PHYSL 210 - GI Lecture Notes PDF

Gastrointestinal Physiology (GI) Lecture 1 recording 1: General Introduction ∙ Functions of the Gastrointestinal Tract (GIT): ▪ Transfer digested organic nutrients, minerals and water, from the external environment into the internal environment: involves digestion...

Gastrointestinal Physiology (GI) Lecture 1 recording 1: General Introduction ∙ Functions of the Gastrointestinal Tract (GIT): ▪ Transfer digested organic nutrients, minerals and water, from the external environment into the internal environment: involves digestion and absorption o Digestion Form absorbable molecules from food through GIT motility, pH changes, and biologic detergents and enzymes (enzymes are predominantly produced by the pancreas) ​ Chemical alteration of food into absorbable molecules o Absorption Movement of digestive food from the intestine into the blood or the lymphatic system ∙ Functions of the Gastrointestinal Tract (GIT): ▪ Functions of the GIT: o Excretion Non-absorbable components of food, bacteria, intestinal cells, and hydrophobic molecules (drugs), cholesterol and steroids are excreted o Host defense Lumen of the GIT is considered to be outside the body ❖ It is continuous with the exterior of the body ❖​ Potential portal for harmful substances and microorganisms The GIT forms a barrier with the outside environment and contains a highly developed immune system ❖ The GIT can inactivate harmful bacteria or other microorganisms ​ Ex: large intestine ∙ Components of the GIT: ▪ Components of the GIT: o Mouth, pharynx, esophagus, the stomach, the small intestine (duodenum, jejunum, ileum), large intestine ▪ 3 accessory organs: o Pancreas, liver, gallbladder Lecture 1 recording 2: Layers of the GIT ∙ Structure of the GIT: ▪ GIT is a long muscular tube stretching from the mouth to the anus o Composition is similar form mid-esophagus to anus The top third of the human esophagus is made of skeletal muscle, while the rest of the GIT is composed of smooth muscle ▪ Tube of the intestine o Lumen Inside of the tube Contains many folds and processes to increase the surface area Circular fold is where the entire inner surface folds in on itself ❖ Contains villi (singular villus) ✔ Villus projects into the lumen of the tube, and below the surface still is a crypt or an invagination ∙ Structure of the GIT: ▪ Layers of the GIT o Mucosa The mucosa contains three different subsections: ❖ Epithelium → a very thin layer of cells ❖ Lamina propria ​ ​ ❖ Muscularis mucosa → a very thin, smooth muscle layer o Submucosa o Muscularis externa (outer muscular layer) o Serosal layer (connective tissue layer) ∙ Layers of the Mucosa: ▪ 3 layers of the mucosa: o Epithelium, lamina propria, muscularis mucosa Epithelium: ❖ A layer of cells that lines all body cavities and surfaces ❖ Epithelial cells are polarized cells: they have a basolateral surface and an apical surface (polarized means that it is different at one surface and different at the other) ✔ Apical surface → inserts the inside of the tube or the lumen of the tube ✔ Basolateral surface → closest to the blood surface, facing away from the tube; basal surface and the  lateral surface ✔ The polarized epithelial layer has different transport proteins at the apical surface compared to the basolateral surface ✔ Transport proteins are confined to the different cell surfaces due to presence of tight junctions ∙ Layers of the Mucosa: ▪ Epithelial layer: o Single layer of cells o Function: Selective uptake of nutrients, electrolytes and water Prevent the passage of harmful substances o Surface area is amplified by the presence of villi and crypts Villus contains a single layer of epithelial cells containing microvilli Crypt is a region which invaginates into the lamina propria o Stem cells within the crypts divide and produce daughter cells which differentiate into a variety of cells (absorptive cells, mucous producing cells, etc) Stem cells divide and migrate up the villus. At the top of the villus, they reach the end of their life and slough off ❖ In the small intestine the epithelial cell layer is replaced every 5 days by others cells coming up ❖ As these cells are dividing rapidly, they are affected by anticancer drugs and are killed by the drugs before they can be replaced → can result in diarrhea, blood stool, etc ▪ Selective Transport of Nutrients Across the Epithelium: o Epithelial layer is selective, allowing specific nutrients across the intestinal epithelium and into the body 2 pathways that chemicals or molecules can use to get across an epithelial layer: ❖ Paracellular pathway → chemicals move between cells across the cell junctions; limited by tight junctions between cells, so only water and small ions can actually diffuse through the tight junctions; not many substances can get through this way in a healthy intestine ❖ Transcellular pathways → cross the cell and therefore require transport proteins (two step process), many nutrients are  absorbed through this pathway ▪ More Layers of the Mucosa: o Lamina propria Includes everything above the muscle layer Connective tissue, small blood vessels - arterioles and capillaries, nerve fibers and lymphatic vessels, immune and inflammatory cells for immune protection ❖ Lacteal or lymphatic vessel o Muscularis mucosa Thin layer of smooth muscle ❖ Not involved in contraction of the GIT and may function in moving the villi Lecture 1 recording 3: More Layers of the GIT ∙ Submucosa: ▪ Beneath the mucosa layer ▪ Submucosa: contains blood vessels, lymphatic vessels, submucosal nerve plexus (network of nerve cell bodies), connective tissue -​ Submucosal nerve plexus relays information to and away from the mucosa ∙ Muscularis Externa: ▪ Muscularis externa: circular muscle, myenteric nerve plexus, longitudinal muscle Circular muscle (thick inner layer): fibers are oriented in a circular pattern and contract and relax to close and open the tube (cause narrowing of lumen) o Myenteric nerve plexus: myo = “of muscle” Regulate the muscle function of the GIT o Longitudinal muscle: lengthens and shortens to control the length of the tube (does not change the diameter) ∙ Serosa:  ▪ Serosa layer: a connective tissue layer (thin) that encases the intestine and forms connections with the intestine and the abdominal wall Lecture 1 recording 4: Blood Supply to the GIT ∙ Blood Supply to the GIT: ▪ GIT blood supply carries away many nutrients as well as other components absorbed from the diet -​ Blood supply transports water-soluble nutrients and other molecules o Lacteals (lymphatic system; lamina propria in the mucosa layer) are important for fat absorption ▪ Food → digested starting in the stomach → absorption