Upper Gastrointestinal Tract Notes

NOTES NOTES UPPER GASTROINTESTINAL TRACT CHEWING & SWALLOWING osms.it/chewing-and-swallowing CHEWING ▪ First step to process ingested food to prepare for digestion, absorption ▪ Three functions ▫ ↓ food particle size → facilitate swallowing ▫ Mix food with saliva → lubrication ▫ Mix food particles with amylase → begin carbohydrate digestion ▪ Teeth move, masticate food into small fragments, tongue functions to taste, roll food around in oral cavity → compact into small ball (bolus) Oral cavity walls ▪ Roof: soft, hard palate ▪ Floor: tongue, mylohyoid muscles ▪ Sides: cheeks ▪ Front: lips, teeth ▪ Involuntary component of chewing ▫ Mouth mechanoreceptors → sensory information to brainstem → reflex oscillatory pattern to muscles of mastication ▪ Voluntary component ▫ Can override reflex chewing at any time Muscles involved with mastication ▪ Temporalis muscle: fan-shaped muscle on both sides of head ▪ Masseter muscle: connects mandible to zygomatic arch of temporal bone ▪ Medial pterygoid muscle: connects mandible to medial pterygoid plate ▪ Lateral pterygoid muscle: located at condylar process ▪ All muscles of mastication innervated by branches of trigeminal (CN V) Figure 38.1 The structures that make up the walls of the oral cavity. OSMOSIS.ORG 309

▪ All muscles coordinate, work together to grind, mechanically break down food ▪ Tongue moves from side to side to reposition food → push it between teeth to be chewed, mixed with saliva → soft, mushy bolus ready for swallowing Figure 38.2 The muscles of mastication. A: The temporalis and masseter muscles are superficial to B: the laterial and medial pterygoid muscles. SWALLOWING food in mouth) → travel via vagus and glossopharyngeal nerves → swallowing center in medulla → sends efferent, motor information via glossopharyngeal, vagus nerves → directs coordinated movement of pharyngeal striated muscle, upper esophagus Three phases ▪ Oral (voluntary) ▫ Tongue presses against hard palate → forces bolus towards oropharynx → pharynx contains high density of somatosensory receptors → activation → swallowing reflex initiation in medulla ▪ Pharyngeal (swallowing reflex) ▫ Soft palate, uvula moves upwards → creates narrow passage → prevents food reflux into nasopharynx → epiglottis closes down over laryngeal opening → larynx moves upwards against epiglottis → act as seal to prevent food entering trachea → upper esophageal sphincter relaxes → food passes from pharynx to upper esophagus → peristaltic wave initiation → food propelled through open upper esophageal sphincter ▫ Breathing inhibited during this phase ▪ Esophageal (swallowing reflex/enteric nervous system) ▫ Swallowing reflex closes upper esophageal sphincter → food cannot reflux back into pharynx → primary peristaltic wave (coordinated by swallowing reflex) → propels food along esophagus → if all food not cleared → distended esophagus → secondary peristaltic wave is initiated by enteric nervous system ▪ Initiated voluntarily in mouth, involuntary thereafter ▫ AKA deglutition ▪ Pharynx has three parts ▫ Nasopharynx ▫ Oropharynx ▫ Throat Swallowing reflex ▪ Somatosensory receptors near pharynx → detect sensory information (e.g. 310 OSMOSIS.ORG Figure 38.3 Locations of the three pharynx divisions and the upper esophageal sphincter.

