary glands increases blood flow by dilating the vasculature it is not required in healthy adults because of the excess of the glands. Vasoactive intestinal polypeptide (VIP) and 524 S E C T I O N 6 â … Berne & Levy Physiology acetylcholine are released from parasympathetic nerve terminals in the salivary glands and are vasodilatory during secretion. Regulation of Salivary Secretion Lumen Control of salivary secretion is exclusively neural. In of contrast, control of most other GI secretions is primar- acinus Na ily hormonal. Salivary secretion is stimulated by both ATP the sympathetic and parasympathetic subdivisions of the K autonomic nervous system. Excitation of either sympathetic K or parasympathetic nerves to the salivary glands stimulates K salivary secretion. Primary physiological control of the salivary glands during the response to a meal is by the Na parasympathetic nervous system. If the parasympathetic Cl supply is interrupted, salivation is severely impaired and H  HCO3 the salivary glands atrophy. Sympathetic fibers to the salivary glands stem from the Na superior cervical ganglion. Preganglionic parasympathetic 2Cl– fibers travel via branches of the facial and glossopharyngeal K nerves (cranial nerves VII and IX, respectively). These fibers form synapses with postganglionic neurons in ganglia in or near the salivary glands. The acinar cells and ducts are supplied with parasympathetic nerve endings. Parasympathetic stimulation increases synthesis and Na secretion of salivary amylase and mucins, enhances the transport activities of the ductular epithelium, greatly increases blood flow to the glands, and stimulates glandular metabolism and growth. Fig. 28.3â … Ionic transport mechanism involved in the secretion of amylase and electrolytes in salivary acinar cells. Ionic Mechanisms of Salivary Secretion Ion Transport in Acinar Cells water prevents the ducts from absorbing too much water Fig. 28.3 shows a simplified view of the mechanisms by osmosis. of ion secretion by serous acinar cells. The basolateral membrane of the cell contains Na+,K+-ATPase and an Swallowing Na+-K+-2Cl− symporter. The concentration gradient for Na+ across the basolateral membrane, which is dependent Swallowing can be initiated voluntarily, but thereafter it is on Na+,K+-ATPase, provides the driving force for entry of almost entirely under reflex control. The swallowing reflex Na+, K+, and Cl− into the cell. Cl− and HCO3− leave the is a rigidly ordered sequence of events that propel food from acinar cell and enter the lumen via an anion channel located the mouth to the pharynx and from there to the stomach. in the apical membrane of the acinar cell. This secretion of This reflex also inhibits respiration and prevents entrance anions drives the entry of Na+ and thus water into the acinar of food into the trachea during swallowing. The afferent lumen across the relatively leaky tight junctions. limb of the swallowing reflex begins when touch recep- Acinar cell fluid secretion is strongly enhanced in response tors, most notably those near the opening of the pharynx, to elevations in intracellular [Ca++] as a result of activation are stimulated. Sensory impulses from these receptors are of the muscarinic receptor for acetylcholine. transmitted to an area in the medulla and lower pons called the swallowing center. Motor impulses travel from the swal- Ion Transport in Ductular Cells lowing center to the musculature of the pharynx and upper Fig. 28.4 shows a simplified model of ion transport esophagus via various cranial nerves and to the remainder processes in epithelial cells of the excretory and striated of the esophagus by vagal motor neurons. ducts. Na+,K+-ATPase located in the basolateral membrane The timing of events in swallowing is shown in Fig. 28.5. maintains the electrochemical gradients for Na+ and K+ that The voluntary phase of swallowing is initiated when the tip drive most of the other ionic transport processes of the cell. of the tongue separates a bolus of food from the mass of In the apical membrane the parallel operation of the Na+/ food in the mouth. First the tip of the tongue and later the H+ antiporter, the Cl−/HCO3− antiporter, and the H+/K+ more posterior portions of the tongue press against the hard