and secretion in the small intestine → processing in the colon → elimination of feces containing ingested material that cannot be digested and absorbed o Blood is highly oxygenated (red) entering the GIT but loses oxygen as it perfuses the intestine (blue) ▪ Blood does not flow directly from GIT back to the heart- blood is taken to the liver before returning to the heart. (because imagine drinking a sugary drink and it goes straight into your systemic circulation - you would be on glucose overload!) o Blood that perfuses the intestine goes to the liver via the portal vein ∙ Portal Circulation: ▪ Portal circulation → circulation that carries (drains) the blood from the intestinal (digestive) tract to (empties it directly in) the liver  o Blood in the portal circulation is nutrient rich o Important for: Liver removes harmful substances (liver acts as a filter and has many Enzymes - detoxification) Processing of nutrients ∙ Portal Circulation: ▪ Other organs in the body are perfused by arterial blood (fully oxygenated) o Liver is an exception: When you have not been eating, ~ 30% of the blood in the liver is from an arterial source (ie. fully oxygenated) ❖ After eating, this is reduced to 10% ▪ Hepatic artery → contains fully oxygenated blood that perfuses the liver ▪ Hepatic portal vein → carries blood to the liver that has already perfused the stomach, pancreas, SI and LI o These two blood supplies mix, so that the liver is perfused with nutrient-rich blood coming from the GIT organs with a poor oxygen content ∙ “In Series” versus “In Parallel” Circulation: ▪ Most organs are perfused in parallel within the systemic circulation, but the liver is perfused in series as the liver is perfused predominantly by blood that has already perfused another organ; blood flows from the digestive organs to the liver -​ Some blood comes from heart but most comes from digestive organs - stomach, pancreas, intestines and it flows in series between them Lecture 1 recording 5: Regulation of GI Processes ∙ Regulation of GI Processes: ▪ GI processes include secretion and motility, or the movement of the GI tract -​ These processes are governed by the volume and composition of what is inside the  intestinal tract ▪ Reflexes regulating GI processes are initiated by: 1. Distension of the GIT wall by the volume of luminal contents 2. Osmolarity of the contents pH of the contents (e.g., eating really salty food will regulate the tract) 3. The concentrations of the specific digestion contents, such as monosaccharides, fatty acids, peptides and amino acids The digestion contents contents initiate different regulatory pathways ▪ These reflexes are propagated by various receptors: Distension of the wall, osmolarity, pH of the contents and the concentration of specific digestion contents initiate reflexes by acting through various receptors located in the wall of the tract ❖ Mechanoreceptors → activated by mechanical stimuli (pressure and stretch) → eating a lot will cause mechanoreceptors to stretch out stomach ❖ Osmoreceptors → activated by a change in osmolarity → eating salty food ❖ Chemoreceptors → activated by specific chemicals ∙ Intrinsic Neural Regulation of GI Processes: ▪ To control motility and secretion ▪ Intrinsic neural regulation: o Intrinsic → contained wholly within the organ o Occurs through nerve plexi located in the GIT wall itself Nerve plexi = branching networks of intersecting nerves o Enteric nervous system → intrinsic nerve regulation Controls the activity of the secretomotor neurons which play a role in secretion and motility Contained completely within the walls of the GIT Large number of neurons: “Brain of the gut” Can function independently of the CNS Critical for involuntary functions ❖ The enteric nervous system allows us to digest our food without having to think about it There are two main nerve networks: myenteric plexus and the submucosal plexus Myenteric plexus: o Found between the two muscle layers, the circular muscle and the longitudinal muscle, of the muscularis externa o Responsible for influencing and regulating the smooth muscle ▪ Submucosal plexus: o Found in the submucosa o Predominantly influences secretion Nerves extend from the submucosal plexus to the mucosa to control secretion  -​ Closer to lumen ▪ The neural activity in one plexus influences the activity in the other o Communication between the two layers occurs so that motility and secretion of digestive enzymes work together -​ Mobile activity ∙ Extrinsic Neuronal Regulation of GI Processes: ▪ Extrinsic → outside of the GIT wall o Extrinsic regulation occurs through the autonomic nervous system (ANS) (parasympathetic and sympathetic divisions) o Nerve fibers from the parasympathetic and sympathetic pathways enter the intestinal tract and synapse with neurons in both plexuses o Through the autonomic nervous system, the CNS can influence motility and secretion Smell of food sends signals through your brain to the GIT through the ANS to start to get ready Different emotional states in the brain (CNS) will influence appetite (stress eating vs not eating) ∙ Autonomic Pathways and Digestion: ▪ Parasympathetic → “Rest and digest” response o Stimulates the flow of a large volume of watery saliva o Stimulates peristalsis (muscle contraction) o Stimulates secretion o Stimulates bile release from the liver ▪ Sympathetic → “Fright, flight, fight” response o Stimulates the small volume of a thick saliva o Inhibits peristalsis o Inhibits secretion ∙ Long and Short Neural Reflex Pathways: ▪ Long reflex = extrinsic pathway  ▪ Short reflex = intrinsic pathway o The pathways coordinate to modify the motility and secretion of the GIT ▪ (From the figure): o Eating a meal activates receptors in GIT wall (mechanoreceptors, osmoreceptors, chemoreceptors) → stimulus from the receptors feeds into the nerve plexus and stimulates the smooth muscle to contract or a gland to secrete → causes a response in the GIT (ie. contraction of the muscle which breaks down the food) o Smell of food when hungry/emotional state → stimulates the CNS → efferent autonomic neurons fire and interact with the same nerve plexus → stimulates the smooth muscle to contract or a gland to secrete → causes a response in the GIT (ie. contraction of the muscle which breaks down the food) Stimulation of CNS causes the same response but response is due to a CNS stimulation o Responses in the GIT can occur without any input from the CNS ▪ Receptors are activated in response to different stimuli causing release of chemical messengers Lecture 2 recording 6: Chemical Messenger Regulation ∙ 2 slides: Chemical Messenger Regulation: and Chemical Messenger Control of