Chapter 38 Gastrointestinal Physiology: Upper Gastrointestinal Tract Figure 38.4 Mastication muscles. A: The temporalis and masseter muscles are superficial to B: the laterial and medial pterygoid muscles. SALIVARY SECRETION osms.it/salivary-secretion SALIVARY GLANDS ▪ Three major salivary glands exist outside oral cavity ▫ Parotid: composed of serous cells → secrete fluid composed of ions, enzymes, water ▫ Submandibular, sublingual: composed of serous, mucous cells → stringy, viscous solution of aqueous fluid, mucin glycoprotein for lubrication ▪ Minor salivary glands (e.g. buccal) scattered throughout oral cavity mucosa ▪ Each gland is paired; all produce saliva which are delivered to oral cavity via ducts ▪ Appearance: cluster of grapes ▫ Each grape = single acinus ▫ Blind end of branching duct system ▪ Saliva formation is two-step process ▫ Acinus lined with acinar cells → produces initial saliva → passes through intercalated duct → striated duct lined with ductal cells → modify initial saliva → myoepithelial cells stimulated neurally → contract → saliva ejected into mouth ▪ Cell types ▫ Acinar cells: produce initial isotonic saliva (mixture of water, ions, enzymes, mucus) ▫ Ductal cells: modify electrolyte concentrations in initial saliva to produce final saliva ▫ Myoepithelial cells: present in acini, intercalated ducts; contract to eject saliva into oral cavity ▪ Innervation of salivary glands ▫ Saliva production stimulated by both parasympathetic (dominant), sympathetic activation (unique feature) ▪ Blood supply ▫ Saliva production stimulated → unusually high blood flow ▫ When corrected for organ size, blood flow is ↑ 10x more than exercising skeletal muscle OSMOSIS.ORG 311

Figure 38.5 Protid glands sit in front of each ear. Submandibular glands sit under the mandible. Sublingual glands (not pictured) are beneath the tongue, under the mouth floor. SALIVA ▪ Produced by salivary glands; rate of 1L/ daily Functions ▪ Initial digestion of starches/lipids by salivary enzymes ▪ Lubricating ingested food to allow movement through esophagus ▪ Diluting, buffering ingested foods (which may be harmful) ▪ Cleanses mouth ▪ Dissolves food chemicals so it can be tasted Saliva composition ▪ Water (97–99.5%) ▪ Electrolytes ▪ Alpha-amylase: initial carbohydrates digestion, like potatoes/rice ▪ Lingual lipase: initial lipid digestion ▪ Mucus ▪ Immunoglobulin A ▪ Kallikrein: protease enzyme; cleaves high molecular weight kininogen → bradykinin → vasodilation → increased blood flow during salivary activity ▪ Lysozyme: enzyme inhibiting bacterial growth, prevents tooth decay ▪ Defensin: acts as local antibiotic ▪ pH 6.5–7.5 ▫ Usually maintained by NaHCO3 312 OSMOSIS.ORG Saliva formation ▪ Initial saliva is isotonic ▫ Concentrations of K+, HCO3-, Na+, Clsimilar to plasma ▪ Final secreted saliva is hypotonic (↓ osmolarity), when compared to plasma ▫ ↑ K+, HCO3-, ↓ Na+, Cl▪ Modification of saliva by ductal cells ▫ Complex transport system ▪ Luminal membrane has three transporters ▫ Na+-H+ exchange ▫ H+-K+ exchange ▫ Cl--HCO3- exchange ▪ Basolateral membrane has two transporters ▫ Na+-K+ ATPase ▫ Cl- channel ▪ Overall action of all transporters together ▫ Absorption of Na+, Cl- → ↓ Na+, Clconcentration in saliva ▫ Secretion of K+, HCO3- → ↑ K+, HCO3concentration in saliva ▫ Net absorption of solute (NaCl > KHCO3) ▪ Process of isotonic saliva → hypotonic saliva ▫ Ductal cells are water impermeable ▫ Due to net absorption (solutes leave saliva, water does not travel with) ▪ Saliva tonicity depends on flow rates ▫ Depends on amount of time saliva in contact with ductal cells (↑ Na+, Cl-