antiporter results in absorption of Na+ and Cl− from the palate. The action of the tongue moves the bolus upward lumen and secretion of K+ and HCO3− into the lumen. and then backward into the mouth. The bolus is forced The relative impermeability of the ductular epithelium to into the pharynx, where it stimulates the touch receptors  CHAPTER 28â … The Cephalic, Oral, and Esophageal Phases of the Integrated Response to a Meal  525 BOLUS TRANSFER FROM THE MOUTH TO THE ESOPHAGUS REQUIRES MULTIPLE EVENTS Bolus in mouth Bolus moves through Bolus pharynx and UES enters esophagus Lumen Pharynx contracts of Na duct ATP UES open K Airway closed Na K Larynx elevated Cl Nasopharynx closed  HCO3 Cl  Tongue thrust up and back Na H 0.2 0.4 0.6 0.8 1.0 1.2 H H  Time (sec) Fig. 28.5 â … Timing of motor events in the pharynx and UES during K Na a swallow. IN THE CLINIC Xerostomia, or dry mouth, is caused by impaired salivary secretion. It can be congenital or develop as part of an autoimmune process. The decrease in secretion reduces the pH in the oral cavity, which causes tooth decay and is Fig. 28.4â … Ionic transport mechanism involved in secretion and associated with esophageal erosions. Reduced secretion also absorption in epithelial cells of the striated and excretory duct of the causes difficulty swallowing. salivary gland. AT THE CELLULAR LEVEL IN THE CLINIC The acinar cells and duct cells of the salivary glands respond to both cholinergic and adrenergic agonists. Nerves stimulate The ability to measure and monitor a wide range of molecular the release of acetylcholine, norepinephrine, substance P, components that are indicative of overall health is useful and VIP by salivary glands, and these hormones increase in diagnosis and monitoring. Saliva is easy to access, and the secretion of amylase and the flow of saliva. These collection of it is noninvasive. It is used to identify individuals neurotransmitters act mainly by elevating the intracellular with disease (presence of biomarkers) and to monitor concentration of cyclic adenosine monophosphate (cAMP) the progress of affected individuals under treatment. In and by increasing the concentration of Ca++ in the cytosol. endocrinology, levels of steroids can be measured in the free Acetylcholine and substance P, acting on muscarinic and form rather than as the free and bound form, as in plasma tachykinin receptors, respectively, increase the cytosolic (e.g., the stress hormone cortisol and the sex hormones concentration of Ca++ in serous acinar cells. In contrast, estradiol, progesterone, and testosterone). Viral infections norepinephrine, acting on β receptors, and VIP, binding to such as human immunodeficiency virus (HIV), herpes, its receptor, elevate the cAMP concentration in acinar cells. hepatitis C, and Epstein-Barr virus infection can be detected Agonists that elevate the cAMP concentration in serous by polymerase chain reaction (PCR) techniques. Bacterial acinar cells elicit a secretion that is rich in amylase; agonists infections, such as Helicobacter pylori, can likewise be that mobilize Ca++ elicit a secretion that is more voluminous detected in saliva, and saliva is also used for monitoring drug but has a lower concentration of amylase. Ca++-mobilizing levels. agonists may also elevate the concentration of cyclic guanosine monophosphate (cGMP), which may mediate the trophic effects evoked by these agonists. prevent reflux of food into the nasopharynx and open a narrow passage through which food moves into the that initiate the swallowing reflex. The pharyngeal phase of pharynx. swallowing involves the following sequence of events, which 2. The vocal cords are pulled together and the larynx is occur in less than 1 second: moved forward and upward against the epiglottis; these 1. The soft palate is pulled upward and the palatopharyngeal actions prevent food from entering the trachea and help folds move inward toward one another; these movements open the upper esophageal sphincter (UES). 