GI Activity: ▪4 categories of chemical messenger regulation: o Endocrine regulation → a hormone secreting gland cell releases hormone across its basolateral (meaning sides of the cell other than the luminal surface - blood side) surface into the blood; the hormone enters the blood and travels to its target cells in one or more distant places in the body (must be released into blood to have action on cell) -​ Chemical messenger passes from cell which produced it into blood and is carried by blood to its (relatively distant) target O Neurocrine regulation → a nerve cell produces an electrical signal resulting in the release of a neurotransmitter which travels across a synapse and acts on a postsynaptic target cell (either a neuron or an effector cell) -​ Chemical messenger is released from a nerve cell, travels across a synapse and acts on a postsynaptic target cell O Paracrine regulation → a local cell releases a paracrine substance which  diffuses through the interstitial fluid to act on target cells in close proximity to the site of release of the paracrine substance; this would occur across the apical surface of the cell into the lumen of the gland -​ Chemical messenger diffuses through interstitial fluid to nearby cells o Autocrine regulation → a local cell releases a substance which acts on the cell that released it -​ Chemical messenger acts on cell that released it ∙ Hormonal Control of GI Activity: ▪ Endocrine cells: o Produce hormones o Found in the epithelium of the stomach and the small intestine o Enteroendocrine cells release hormones which control GI functions -​ One surface of each endocrine cell is exposed to the GI lumen → chemical substances in lumen stimulate cell to release hormones across opposite surface of cell into blood vessels in lamina propria ∙ Hormonal Control of GI Activity: ▪ GI hormones: (These 3 we will look at in more detail) o Secretin, cholecystokinin (CCK), gastrin (glucose-dependent insulinotropic peptide/GIP is also another one → not looked at in detail) All peptide hormones Each hormone participates in a feedback control system that regulated some aspect of the GI lumen Most of these hormones affect more than one type of target cell ∙ CCK As an Example: ▪ CCK: o Release stimulated by the presence of fatty acids and amino acids in the small intenstine o Released into blood o Stimulates the pancreas to increase digestive enzyme secretion and causes contraction of the gallbladder Contraction of the gallbladder releases bile acids for fat breakdown Absorption of fats and amino acids stops the release of CCK ❖ This is a negative feedback control system ∙ Major Hormones of the GIT: (We will look at these hormones in more detail later) Lecture 2 recording 7: Intestinal Motility ∙ Intestinal Motility: ▪ Intestinal motility: stimulated by contraction and relaxation of the two muscle layers in the outer portion of the GIT; causes contents to move along tract o Peristalsis - the main driving force for food moving through the intestinal tract; propulsion Circular muscle contracts on the oral side of a bolus of food (Longitudinal layer relaxes) Circular muscle contracted moves toward the anus, propelling the contents of the lumen in that direction, as the ring moves, the circular muscle on the other side of the distended area relaxes (Longitudinal muscle contracts), facilitating smooth passage of the bolus ∙ Intestinal Motility: ▪ Segmentation - important for the mixing of food o Involves contraction and relaxation of intestinal segments with very little net movement of the food towards the large intestine o Mostly occurs in the small intestine o Functions: Allows the mixing of the contents of the GIT with digestive enzymes Slows the transit time to allow for the absorption of nutrients and water  ∙ Basic Electrical Rhythm: ▪ Pacemaker cells: o Cells in the GIT that are distributed throughout the smooth muscle cells o Constantly under spontaneous depolarization-repolarization cycles called slow waves Slow waves give the GIT the basic electrical rhythm ❖ Under all circumstances the pacemaker cells undergo spontaneous depolarization-repolarization cycles and every time this happens, if there is a stimulus, there is the potential for action potential generation and muscle contraction ❖ Slow waves are propagated through the circular and longitudinal muscle layers through gap junctions ❖ In the absence of any neural or hormonal input, the spontaneous slow waves do not result in any contraction; only when there is a stimulation, such as an excitatory hormone or neurotransmitter, further depolarization occurs and the membrane potential is increased enough that threshold is reached and an action potential is generated resulting in muscle contraction ∙ Basic Electrical Rhythm: ▪ Slow waves: o At rest, period fluctuations drift up and down due to regular variations in ion flux across the membrane o With an excitatory input, the slow waves are depolarized above threshold, and an action potential occurs leading to smooth muscle contraction ▪ The number of action potentials fired is proportional to the force of the contraction o The frequency of the contraction is dictated by the basic electrical rhythm and the force of contraction is mediated by neuronal and hormonal input Lecture 2 recording 8: Gastrointestinal Control ∙ Phases of Gastrointestinal Control (The next 2 slides are combined together): ▪ Neural and hormonal control of the gastrointestinal system is divisible into 3 phases: o It is classified based on where the stimuli initiates the reflex, or where the stimulus is perceived Each of these phases of control is named for the site at which the various stimuli initiate the reflex and not for the sites of effector activity Cephalic phase: head ❖ This phase is initiated through stimulation of receptors in the head by the sight, smell, taste and chewing of food and the emotional state ❖ These reflexes are predominantly regulated by parasympathetic fibers that activate neurons in the GIT nerve plexuses Gastric phase: stomach ❖ Receptors in the stomach are stimulated by distension, or stretching of the stomach, acidity, amino acids and peptides ❖ The responses to these stimuli are mediated by both short and long neural reflexes ✔Gastrin (hormone) represents the short reflex ✔Acetylcholine represents the long neural reflex Intestinal phase: intestine ❖ Receptors in the intestine are stimulated by distension, acidity, osmolarity and digestive products ❖ The intestinal phase is mediated by short and long neural reflexes and by the hormones secretin, CCK and GIP, which are all secreted by endocrine cells in the small intestine ∙ Control of Food Intake: ▪ Hypothalamus: o Important for maintaining homeostasis, command centre for neural and endocrine control coordination and for control of behavior o Contains a feeding centre in the lateral region Activation of this region increases hunger Animals with lesions in this region become anorectic and lose weight o Contains a satiety center in the ventromedial region Activation of this region makes you feel full Animals with lesions in this area overeat and become obese ∙ Factors that Influence Food Intake: ▪ Orexigenic factors: o Increase intake Neuropeptide Y → neuropeptide in the hypothalamus that stimulates hunger or appetite Ghrelin → synthesized and released from the endocrine cells in the stomach during fasting; when you start to starve. ghrelin is released into the blood and travels to the hypothalamus stimulating the release of neuropeptide Y in the hypothalamus feeding centre to try and increase  food intake ▪ Anorexigenic factors: o Decrease intake or cause a loss of appetite o Leptin → produced by adipose or fat tissue o Insulin → produced by the pancreas; stimulates a reduction in food intake o Peptide YY → released from the intestine to reduce food intake o Melanocortin → released directly from the hypothalamus acts to reduce intake of food ∙ Factors Affecting Food Intake: Leptin: ▪ Take in more energy/eat more than burned during exercise → deposit fat in tissues → increased secretion of leptin from the adipose tissue → plasma leptin concentrations increase → leptin travels to the hypothalamus through the blood altering the activity of the integrating center in the hypothalamus → leptin inhibits neuropeptide Y release (neuropeptide stimulates eating) → results in a decrease in appetite and reduced energy intake and an increase in the metabolic rate ∙ Factors Affecting Food Intake: ▪ Lack of leptin results in no appetite regulation, overeating and obesity → become leptin resistant and leptin does not make it to the hypothalamus Lecture 2 recording 9: Regulation of Water Intake ∙ Regulation of Water Intake (The next two slides are combined together): ▪ Hypothalamus: o Contains a thirst centre o Stimulated by: 1.Increased plasma osmolarity (most important factor under physiological conditions) Increased plasma osmolarity stimulates osmoreceptors (sensory receptors in the thirst centre of the hypothalamus) → becoming thirsty after eating a bag of chips ❖ Increased osmolarity of the blood stimulates thirst and the release of a hormone called vasopressin or antidiuretic hormone resulting in conservation of water at the kidney 2.Decreased plasma volume (requires a significant volume loss) Pathophysiological conditions (large blood loss or diarrhea and vomiting) which cause dehydration and reduce plasma volume ❖ A significant decrease in blood volume will reduce blood pressure and stimulate arterial baroreceptors which will act to  alter sympathetic and parasympathetic outflow to increase arterial pressure towards normal levels ❖ Intrarenal baroreceptors within the kidneys ✔Juxtaglomerular cells located in the walls of the afferent arterioles act as pressure receptors ✔When blood pressure in the kidneys decreases, baroreceptors in the kidney afferent arteries are stimulated and activate the renin-angiotensin system ✔Activation of the renin-angiotensin system produces angiotensin II, which has a direct effect on the hypothalamus to increase thirst; studied in experimental animals, but its occurrence in humans has not been proven 3.A dry mouth and throat stimulates thirst 4.Prevention of over-hydration Occurs so that a person stops drinking well before water is absorbed by the GIT and has had a chance to affect baroreceptors and osmoreceptors in the body Mediated by stimulus from the mouth, throat and the GIT ∙ Water Intake Summary: ▪ (Summary of this section) * question mark indicates that evidence comes from experimental models* Lecture 2 recording 10: Salivary Glands ∙ Salivary Glands: ▪ 3 main pairs of large glands: parotid, submandibular, sublingual * one of each gland on either side of the face * -​ Parotid: watery (serous) secretion -​ Submandibular: serous/mucous secretion -​ Sublingual: mucous secretion ​ Adult produces ~1500 mL of saliva/day  ∙ Composition of Saliva: ▪ Saliva: o Hypotonic, slightly alkaline o Made of: Water (97-99.5%) Electrolytes - potassium and bicarbonate (gives alkaline nature); poor in sodium and chloride (bicarbonate is useful for neutralizing acid from your food or acid from stomach reflux to prevent tooth decay) Digestive enzymes - amylase (breaks down starches into disaccharides and trisaccharides); lipase (breaks down fat into fatty acids) Glycoproteins, such as mucin (when combined with water mucin is called mucus) Antimicrobial factors Lysozyme - breaks down the bacterial cell wall Lactoferrin - chelates iron which prevents the multiplication of bacteria as iron is required for bacterial growth ∙ Functions of Saliva: ▪ Moistens and lubricates the food to make it easier to swallow ▪ Initiates digestion with digestive enzymes (amylase and lipase) ▪ Dissolves a small amount of food to allow it to diffuse to the taste buds ▪ Prevents microbial colonization due to the presence of antibacterial factors ▪ Aids in speech ▪ Buffers - contains bicarbonate which helps to neutralize acid from food or acid reflux Lecture 2 recording 11: Formation of Saliva and Regulation of Salivary Gland Function ∙ Anatomy of the Salivary Glands: ▪ Structure of a salivary gland or a salivary duct: o Salivary glands are made up of many microscopic ducts that branch out from grossly visible ducts o Composed of 3 different cell types: acinar cells, ductal cells, myoepithelial cells (Myo = “of muscle”) Acinar cells → secrete the initial saliva Ductal cells → create the alkaline and hypotonic nature of saliva Myoepithelial cells → have characteristics of both smooth muscle (can contract) and epithelial cells o Saliva moves from the acinus to the striated duct; myoepithelial cells contract to constrict the acinus end of the duct and move the components of the saliva towards the striated duct ∙ Formation of Saliva: ▪ Tight junctions: O Acinar cells have tight junctions between them which are leaky and allow the passage of water and small ions through them O Ductal cells have tight junctions which do not allow the passage of water through ▪ Saliva is hypotonic and alkaline: o All of the components of saliva are pumped into, or passed into, the lumen of the acinus o The primary secretion from the acinar cells is not yet alkaline or hypotonic; it is isotonic (has a similar osmolarity to the blood) The primary secretion will contain sodium, potassium, chloride, bicarbonate and water (which are