Chapter 38 Gastrointestinal Physiology: Upper Gastrointestinal Tract absorption, ↑ K+ secretion) ▫ ↑ flow rate (4mL/min): composition parallels plasma, initial saliva produced by acinar cells ▫ ↓ flow rate (1mL/min): most dissimilar composition to plasma ▫ Exception: HCO3- remains constant, despite flow changes; selective parasympathetic stimulation; ↑ flow rate → ↑ HCO3- parasympathetic stimulation → ↑ HCO3- secretion Saliva secretion regulation ▪ Minor salivary glands continuously secreting small amounts to keep oral cavity moist ▪ When food enters → major glands activated → large amounts of saliva produced ▪ Two unique features ▫ Exclusive neural control by autonomic nervous system (other gastrointestinal secretions controlled both neurally, hormonally) ▫ Saliva secretion ↑ by both sympathetic + parasympathetic ▪ Parasympathetic innervation ▫ Activity ↑ with visual stimulus of food, smell, nausea, conditional reflexes (e.g. Pavlov’s salivating dog) ▫ Activity ↓ with fear, sleep, dehydration ▫ Chemoreceptors, mechanoreceptors in oral cavity stimulated → signal carried via facial (CN VII), glossopharyngeal (CN IX) nerves → salivatory nucleus in brain stem (medulla and pons) ▫ Vinegar and citric juice → strongest chemoreceptor stimulus ▫ Postganglionic neurons → release acetylcholine (ACh) → bind muscarinic receptors → ↑ IP3 + intracellular Ca2+ → saliva secretion ▪ Sympathetic innervation ▫ Thoracic segments T1–T3 → preganglionic nerves → synapse on superior cervical ganglion → postganglionic sympathetic neurons release norepinephrine (NE) → bind to beta-adrenergic > alpha-adrenergic receptors on acinar/ductal cells → stimulation of adenylyl cyclase → ↑ cAMP → ↑ saliva secretion SLOW WAVES osms.it/enteric-nervous-system-and-slow-waves ENTERIC NERVOUS SYSTEM ▪ AKA ‘gut brain’ ▪ Contains over 100 million neurons (more than spinal cord) ▪ Intrinsic/“in-house” nerve plexuses spread throughout GI tract like chicken wire ▪ Semiautonomous enteric neurons made up of two nerve plexuses (ganglia connected by unmyelinated tracts) ▫ Submucosal nerve plexus → located in submucosa; innervates secretory cells; controls local digestive secretions ▫ Myenteric nerve plexus → located between circular, longitudinal muscle layers in muscularis externa; major controller of gastrointestinal (GI) tract motility ▪ Enteric nervous system connected to central nervous system (CNS) via ▫ Afferent visceral fibers ▫ Sympathetic, parasympathetic branches ▫ Synapse with intrinsic plexus neurons OSMOSIS.ORG 313

Figure 38.6 The enteric nervous system is found within the walls of the entire gastrointestinal tract. The submucosal plexus is found in the submucosa and the myenteric plexus is found within the muscularis externa between the longitudinal and circular muscle layers. Figure 38.7 The gastrointestinal portions of the visceral motor system. Sympathetic division: preganglionic fibers are in the lower thoracic and upper lumbar segments of the spinal cord, and they synapse in ganglia located near the spinal cord. Parasympathetic division: preganglionic fibers arise from the brainstem (vagus nerve) and sacral component of the spinal cord (pelvic nerve), and synapse in a neural plexus on or very near the target organ. 314 OSMOSIS.ORG

