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April 22, 2005 Introduction and GI Regulation Ron Lynch, Ph.D. 626-2472 Functional Anatomy of the Alimentary Canal Objectives: 1. Identify the location of each organ along the alimentary canal, and in general terms, the contribution each makes to the gastrointestinal system. 2. Know the general organization and components of the cellular layers which make up the walls of the alimentary canal. Overview of the Functional Anatomy of the Alimentary Canal: The gastrointestinal system operates principally to extract energy and metabolic building blocks from the food presented to it. This is accomplished through a series of coordinated movements that mechanically fragment food materials and mix them with copious enzymatic secretions which chemically process the foodstuffs into constituents small enough for absorption and utilization. In order to understand the integrative aspects of gastrointestinal function, a review of the anatomical and histological layout of the alimentary canal and its ancillary organs is required. I. Gross Anatomy of the Alimentary Canal: To move food from the mouth to the stomach, the chewed food must be mixed with saliva. Saliva is produced by Salivary glands : several glands found within the oral Sublingual cavity. The primary glands are bilateral Submaxillary pairs with the parotids, sublingual and submaxillary being most important. The chewed and swallowed food, now referred to as chyme, moves through the esophagus to the stomach. A reflex which Liver Gallbladde r coordinates muscle relaxation distal to the bolus of chyme, and contraction Duodenum proximal to the bolus is required to Ascending efficiently move the chyme into the colon stomach. In addition, a region of smooth Cecum muscle at the esophageal/stomach junction Appendix regulates flow into or back out (retrograde) of the stomach. This region, Ileum referred to as the lower esophageal sphincter, is also relaxed during a coordinated swallowing reflex but quickly closes thereafter. Pharynx UES Esophagus LES Stomach Pancreas Transverse colon Descending colon Jejunum Sigmoid Rectum Histologically the most proximal portion of the stomach contains mucus secreting “cardiac glands”. The segment comprising the next 70-80% of the stomach contains acidic secreting oxyntic glands, and is referred to as either the body or fundus regions. The segment of the distal stomach prior to the connection with the small intestine is referred to April 22, 2005 Introduction and GI Regulation Ron Lynch, Ph.D. 626-2472 as the pylorus. Functionally, the most proximal 1/3 of the stomach has the ability to increase its diameter to "accommodate" the incoming bolus of chyme. Tonic contraction/relaxation of the smooth muscle in this region allows for the initial accommodation, but also is important for slowly contracting down on the chyme forcing more of it aborally (away from the oral cavity) to mix with acid and begin digestion. The distal 2/3 of the stomach carries out intense contractile activity while chyme remains therein. The most distal region of the stomach, the pylorus, acts as a gate (pyloric sphincter) for entrance of chyme into the small intestine. In addition, the pyloric glands in this region secrete the hormone gastrin into the blood in response to stimulatory factors found within the chyme in the stomach lumen. Full digestion of nutrients in the chyme occurs within the small intestine. Functionally, the small bowel is delineated into three regions (proximal to distal); the duodenum, jejunum and ileum. In the duodenum, acidic chyme leaving the stomach is neutralized by HCO3 and mixed with digestive enzymes. Both HCO3 and the enzymes are produced in the pancreas. Bile is produced in hepatocytes, and during periods of fasting (overnight) the bile is stored in the gall bladder where it is concentrated. The secretions from the pancreas are carried to the duodenum via an extensive ductal system which combines with the bile ductal system prior to entrance to the small intestine. A competent common bile duct and sphincter are required for a normal digestive pattern in the small intestine. As the chyme moves aborally the epithelial cells efficiently absorb the digestion products in their simplest monomeric and dimeric forms. Most absorption of water and nutrients occurs within the jejunum. The ileum is a specialized region containing specialized transporters; absorption of specific vitamins and reabsorption of bile occur here. The junction between ileum and the colon (ileocecal sphincter) regulates passage of "nondigested" chyme into the colon, but importantly retards retrograde flow of bacteria from the colon to the ileum. The large intestine is an important storage organ. Bacteria housed within it further digest the chyme contents to extract all possible nutrients. The colon also reabsorbs about 5-10% of the total water, and it is at this level that water resorption is regulated. II. Blood Flow to the Alimentary Organs: The Splanchnic Circulation. Splanchnic circulation refers to the vasculature which brings