all in the blood vessel) Enzymes, as well as mucous, are produced within the acinar cells and added to the saliva through exocytosis Acinar cells have very leaky tight junctions; electrolytes in the primary secretion (bicarbonate, chloride and potassium) are actively secreted into the saliva and sodium and water can follow between the cells into the saliva through the leaky tight junctions ❖ Movement of substances between cells = paracellular transport (sodium and water) ❖ Primary secretion is isotonic because there is no limitation to the passage of sodium and water through the leaky tight junctions Myoepithelial cells contract to push the saliva into the region where there are ductal cells ❖ Ductal cells modify the saliva to form the hypotonic and alkaline saliva ✔Sodium and chloride are actively taken up into the cells from the saliva and there is a net gain of potassium and bicarbonate; saliva is hypotonic due to loss of sodium and chloride ♦ Bicarbonate makes the saliva basic or alkaline  ∙ Formation of Saliva: A Summary: (This is a summary of the previous slides) ▪ Acinar cells → secrete the initial saliva o Water, electrolytes, and proteins (Enzymes and mucous) Proteins are released by exocytosis Cl-, HCO3- and K+ are actively secreted Na+ and H2O follow paracellularly via (Leaky) tight junctions ▪ Initial secretion is isotonic (Ionic composition comparable to plasma) due to leakiness of acinar cell layer ▪ Myoepithelial cells contract and expel formed saliva from acinus into the duct ▪ Ductal cells → modify the initial saliva to a hypotonic, alkaline state o Net loss of Na+ and Cl- (Active reabsorption) o Addition of K+ and HCO3-(Active secretion); to a lesser extent o Duct cells are tightly joined and impermeable to H2O ∙ Regulation of Salivary Gland Function: ▪ Regulation of saliva production: o No hormonal regulation o Regulated by parasympathetic and sympathetic pathways -​ Basal level of saliva production ~0.5 mL/min -​ After stimulation can increase 10-fold -​ No hormonal regulation (unusual; only GIT component) Both stimulate salivary secretion ❖ Parasympathetic stimulation: ✔ Dominant regulatory pathway ✔ Increases blood flow to the salivary glands resulting in increased secretion of saliva; blood flow provides the metabolic and fluid requirements to sustain high rates of secretion ✔Important for protein secretion from acinar cells, ✔Stimulates myoepithelial cells to contract to increase flow of saliva ∙ Regulation of Salivary Gland Function: ▪ Parasympathetic pathways: o Stimulated by the smell and taste of food, by pressure receptors in the mouth and during situations of nausea o Can be inhibited and reduce salivary production by tiredness or fatigue, during sleep, fear, dehydration (talking a lot inhibits the parasympathetic pathway which reduced saliva production) o Some drugs have a dry mouth side effect ( psychiatric drugs have anticholinergic effects and reduce parasympathetic stimulation of the salivary glands)  ▪ Sympathetic pathways: o Stimulatory but is minor o Increases saliva flow o Increase protein secretion from the acinar cells and stimulate the myoepithelial cells to contract to increase flow Lecture 3 recording 12: Role of Saliva in Digestion ∙ Role of Saliva in Digestion: ▪ Amylase: o Found in saliva o An enzyme that can breakdown starches o Also called ptyalin o Inhibited by the acidic pH in the stomach once swallowed o Greater than 95% of carbohydrates consumed are digested in the small intestine by pancreatic amylase Role of saliva in digestion is very small -​ Chewing on soda crackers for 2-3 minutes it will start to taste sweet because the starches are breaking down into sugars ∙ Plant starch is made up of glucose polymers including amylose and amylopectin ▪ - Polymer → a large molecule made up of many repeated subunits o Amylose → a straight chain of glucose molecules with alpha-1,4 linkages o Amylopectin → chain of glucose molecules with alpha-1, 4 linkages as well as alpha-1,6 linkages o Amylase → can only cleave the internal alpha-1, 4 linkages o Amylose → breakdown leads to the formation of maltose (disaccharide) and maltotriose (trisaccharide) o Amylopectin → breakdown leads to the formation of maltose, maltotriose and alpha-limit dextrin Amylase can only cleave the alpha-1,4 linkages; it cannot cleave the alpha-1,6 six linkages so it generates these branched glucose molecules in alpha-limit dextrin. It cannot cleave off a single glucose molecule ∙ Role of Saliva in Digestion: ▪ Lingual lipase: o Found in saliva  o Stable in acid - can remain active in the stomach (unlike amylase) ▪ Amylase and lingual lipase: o May be more important during pathological conditions where there is reduced pancreatic activity Pancreatic secretions include digestive enzymes -​ Pathological conditions (ie. Pancreatic insufficiency) o Important for neonates as they tend to have immature digestive systems ∙ Salivary Pathophysiology (Xerostomia “dry mouth”): ▪ Conditions where salivary secretion is impaired: o Congenital o Sjögrens syndrome - autoimmune disease; the immune system destroys the salivary glands o Side effects of drugs - antidepressants, psychotropic, antihypertensives, anti cancer drugs → cause extremely dry mouth o Radiation treatment → damage of salivary glands ▪ Xerostomia = dry mouth ∙ Salivary Pathophysiology (Xerostomia “dry mouth”): ▪ Consequences impairment to salivary secretion: o Dry mouth o Decreased oral pH Tooth decay ​ Esophageal erosions as there is no saliva to neutralize the stomach acid that is coming up into the esophagus o Difficulty in lubricating and swallowing food ▪ Treatment: o Frequent sips of water and fluoride treatment to combat the microbial populations which flourish in the absence of saliva Lecture 3 recording 13: Swallowing and the Esophagus ∙ Swallowing: ▪ Swallowing: o A series of reflexes (complex) o Initiated by pressure receptors in the wall of the pharynx Pharynx → the passage at the back of your throat that is common to air and food Receptors are stimulated by food or liquid entering the pharynx and send signals to the swallowing centre in the brainstem which signals muscles in the pharynx, the esophagus and the respiratory muscles ∙ Swallowing: (You do not need to memorize the function of the pharynx, larynx, glottis, epiglottis…they are given to help understand the process of swallowing)  ▪ Pharynx → the passage at the back of your throat that is common to air and food ▪ Larynx → air passage between the pharynx and the trachea; voice box as it contains the vocal cords ▪ Glottis → area in the larynx around the vocal cords, where the air passes through the vocal cords ▪ Epiglottis → flap of cartilage that