Chapter 38 Gastrointestinal Physiology: Upper Gastrointestinal Tract SLOW WAVES ▪ Unique feature of GI tract electrical activity ▫ Oscillating depolarizations, repolarization of membrane potential of GI smooth muscle cells ▪ Depolarization → membrane potential becomes less negative → moves towards threshold → burst of action potentials (APs) occur on top of slow wave (plateau) → contraction/smooth muscle tension → membrane potential becomes more negative → moves away from threshold → repolarization → smooth muscle relaxation Frequency ▪ Intrinsic rate is 3–12 slow waves/minute ▪ Not determined by hormonal/neural input, however can modulate amount of APs at plateau → ↑/↓ contraction strength ▪ Each part of GI tract has characteristic frequency ▫ Stomach → slowest (3/min), duodenum → fastest (12/min) Mechanism ▪ Cyclic opening of Ca2+ channels → Ca2+ influx → depolarization ▪ Plateau phase maintained by continuous Ca2+ influx ▪ Opening of K+ channels → K+ outflux → repolarization Slow wave origin ▪ Myenteric plexus is network of nerves, located between longitudinal, circular layers in muscularis externa ▪ Interstitial cells of Cajal located in myenteric (Auerbach) plexus ▫ Referred to as ‘pacemaker’ cells of GI tract smooth muscle ▫ Cyclic, spontaneous depolarizations, repolarization occur in these cells → rapid spread to adjacent smooth muscle cells via gap junctions ▪ Pacemaker → frequency → AP rate → coordinated smooth muscle contraction ▪ Slow waves to contractions ▪ Subthreshold slow waves → can produce weak contraction ▪ Even without AP occurrence → smooth muscle not completely relaxed/tonically contracted ▪ Above threshold slow waves → APs occur on top of slow wave → stronger contraction → phasic contraction ▪ ↑↑ APs on top of slow wave → ↑↑ phasic contraction strength ▪ Unlike skeletal muscle, where each AP results in twitch/separate contraction, smooth muscle APs summate into one long contraction Figure 38.8 Slow wave origin and mechanism. Slow waves are generated by spontaneous depolarization and polarization of Cajal cells, which are attached to smooth muscle cells via gap junctions. The slow wave potentials travel through the smooth muscle cells → voltagegated calcium channels open → weak depolarization of smooth muscle cells → weak tonic contractions that maintain the tone of the gastrointestinal tract. OSMOSIS.ORG 315

Figure 38.9 Slow wave potentials from enteric nervous system + action potentials from extrinsic nervous system → threshold potential for peristaltic contractions. Strength of contraction is determined by number of action potentials above each slow wave; rate of contraction is determined by the rate of the slow waves. ESOPHAGEAL MOTILITY osms.it/esophageal-motility GI MOTILITY ▪ Generally, GI motility refers to contraction, relaxation of GI walls, sphincters ▪ GI contractile tissue is all smooth muscle except ▫ Pharynx ▫ Upper ⅓ esophagus ▫ External anal sphincter ▪ Smooth muscle cells connected together via gap junctions → rapid cell-to-cell transfer of action potentials → coordinated contractions Two types of smooth muscle ▪ Circular: ↓ segment diameter ▪ Longitudinal: ↓ segment length ▪ Both contained within muscularis externa layer Two types of contractions ▪ Phasic: periodic → relaxation ▫ Located in esophagus, small intestine ▪ Tonic: constant level of contraction, without regular intervals of relaxation ▫ Located in lower esophagus, upper stomach, ileocecal valve, internal anal sphincter 316 OSMOSIS.ORG Sphincters ▪ Specialized circular muscle separating adjacent GI tract regions ▪ Maintain positive pressure → anterograde, retrograde flow prevented ▪ Smooth muscle contraction → peristalsis of GI contents to sphincter → sphincter transiently lowers pressure → relaxation → passage of contents to adjacent organ ▪ Locations ▫ Upper esophageal sphincter: pharynxupper esophagus ▫ Lower esophageal sphincter: esophagus-stomach ▫ Pyloric sphincter: stomach-duodenum ▫ Ileocecal sphincter: ileum-cecum ▫ Internal and external sphincters: preserves fecal continence ESOPHAGUS Key features ▪ Muscular 25cm/9.8in tube divided into three regions ▪ Cervical: connects with pharynx behind trachea; separated by upper esophageal sphincter