526 S E C T I O N 6 â … Berne & Levy Physiology 3. The UES relaxes to receive the bolus of food. functions are mechanical and consist of pharyngeal stimu- 4. The superior constrictor muscles of the pharynx then lation during swallowing and distention of the esophageal contract strongly to force the bolus deeply into the wall itself. The pathways are exclusively neural and involve pharynx. both extrinsic and intrinsic reflexes. Mechanosensitive A peristaltic wave is initiated with contraction of the afferents in both the extrinsic (vagus) nerves and intrinsic pharyngeal superior constrictor muscles, and the wave neural pathways respond to esophageal distention. These moves toward the esophagus. This wave forces the bolus of pathways include activated reflex pathways via the brain- food through the relaxed UES. During the pharyngeal stage stem (extrinsic, vagus) or solely intrinsic pathways. The of swallowing, respiration is also reflexively inhibited. After striated muscle is regulated from the nucleus ambiguus the bolus of food passes the UES, a reflex action causes the in the brainstem, and the smooth muscle is regulated by sphincter to constrict. parasympathetic outflow via the vagus nerve. The changes in function resulting from mechanosensitive stimuli and activation of reflex pathways are peristalsis of striated and IN THE CLINIC smooth muscle, relaxation of the LES, and relaxation of the Gastroesophageal reflux disease (GERD) is commonly proximal portion of the stomach. referred to as heartburn or indigestion. It occurs when the lower esophageal sphincter allows the acidic contents of the Functional Anatomy of the Esophagus stomach to reflux back into the distal part of the esophagus. This region of the esophagus, unlike the stomach, does not and Associated Structures have a robust system to protect the mucosal lining. Thus the acid will activate pain fibers and thereby result in discomfort The esophagus, like the rest of the GI tract, has two muscle and pain. This is not an uncommon phenomenon, even in layers—circular and longitudinal—but the esophagus is one healthy individuals. In the long term, continual reflux can of two places in the gut where striated muscle occurs, the result in damage to the esophageal mucosa. In this case, other being the external anal sphincter. The type of muscle this condition is classed as GERD and can be treated by H2 receptor antagonists that reduce gastric acid secretion (striated or smooth) in the esophagus varies along its length. (e.g., ranitidine [Zantac]) or by proton pump inhibitors (e.g., The UES and LES are formed by thickening of striated or omeprazole [Prilosec]). circular smooth muscle, respectively. Motor Activity During the Esophageal Phase Esophageal Phase The UES, esophagus, and LES act in a coordinated manner to propel material from the pharynx to the stomach. At the The esophagus, the UES, and the lower esophageal end of a swallow, a bolus passes through the UES, and the sphincter (LES) serve two main functions (Fig. 28.6). First, presence of the bolus, via stimulation of mechanoreceptors they propel food from the mouth to the stomach. Second, and reflex pathways, initiates a peristaltic wave (alternating the sphincters protect the airway during swallowing and contraction and relaxation of the muscle) along the esopha- protect the esophagus from acidic gastric secretions. gus that is called primary peristalsis (Fig. 28.7). This wave The stimuli that initiate the changes in smooth muscle moves down the esophagus slowly (3–5â ¯cm/s). Distention activity that result in these propulsive and protective of the esophagus by the moving bolus initiates another Propulsive Protective functions effects Food transfer to Pharynx esophagus Allows entry of food Protects airway from into esophagus UES swallowed material Protects airway from gastric reflux Transports bolus from Clears material pharynx to stomach refluxed from stomach Esophagus LES Protects esophagus Allows entry of food from gastric reflux into stomach Fig. 28.6â … The esophagus and associated sphincters have multiple functions involved in movement of food from the mouth to the stomach and also in protection of the airway and esophagus.  CHAPTER 28â … The Cephalic, Oral, and Esophageal Phases of the Integrated Response to a Meal  527 Pharynx 60 30 Upper 0 esophageal 90 sphincter (UES) 60 30 0 90 60 mm Hg 30 Esophageal 0 body 60 30 0 60 30 0 60 Lower 30 esophageal 0 sphincter (LES) 3 sec Swallow Fig. 28.7 â … Changes in pressure in the different regions of the pharynx, esophagus, and