closes off the trachea when swallowing so food cannot enter the lungs ▪ Chew food → tongue pushes it to the back of throat→ soft palette elevates to stop food from entering nose → impulses from the swallowing centre inhibit respiration, raise the larynx and close the glottis → epiglottis covers the trachea to prevent fluid or liquid from entering the trachea → food descends into the esophagus ∙ Esophagus: ▪ Esophagus: o A tube containing skeletal muscle in the top 1/3 and smooth muscle in the lower 2/3 ○​ Food passes very rapidly o No absorption in the esophagus o Mucus is secreted to lubricate and aid in the passage of the food. ○​ Exposed to rough/abrasive epithelium to protect → has specialized epithelium to protect o Stratified squamous epithelium (20-30 cells thick) Layers of flattened cells, or stratified cells ❖ Stratified = in layers (compare to squamous = flattened ❖ Protect the underlying regions of the esophagus from rough food entering ∙ Esophagus: ▪ Upper esophageal sphincter just below the pharynx o Ring of skeletal muscle ▪ Lower esophageal sphincter located where the esophagus joins the stomach o Ring of smooth muscle ▪ Both of sphincters are closed except when swallowing, vomiting or burping  ∙ Esophageal Phase of Swallowing: ▪ Upper esophageal sphincter relaxes to allow the food to pass through → sphincter closes and glottis opens to breathe again → peristaltic waves move the food bolus down the esophagus towards the stomach (~ 5 - 9 seconds from top to stomach) → lower sphincter at the stomach opens and allows food to pass through → sphincter closes ▪ Main force for this swallowing phase is peristalsis o Gravity not necessary for this phase of swallowing (gravity only assists, not required in space) ∙ Heart Burn: ▪ Lower esophageal sphincter prevents gastric contents from reaching the esophagus o Aided by the equal pressure of the lower esophagus and the stomach (no pressure gradient forcing the gastric contents out) ▪ When small amounts of acid get into the esophagus: o Stimulation of peristalsis to push the acid back into the stomach o Increased salivary secretion o Aids with neutralization of the acid with saliva and clearance of the acid out of the esophagus ▪ Heartburn: o Lower esophageal sphincter does not close properly o A big meal o During pregnancy Lecture 3 recording 14: The Stomach ∙ The Stomach: ▪ Muscular organ ▪ A sac located between the esophagus and the small intestine ▪ Functions: o Storage of food o Mechanical breakdown of food (breaking food into smaller pieces) o Chemical breakdown of food Secretes pepsinogen ❖ Cleaved to form an enzyme called pepsin ✔Pepsin is important for initiating protein digestion Secretes hydrochloric acid (HCl) ❖ Dissolves food and partially digests macromolecules in food o These different steps reduce the food to fragments of proteins and polysaccharides, droplets of fat, salt and water, which is referred to as chime ▪ HCl also results in the “partial” sterilization of food (attempt at sterilization, some bacteria - probiotics can survive and end up in LI which is helpful in building gut microbia) ​ Bug → overloaded, stomach can only kill so much ∙ More Stomach Functions:  ▪ Functions: o Controls the rate at which food enters the small intestine (powerhouse of digestion) o Secretes intrinsic factor A glycoprotein important for the absorption of Vitamin B12 in the ileum Vitamin B12 is required for normal red blood cell formation Fail to absorb Vitamin B12 can result in pernicious anemia and red blood cell deficiency ▪ Very little absorption occurs across the stomach - the stomach is not an absorption phase o Alcohol can be absorbed across the stomach and a small amount of water ∙ Stomach Components: ▪ Anatomy of the stomach: o Fundus and body: Upper part of stomach Both have thin layer of smooth muscle Mucus, pepsinogen and hydrochloric acid are secreted -​ Function similarly and similar anatomy o Antrum: Lower region of the stomach Thicker smooth muscle layer Important for physically breaking down, mixing and grinding food Mucus, pepsinogen and gastrin are secreted ▪ Pyloric sphincter → controls emptying of the stomach -​ Duodenum is the first portion of the small intestine ∙ Secretions of the Stomach: ▪ Exocrine → a chemical messenger secreted into ducts and then onto an epithelial surface without passing into the blood o Endocrine requires passage into the blood o Major exocrine secretions of the stomach include mucus, hydrochloric acid and pepsinogen: Mucus → protects the stomach epithelium from acid and digestive enzymes, predominantly pepsin ❖ Helps to avoid self-digestion HCl → important for the hydrolysis (breakdown) of proteins into their component amino acids, dissolving food, digesting macromolecules and sterilization of food Pepsinogen → precursor to the enzyme pepsin which is important for the digestion of proteins ∙ Secretions of the Stomach: ▪ Minor secretions of the stomach:  o Intrinsic factor for Vitamin B12 absorption o Gastrin (endocrine) A hormone important for stimulating HCl production and increasing stomach motility o Histamine (paracrine - can be considered exocrine) Stimulates HCl production o Somatostatin (Paracrine) Inhibits HCl production Lecture 3 recording 15: Cell Types of the Stomach ∙ Generalized Gastric Gland: ∙ Generalized gastric gland → it is called generalized because some of these cell types are not found in all regions of the stomach ▪ Mucous cell o At luminal end of gland o Produce mucus to protect the stomach lining from cell digestion ▪ Parietal cell o Secretes intrinsic factor and hydrochloric acid (HCl) o Found mostly in the body and the fundus of the stomach (not found in the antrum) ▪ (Remainder of cells (chief cell, enteroendocrine cell, ECL cell, D cell) will look at more detail in next slides) ∙ Cell Types and their Functions: ▪ Chief cell o Found in gastric glands in all regions of the stomach o Secretes pepsinogen Pepsinogen is an inactive precursor to pepsin ❖ Zymogen is a precursor for a protein that is not active and some type of chemical reaction needs to occur to make it active ❖ Pepsinogen is cleaved by stomach acid to pepsin  ❖ Pepsin accelerates protein digestion ▪ Enteroendocrine cell o Found in gastric glands in the antrum o Also known as G cells o Secretes gastrin (hormone) Stimulates HCl production by the parietal cell Stimulates GI motility ∙ Cell Types and their Functions: ▪ Enterochromaffin-like cell (ECL cell) o Found in gastric glands in all regions of the stomach (More in antrum) o Secretes histamine Histamine stimulates HCl production ▪ D-cell o Found in gastric glands in all regions, but more are found in the antrum o Secretes somatostatin