Chapter 38 Gastrointestinal Physiology: Upper Gastrointestinal Tract ▪ Thoracic: suprasternal notch to esophageal hiatus in diaphragm ▪ Abdominal: esophageal hiatus to esophageal opening into stomach; separated by lower esophageal sphincter Layers ▪ Adventitia ▫ Thick fibrous connective tissue; outermost ▪ Muscularis externa ▫ Outer longitudinal, inner circular muscle layers; myenteric plexus lies between ▪ Submucosa ▫ Dense layer of connective tissue containing blood vessels, lymphatics, mucus glands secreting mucus to lumen via ducts; contains submucosal (Meissner) plexus ▪ Mucosa → three layers ▫ Muscularis mucosa (outermost layer of longitudinal muscle) ▫ Lamina propria ▫ Epithelial layer Figure 38.10 Regions of esophagus, associated structures. Figure 38.11 Layers of esophageal mucosa. OSMOSIS.ORG 317

Innervation ▪ Intrinsic: Vagus nerve (CN X) ▪ Extrinsic: Myenteric plexus in muscularis externa Function ▪ Esophageal motility propels food bolus from pharynx → stomach ▫ Food bolus formed in oral cavity → upper esophageal sphincter opens → bolus passes pharynx to upper esophagus → upper esophageal sphincter closes → primary peristaltic contraction → series of coordinated sequential contractions → each segment contracts → creates area of high pressure behind bolus → pushed down esophagus ▪ If not all food pushed through → distension of esophageal wall → activation of mechanoreceptors in mucosal layer → afferent, sensory information to enteric nervous system and myenteric plexus → coordination of muscle contractions above site of distension + relaxation below it → secondary peristaltic wave ▪ Esophagus has thick muscularis externa compared to other parts of GI tract ▪ Primary peristaltic wave travels approximately 3cm/sec ▫ Solid food takes approximately 10 seconds to travel from cervical region → stomach ▫ Liquids approximately 1–2 seconds ▫ Accelerated by gravity (sitting/standing > lying supine) 318 OSMOSIS.ORG ▪ Food bolus approaches lower esophageal sphincter → opening mediated by peptidergic fibers of vagus nerve, release vasoactive intestinal peptide (VIP) → lower esophageal sphincter smooth muscle relaxation → at same time, orad region of stomach relaxes (phenomenon referred to as receptive relaxation) → pressure decreases in orad stomach → food bolus propelled into stomach → lower esophageal sphincter closes immediately, returns to high pressure resting tone → prevents reflux Intrathoracic esophagus ▪ Upper, middle esophagus located in thorax, only lower esophagus located in abdomen ▪ Intraesophageal pressure = intrathoracic pressure which is < atmospheric pressure ▪ Intraesophageal pressure < intra abdominal pressure ▪ This pressure difference causes two problems ▫ Inhibiting air from entering upper esophagus (air will travel down pressure gradient, esophagus essentially sucking air in); prevented by upper esophageal sphincter (always in closed resting state) ▫ Inhibiting gastric contents from entering lower esophagus (reflux); prevented by lower esophageal sphincter (always in closed resting state) ▫ Conditions where intraabdominal pressure ↑↑ (e.g. pregnancy, morbid obesity) → gastroesophageal reflux

Chapter 38 Gastrointestinal Physiology: Upper Gastrointestinal Tract GASTRIC MOTILITY osms.it/gastric-motility-and-secretions STOMACH ▪ Anatomy differentiated based on motility, stomach can be divided into orad (proximal), caudad (distal) ▫ Orad region: fundus, proximal body; thin-walled ▫ Caudad region: distal body, antrum; thick-walled (stronger contractions to mix chyme, propel to small intestine) Figure 38.12 Divisions of the stomach. Layers ▪ Mucosa: innermost layer; modified → contains various glands filled with different cells → secrete components of gastric juice ▪ Submucosa: contains submucosal plexus → controls secretions and gastric blood flow, contains blood vessels ▪ Muscularis externa: modified ▪ Serosa: outermost layer ▪ Three layers of stomach muscles that involuntarily contract to produce peristalsis ▫ Outer longitudinal layer ▫ Middle circular layer ▫ Inner oblique layer (unique to stomach) Innervation ▪ Extrinsic: autonomic nervous system ▪ Intrinsic: myenteric receives parasympathetic innervation (via vagus nerve), sympathetic innervation (via fibers from celiac ganglion); submucosal plexuses Figure 38.13 Layers of the stomach. OSMOSIS.ORG 319