blood to and from the major abdominal organs including the liver, spleen, stomach, pancreas, large and small intestine. This vascular system is the major blood reservoir containing between 20-40% of total blood volume. More than 60% of the total splanchnic blood volume can reside in venules making the splanchnic venous circulation the primary source for mobilizing blood during crisis (eg., hemorrhage). Fluid exchange in the splanchnic system also is very high. Secretions by the digestive tract amount to 7-8 liters/day with 1-2 liters/day of H2O ingested. This volume is April 22, 2005 Introduction and GI Regulation Ron Lynch, Ph.D. 626-2472 approximately 2 to 3 times the body's plasma volume. Thus, changes in fluid exchange between the GI tract and the systemic circulation can dramatically alter blood plasma volume. II. General Anatomical Characteristics Splanchnic Circulation – refers to all organs fed by celiac, superior mesenteric and inferior mesenteric arteries. Hepatic Circulation – refers to liver blood flow. Mesenteric circulation –- refers to intestinal blood flow. Organization of blood flow to and from splanchnic organs. For most splanchnic organs blood flows to each through a branch of one of the three major arteries from the aorta and then collects into the portal vein to drain to the liver. The liver also receives blood from the hepatic arterial branch of the celiac artery. Hence, blood passes both in parallel circuits and in series circuits through the splanchnic vessels. Numbers in parentheses indicate the blood flow in milliliters per minute through the named vessels that might be expected in an average adult male. Blood flow (value) in ml/min Lymphatic Flow from the Alimentary Canal and GI organs can be up to 25 ml/min Blood Flow in the Portal Vein. Blood collected from all of the alimentary organs flows into the portal vein. The flow of blood in the portal vein to the liver is important in metabolic clearance of ingested substances from the blood such as nutrients (glucose), drugs and toxins. Thus, the positioning of the liver at the entrance for blood into the systemic circulation is important for screening substances absorbed from the alimentary canal. III. Structural Characteristics of the Intestinal Wall Lymph node Villus Epithelium and Mucosa Muscularis mucosa Submucosa (contains most nerves and bloood vessels) Circular muscle Longitudinal muscle Serosa (connective tissue) Myenteric plexus Submucosal plexus Gland in submucosa April 22, 2005 Introduction and GI Regulation Ron Lynch, Ph.D. 626-2472 The wall of the alimentary canal exhibits a consistent arrangement along its length. The outer surface is covered with a layer of connective tissue called the serosa. Immediately under the serosa is a layer of smooth muscle which runs longitudinally along the length of the canal (longitudinal muscle) used for propulsive movements. The next obvious layer of cells is another muscle layer which encircles the canal (circular muscle), and is important for changing lumen diameter including the sphincters. Between the muscle layers is a network of nerves that exhibit a large amount of cell to cell synapses. This layer of nerves regulates activity in both muscle layers and is referred to as the myenteric plexus. Under the circular muscle lies a highly variable layer of tissue with respect to depth and content called the submucosa (i.e., under the mucosa or lumen lining). The striking feature of the submucosa is the large amount of glandular tissue in specific areas like the stomach. Also, on the serosal side of the submucosa next to the circular muscle layer is a second layer of nerve cells (the submucosal plexus). Activity in these nerves regulates circular muscle contractility, as well as, secretory activity in the glands and absorptive activity of the epithelial lining. The epithelial cells provide several functional characteristics to the alimentary tract, but most important these cells are responsible for all absorption, fluid secretion and acting as a protective barrier to infiltation against bacteria and toxins. GASTROINTESTINAL NERVOUS SYSTEM 1. Understand the general organization and function of the enteric nervous system. 2. Determine the differential regulation of GI functions by sympathetic and parasympathetic innervation. 3. Understand the concept of Summation of Signals and how this relates to the integration of information determining a response. I. Enteric (Intrinsic) Nervous System: Within the wall of the alimentary canal are two dense layers of neurons which are critically important for coordinating the various functions required for digestion and absorption of nutrients. The layer of nerves found beneath the mucosa is referred to as the submucosal plexus. Nerves within this plexus send out processes which synapse on other nerves within the plexus (inter-neurons), as well as, effector cells (secretory, endocrine) located within the mucosa and submucosa, and smooth muscle cells in the circular layer. April 22, 2005 Introduction and GI Regulation Myenteric ganglion Interganglionic fiber tract Ron