Regulator that negatively regulates HCl production (inhibits) ∙ Parietal Cell: ▪ Found in gastric glands in the fundus and body regions of the stomach ▪ Also called oxyntic cell ▪ Secretes HCl and intrinsic factor ▪ Modified surface with canaliculi o Canaliculi increase the surface area of the cells to maximize the secretion of the acid and intrinsic factor into the lumen of the stomach o An inactive parietal cell has much less defined, or smaller, canaliculi o As the parietal cell is activated, the canaliculi become more defined Movement of membrane to the canaliculi, distending them and greatly enlarging them, and insertion of proton pumps ▪ Many mitochondria to produce ATP required for active acid secretion Lecture 3 recording 16: Acidification of the Stomach Lumen and Pepsinogen Release ∙ Acidification of the Stomach Lumen: ▪ Multiple transporters and channels acidify the stomach lumen while maintaining a neutral pH in the cell -​ Stomach secretes ~2L of 0.1 M H+Cl-/day -​ Lumen pH 1 versus cytosol pH 7 ∙ Acidification of the Stomach Lumen: ▪ Parietal cell o Apical surface faces the stomach lumen o Na+/K+ ATPase Pumps 3 Na+ out of the cell and pumps 2 K+into the cell for every molecule of ATP hydrolyzed Establishes electrochemical gradients with a high concentration of K+ inside the cell and a low concentration of Na+inside the cell + + o H /K ATPase: Apical/luminal membrane of the parietal cell Pumps out a proton (acid) from the parietal cell into the stomach lumen -​ Primary active transport pathway (ATP is hydrolyzed) → electroneutral, active transport as ions are moved up concentration gradient As acid is leaving the parietal cell, the cell will become more basic ❖ Mechanisms prevent the cytosolic pH of the parietal cell from becoming too basic o Carbonic anhydrase: Parietal cell gets rid of base by removing bicarbonate (HCO3 = bicarbonate, a base) Catalyzes the formation of H2CO3 (carbonic acid) from H2O and CO2 (CO2 is produced during metabolism) H2CO3 dissociates into H+ (For secretion into lumen) and HCO3- o Cl-/HCO3- exchanger: Excess HCO3 is pumped out in exchange for a chloride ion (Cl-) (secondary active transport) - -​ Critical step (in conjunction with CA) for maintenance of neutral cellular pH​ ​ o K+channels: As protons are pumped out through the apical primary active transporter, K+levels increase in the cytosol; K+channels in the apical surface open and allow K+ to leave the cell down its concentration gradient Diffusion through channels Loss of positive charge with every K+ion lost; must lose a negative charge to compensate through the loss of Cl + o Cl channels: Apical membrane Cl lost into lumen of stomach as diffuses through Cl channel Compensates for loss of positive charge through K+channels o HCl is secreted into the lumen of the stomach as a proton leaves the cell through the apical H+/K+ ATPase and Cl through the Cl channel ∙ Acidification of the Stomach Lumen (2 slides): (Summary of transporters/channels involved in acid secretion from parietal cell) ∙ Regulation of Acid Secretion: ▪ Regulatory components to acid secretion: o Chemical messengers regulate the insertion of the H+/K+ ATPase into the plasma membrane of the parietal cell → acid secretion 4 chemical messengers that regulate insertion: ❖ Gastrin: ✔ Gastric hormone released by G cells ✔ Stimulates insertion of the H+/K+ ATPase into the canalicular membrane that is becoming more defined, stimulating HCl secretion ❖ Acetylcholine: ✔ Neurotransmitter ✔Increased parasympathetic activity causes the release of acetylcholine ✔increases insertion of the H+/K+ ATPases into the cell membrane, stimulating acid production ❖ Histamine: ✔Paracrine released from the ECL-cells ✔ Stimulates insertion of the H+/K+ ATPase into the membrane, stimulating acid secretion ❖ Somatostatin: ✔ Paracrine released from D-cells ✔Inhibits the release of HCl, gastrin and histamine ❖ Histamine potentiates the effects of gastrin and acetylcholine to stimulate acid production → primary target to treat ulcers (H2 not H1 therefore no affected by congenital types like Hay fever)  ∙ Pepsinogen Secretion and Activation: ▪ Pepsinogen: o Secreted by chief cells as an inactive precursor o Release is stimulated by the enteric nervous system o Parallels the release of HCl (same effects exerted) o Cleaved and activated to pepsin by acidic pH in the lumen Release of an inactive precursor is a mechanism to prevent autodigestion Pepsin is irreversibly inactivated in SI -​ Pepsin is active only at a low pH: irreversible inactivated when it enters small intestine Lecture 4 recording 17: Regulation of Gastric Secretions ∙ The Phases of Gastric Secretion: ▪ Regulation of stomach secretion is divided into 3 phases: cephalic phase, gastric phase and intestinal phase o Cephalic phase → stimulation in the brain Sight, smell or taste of food provides excitatory stimulation mainly via the vagus nerve to the stomach Vagal nuclei in the brain cause the parasympathetic nerve to release acetylcholine at the parietal cell; results in the stimulation of acid production o Gastric phase → occurs when food reaches the stomach Major phase for regulating acid production Stimulatory phase mediated mainly via the release of gastrin Food in the stomach causes G cells to release gastrin into the blood Gastrin interacts with the parietal cell to increase acid production o Intestinal phase → occurs when food that has been partially broken down by the stomach enters the SI (duodenum)  Inhibitory phase Mainly inhibitory due to the presence of acid, fat, digestion products and hypertonic solutions in the duodenum Mediated by gastrointestinal hormones including secretin and CCK ❖ Secreted by small intestinal epithelial cells ❖ Enter the blood and have a negative influence on gastrin production ∙ Regulation of Gastric Secretion: Interaction Between Various Factors: ▪ 4 chemical messengers that regulate the insertion of the H+/K+ ATPase into the plasma membrane of the parietal cell: gastrin, ACh, histamine, somatostatin ▪ Parietal cell produces acid: o ACh, histamine and gastrin directly stimulate acid secretion → gastrin hormone is released into the blood where it can directly act on the cell o Somatostatin negatively regulates acid secretion ▪ Indirect effects on acid secretion from parietal cell: o ACh: Stimulates ECL cells to release histamine which stimulates the parietal cell Inhibits somatostatin production from the D cells to stimulate acid secretion Stimulate G cells to produce gastrin which stimulates acid secretion o Gastrin: Stimulates ECL cells to release histamine which stimulates the parietal cell ▪ Once acid secretion is occurring at a high rate: o ACh is