COMPONENTS OF GASTRIC MOTILITY ▪ Three components ▪ Receptive relaxation ▫ Relaxation of lower esophageal sphincter, orad stomach region to receive food bolus from esophagus ▪ Gastric contractions to break up bolus, mix with gastric secretions → initiate digestion ▪ Gastric emptying → propelling chyme to small intestine ▫ Gastric emptying rate hormonally determined → allows adequate time for small intestine digestion/absorption ▫ Liquids (faster); solids (slower) Receptive relaxation ▪ Vasovagal reflex: both afferent, efferent limbs of reflex carried within vagus nerve ▫ Lower esophageal distension → relaxation, opening of lower esophageal sphincter → mechanoreceptors detect distension → send afferent sensory information to CNS through sensory neurons → CNS transmits efferent information to orad stomach smooth muscle wall → postganglionic peptidergic vagal nerve fibers release VIP → orad stomach ↓ pressure, ↑ volume → allows food bolus passage ▫ Vagotomy inhibits receptive relaxation ▪ Stomach can accommodate up to 1.5L of food Gastric contractions ▪ Thick, muscular caudad region of stomach produces strong contractions needed to mix food with gastric secretions, digest food ▪ Contraction waves begin in middle stomach body → progressively ↑ strength as food approaches pylorus ▪ Periodically, portion of gastric contents propelled through pylorus to duodenum ▫ However, most gastric contents undergo retropulsion (propelled back into stomach for further mixing) ▪ Majority of the chyme not initially injected through pylorus to duodenum since contraction wave closes pyloric sphincter ▪ Frequency of slow waves in caudad stomach; bringing membrane potential to 320 OSMOSIS.ORG threshold so APs can occur ▫ 3–5/min → frequency of caudad stomach contraction approximately same ▫ Slow wave frequency not influenced by neural/hormonal input ▫ Frequency of APs, contraction force are influenced by neural/hormonal input ▪ Frequency of APs, force of contraction ↑↑ by ▫ Parasympathetic stimulation ▫ Gastrin ▫ Motilin ▪ Frequency of APs, force of contraction ↓↓ by ▫ Sympathetic stimulation ▫ Secretin: hormone produced by duodenal S cells; regulates water homeostasis, GI tract secretions ▫ Gastric inhibitory peptide (GIP): hormone secreted by intestinal K cells; inhibits gastric acid secretion, stimulates insulin secretion ▪ Migrating myoelectric complexes ▫ Periodic gastric contractions during fasting ▫ Function: clear stomach of remaining content from last meal ▫ 90-minute intervals ▫ Mediated by motilin Gastric emptying ▪ Emptying stomach of 1.5L postmeal can take approximately three hours ▪ Emptying rate closely monitored/regulated to allow ample time for stomach acid neutralization in duodenum, digestion/ absorption of nutrients ▪ Emptying speeds ▫ Liquids > solids ▫ Isotonic contents > hyper/hypotonic contents ▪ Solid particles must be < 1mm3; retropulsion continues until this size reached ▪ Factors that ↑ gastric emptying time (slows gastric emptying process) ▫ ↓ pH in duodenum (presence of H+ ions); mediated by enteric nervous system ▫ H+ receptors in duodenal mucosa detect ↓ pH of intestinal contents → activate