Lynch, Ph.D. 626-2472 Circular muscle Submucosal ganglion Longitudinal 200 um Mucosa Enteric neurons of the submucosal and myenteric plexuses in the wall of the GI tract. The plexuses consist of ganglia interconnected by fiber tracts. (Redrawn from Wood JD: In Johnson RL, editor: Physiology of the gastrointestinal tract, ed 2, New York, 1987, Raven Press). The myenteric plexus of nerves reside between the circular and longitudenal smooth muscle. These nerves primarily regulate and coordinate contractility of the muscle layers. Visceral smooth muscle contractility is generally under inhibitory control. Since the secretory and contractile functions of the alimentary canal are coordinated within the plexus network of the gut, the intestinal sensing and regulation of motor activity has been referred to as a "visceral brain." This network also allows for the elaboration of local "reflex arcs" throughout the gut. II. Extrinsic (Autonomic) Regulation of Alimentary Functions. A. Sympathetic Innervation: Pre-vertebral ganglia provide innervation via adrenergic (norepinephrine) fibers to the enteric plexi, and directly to vascular smooth muscle. The primary consequence of sympathetic stimulation is a general inhibition of motor and secretory function which includes enhanced contraction of the alimentary sphincters via activation through the submucosal plexus. Possibly the most important response to sympathetic output is vasoconstriction (blood vessels) through direct innervation of blood vessels. B. Parasympathetic Innervation. All parasympathetic fibers synapse on neurons within the enteric plexi of the alimentary canal. The primary response to parasympathetic stimulation is a general increase in motor and secretory function within the alimentary canal, and ancillary organs. Integration of Signals. Signals are integrated primarily at the level of the enteric nervous system, but also through long reflexes centered in the prevertebral ganglia and spinal cord. ENDOCRINE CONTROL OF GI FUNCTION: 1. Identify the four primary GI hormones, their primary physiological actions and roles in regulating GI function. 2. Understand the categories of endocrine, paracrine and neurotransmitter, and by April 22, 2005 Introduction and GI Regulation Ron Lynch, Ph.D. 626-2472 which of these mechanisms the GI regulatory peptides act. The GI tract is the largest endocrine organ in the body. It produces a wide variety of hormones and biologically active peptides. General features of gut hormones include their peptide nature (generally 50 or so amino acid residues), synthesis in a precursor form (generally via an N-terminal "signal sequence"), and intracellular or intragranular processing prior to secretion. April 22, 2005 Introduction and GI Regulation Ron Lynch, Ph.D. 626-2472 Characteristics of the Major Gastrointestinal Hormones I. A. B. Hormones of the GI Tract Gastrin 1. Released by G-cells in the antral portion of stomach in response to neural stimulation, peptides in the stomach, and stretch of the stomach 2. Actions: Stimulates HCl secretion and growth of stomach and pancreas. Secretin 1. secreted by duodenal cells in response to elevated acidity and increased fat 2. Actions: Stimulates secretion of bicarbonate by pancreas and biliary tract C. Cholecytokinin (CCK) 1. secreted by duodenal I-cells; stimulated by certain essential amino acids and long-chain fatty acids in duodenum, some CCK cells in jejunum and colon. 2. Actions: stimulates pancreatic secretion of enzymes and gall bladder contraction and promotes growth of pancreatic cells. D. Glucose-dependent insulinotropic peptide - GIP. 1. Released from duodenal K-cells in response to luminal glucose & fat. 2. Primary action is to promote insulin release. GI hormones can be delineated into two families. CCK and the gastrins comprise one family. A 5 amino acid stretch at the C-terminus is identical, and all gastrin-like activity is expressed by this fragment. Gastrin and CCK elevate Ca2+ within target tissues. The second family is related to secretin. Included in this family are VIP (Vasoactive Intestinal Peptide), GIP and glucagon; these peptides elevate cAMP in target tissues. III. Distribution of GI active peptides. The primary GI hormones are produced in and secreted by specialized cells scattered throughout the small intestine (or distal stomach – gastrin) and specifically located within the crypts of Lieberkuhn. These mucosal endocrine cells structurally resemble mucosal cells involved in digestion and absorption in having brush borders, but have secretory granules that are released to the blood (basolateral secretion) upon stimulation. Many peptides which modulate GI function are located within enteric neurons including CCK, substance P, neurotensin and VIP and therefore are considered neurotransmitters. Several other peptides are active modulators of GI function, and act in a paracrine fashion (i.e. they are secreted by specific cells and act only at sites near their site of release). These include Somatostatin which decreases gastrin secretion and Histamine which stimulates acid secretion