Chapter 38 Gastrointestinal Physiology: Upper Gastrointestinal Tract interneurons in myenteric plexus → relay info to gastric smooth muscle → ↑ gastric emptying time/slows gastric emptying process → allows time to neutralize acid by pancreatic HCO3-. ▫ ↑ fatty acids (highly fatty meal) ▪ The hormone cholecystokinin (CCK) secreted from duodenal I cells when fatty acids present in duodenum → slows gastric emptying ( ↑ gastric emptying time) → allow adequate time for fat to be digested/ absorbed GASTRIC SECRETION osms.it/gastric-motility-and-secretions ▪ Altogether gastric mucosa secretes fluid referred to as ‘gastric juice’ ▪ Four major components ▫ HCl ▫ Pepsinogen ▫ Intrinsic factor (needed for vitamin B12 absorption in ileum) ▫ Mucus (protects gastric mucosa from corrosive acids, lubricates) ▪ Oxyntic glands ▫ Found in body of stomach ▫ Empty secretions via ducts into lumen of stomach ▫ Opening of duct in gastric mucosa referred to as pits, lined by epithelial cells superficially Secretory cells ▪ Found in gastric glands ▪ Mucous neck cells ▫ Scattered around neck, basally ▫ Produce thin watery mucus (different from mucous cells of surface epithelium) ▪ Parietal (oxyntic) cells ▫ Found more apically; scattered around chief cells ▫ Produce HCl, intrinsic factor ▪ Chief cells ▫ Found basally ▫ Produce pepsinogen (inactive form of pepsin); activated by HCl ▫ Also produce lipases (15% of GI lipolysis) ▪ Enteroendocrine cells ▫ Found deep in gland ▫ Release various chemical messengers directly into lamina propria (e.g. histamine, serotonin act via paracrine mechanism, somatostatin acts via paracrine/hormone mechanism) ▪ G cells ▫ Secrete gastrin → bloodstream → ↑ HCl secretion by parietal cells, ↑ pepsinogen secretion by chief cells + ↑ contraction of stomach muscles ▪ Pyloric glands found in antrum of stomach ▫ Similar configuration to oxyntic glands but with deeper pits ▫ Mucous neck cells secrete mucus, HCO3-, pepsinogen → pyloric ducts ▫ G cells secrete gastrin → circulation OSMOSIS.ORG 321

Figure 38.14 Location of secretory cells within gastric glands and in the stomach, as well as secretory products. Mucosal barrier ▪ Stomach is harshest, most corrosive environment in entire GI tract ▫ Due to HCl, protein-digesting enzymes ▪ To combat these conditions ▫ Thick bicarbonate-rich mucus ▫ Tight junctions joining epithelial cells together (prevents gastric juice leakage) ▫ Undifferentiated stem cells → shed and replace damaged epithelial mucosal cells HCl secretion and mechanism ▪ Parietal cells → HCl secretion → gastric content pH 1–2 ▪ Functions to convert inactive pepsinogen (secreted by chief cells) → active pepsin → protein digestion; also functions to kill ingested bacteria ▪ Apical membrane of gastric gland has two transporters ▫ H+-K+ ATPase: H+ secreted into stomach lumen; primary active process (H+ and K+ flow against electrochemical gradient); site of action by proton pump inhibitors (e.g. omeprazole) ▫ Cl- channel: Cl- follows H+ into lumen; passive process 322 OSMOSIS.ORG ▪ Basolateral membrane has two transporters ▫ Na+-K+ ATPase ▫ Cl--HCO3- exchanger ▪ Basolateral membrane cells contain carbonic anhydrase ▫ CO2 + H2O → H2CO3 → H+ + HCO3▫ H+ then secreted with Cl- into lumen of stomach ▫ HCO3- is absorbed into blood → ‘alkaline tide’ (↑ blood pH in gastric venous blood after meal) ▪ Overall net HCl secretion, net HCO3absorption HCl secretion modulation ▪ Gastrin (secreted into systemic circulation by gastric antral G cells) ▫ Reaches parietal cells via endocrine mechanism ▫ Binds to CCKB receptors of parietal cells (affinity for gastrin = CCK) ▫ Stimulates H+ secretion via IP3/Ca2+ second messenger mechanism ▫ Triggers for gastrin secretion: stomach distension, small peptides, amino acids in stomach, vagus nerve stimulation ▫ Can indirectly stimulate H+ secretion by ↑ histamine release from endochromaffin-like (ECL) cells

Chapter 38 Gastrointestinal Physiology: Upper Gastrointestinal Tract ▪ Histamine ▫ Released from ECL cells in gastric mucosa ▫ Paracrine diffusion mechanism to nearby parietal cells ▫ Binds to H2 receptors coupled to G2 protein → stimulation of adenylyl cyclase → ↑ cAMP → activation of protein kinase A → ↑ secretion of H+ by parietal cells ▫ Site of action of the H2 blockers (e.g. cimetidine) ▪ ACh ▫ Released by vagus nerve (directly innervate parietal cells) ▫ ACh directly binds to parietal cell M3 receptors → activation of phospholipase C → releases diacylglycerol (DAG) and IP3 from membrane phospholipids → ↑ intracellular Ca2+ → Ca2+ and DAG → activate protein kinases → ↑ H+ secretion by parietal cells ▫ Site of action of antimuscarinics (e.g. atropine); atropine does not block HCl secretion completely ▫ Will block direct vagal effects on parietal cells ▫ Will not block indirect vagal effects on gastrin secretion since neurotransmitter is gastrin-releasing peptide (GRP), not ACh ▫ Can indirectly stimulate H+ secretion by ↑ histamine release from ECL cells ▪ Rate of H+ secretion is regulated by individual actions of gastrin, histamine, ACh or by the combination of them via potentiation (ability of two or more stimuli to interact together to produce a greater combined response than sum of individual effects) Cephalic phase of gastric secretion ▪ 30% of total HCl secretion ▪ Stimuli: smell and taste of food, chewing, swallowing, conditional reflexes in anticipation of eating (ex. Pavlov’s dog) ▪ Two physiological mechanisms ▫ Direct vagal stimulation of parietal cells ▫ Indirect vagal stimulation of parietal cells via gastrin Gastric phase of gastric secretion ▪ 60% of total HCl secretion ▪ Stimuli: gastric distension, amino acid/small peptide presence Figure 38.15 Mechanism of HCl secretion by parietal cells in the stomach’s gastric glands. Dotted lines indicate passive diffusion, whereas solid lines indicate active transport. OSMOSIS.ORG 323

▪ Four physiological mechanisms ▫ Distension → direct vagal stimulation ▫ Distension → indirect vagal stimulation (via gastrin) ▫ Antral distension → local gastrin release reflex ▫ Amino acids/small peptides → G cells → gastrin release ▪ Caffeine, alcohol are also HCl secretion stimulants Intestinal phase of gastric secretion ▪ 10% of total HCl secretion ▪ Mediated by protein digestion products Inhibition of HCl secretion ▪ First major factor is ↓ pH of gastric contents ▫ Gastrin secretion inhibited by low pH ▫ Chyme moved to small intestine → no longer requirement of pepsinogen → pepsin ▪ Second major factor is somatostatin ▫ Secreted by D cells in stomach ▫ Inhibits H+ secretion from parietal cells ▫ Direct mechanism: somatostatin → binds to receptor on parietal cell coupled with Gi protein → ↓ adenylyl cyclase → ↓ cAMP → ↓ H+ secretion ▫ Indirect mechanism: somatostatin inhibits ECL, G cell release of histamine, gastrin, respectively ▪ Prostaglandins (e.g. prostaglandin E2) also inhibit histamine’s stimulatory action on H+ secretion via Gi protein → ↓ adenylyl cyclase pathway 324 OSMOSIS.ORG