released from the parasympathetic nerves As eating and acid production are occurring, the stimulation will be reduced o Acid production itself has a negative effect on gastrin release  H+released from the parietal cell inhibit gastrin release from G cells o Somatostatin: Somatostatin inhibition by ACh is reduced as ACh levels decrease Has a direct negative effect on the parietal cell and inhibits acid secretion from the parietal cell Can inhibit histamine release from the ECL cells Can inhibit gastrin release from the G cell ∙ Regulation of Gastric Secretion: Interaction Between Various Factors (2 slides): (Summary of the diagram) ​ Acetylcholine, gastrin, and histamine all directly increase acid secretion by parietal cell ​ Somatostatin inhibits acid secretion by parietal cell ​ Acetylcholine also increases acid secretion by the parietal cell by: ○​ Stimulating the release of gastrin from G cells (increasing stimulant) ○​ Stimulating the release of histamine from enterochromaffin-like cells (ECL) (increasing stimulant) ○​ Inhibiting somatostatin release from D-cells (inhibiting inhibitor) ​ Gastrin can also increase acid secretion by the parietal cell by stimulating histamine release (increasing stimulant) ​ Once acid secretion is at a high rate: ○​ Parasympathetic input will be reduced (Cephalic phase) ○​ Negative feedback occurs for gastrin production (acid inhibits release) ○​ Somatostatin release increases due to: ​ Reduced parasympathetic inhibition of D cell ​ Direct stimulation of somatostatin release by acid ​ Somatostatin then: ​ Directly inhibits acid secretion from parietal cell ​ Inhibits histamine release from ECL cell ​ Inhibits gastrin release from G cell Lecture 4 recording 18: Gastric Motility ∙ Gastric Motility: ▪ Important for breaking down food -​ Empty stomach is small (50mL), diameter slightly larger than small intestine ▪ Huge capacity to stretch o After you consume of a meal, smooth muscle in the stomach relaxes, allowing the stomach to increase without increasing pressure o This relaxation is mediated by the parasympathetic nerves to the enteric nervous system ▪ Arriving food causes peristaltic wave: o Weak contractions in the body of the stomach o Antrum powerfully contracts to allow the mixing of the luminal contents and closes the pyloric sphincter Pyloric sphincter → sphincter between the antrum and the duodenum Closure of the sphincter results in a small amount of stomach contents reaching the duodenum, but most is retained and forced backwards towards the body of the stomach to allow more mixing to occur ∙ Gastric Motility: ▪ A peristaltic wave in the body of the stomach and a stronger force of contraction in the antrum will result in the pyloric sphincter closing o A small amount of chyme will enter the duodenum; the backwards flow of contents towards the body of the stomach allows mixing due to this muscle contraction ∙ Electrical Basis of Stomach Motility: ▪ Stomach has pacemaker cells in the smooth muscle layer: o Spontaneous slow waves of depolarization and repolarization Spontaneous slow waves are the basic electrical rhythm In the absence of neural or hormonal input, the basic electrical rhythm does not cause any contractions as depolarizations are too small ❖ The basic electrical rhythm allows the timing of contractions ▪ Excitatory hormones and neurotransmitters will act upon the smooth muscle to further depolarize the membrane, resulting in contraction o Amount of stimulus determines strength of the contraction o The frequency of the contraction is determined by the basic electrical rhythm (preset) Lecture 4 recording 19: Gastrointestinal Complications ∙ Vomiting: ▪ Cause of vomiting: o Psychogenic (sight, smells, etc) o Gastrointestinal disturbances (infections/distension/obstruction)  o Inner ear infections o Chemoreceptors in the brain and the gastrointestinal tract that can detect toxins (brain or GIT) o Pressure in the CNS ▪ All of the different stimuli feed into the vomiting centre located in the medulla oblongata ▪ Nausea, salivation (alkaline to protect teeth), breath held in mid-inspiration ▪ Glottis closes off trachea ▪ Lower esophageal sphincter and esophagus relax ▪ Diaphragm and abdominal muscles contract ▪ Reverse peristalsis moves upper intestinal contents into stomach (stomach contents out of body) ▪ Stomach contents move up through esophagus and out through mouth (Soft palate is raised), prevention of going through nose ∙ Vomiting: Beneficial and Negative Consequences: ▪ Benefits: o Remove harmful substances before they are taken into your body o Nausea and feeling bad associated with vomiting are a negative conditioning, so that if you experience these, they may prevent you from consuming the noxious substance again or for a little while ▪ Negative consequences: o Dehydration (water that is normally absorbed is lost) o Electrolyte imbalance o Metabolic alkalosis → a condition in which the pH of a tissue is elevated beyond the normal range, due to the loss of acid from your stomach o Acid erosion of tooth enamel (bulimia → tooth decay) ∙ Ulcers: ▪ Peptic ulcers: o Damage to or erosion of the GIT mucosa o Occurs in regions which are acidic such as the esophagus, the stomach or the duodenum ▪ What causes an ulcer? o Imbalance of aggressive factors (acid and pepsin) and protective factors (mucus and bicarbonate) o Most common cause of ulcers: infection from the bacterium Helicobacter pylori, which results in inflammation of the lining and irritation and eventually chronic inflammation and erosion o Non-bacterial factors: non-steroidal anti-inflammatory drugs which reduce prostaglandin production, smoking, excessive alcohol, gastrinomas (aspirin and ibuprofen→ inhibit prostaglandin production causing stomach erosion) -​ Stress, gastrinomas (tumors) ∙ Ulcers: ▪ Treatment for ulcers:  o Antibiotics to get rid of the H. pylori infection o H+/K+ pump inhibitors (reduce the amount of acid in stomach allowing the stomach lining to heal) o Histamine receptor antagonists o Prostaglandin-type drugs ∙ Ulcers: ▪ An ulcer can occur in the esophagus, stomach, duodenum -​ Eroding of wall of stomach ∙ Gastric Bypass Surgery: ▪ Is the stomach essential for life? o No, it is not essential, but problems can occur without it o What problem would occur if you had a very small stomach or a stomach removed? Stomach is important for producing intrinsic factor ❖ Intrinsic factor is secreted by the stomach lining and aids in vitamin B12 absorption ❖ People that have lost a lot of their stomach must have Vitamin B12 injections so they do not become anemic Stomach is useful for reducing the amount of bacteria that enter your system- HCl the stomach secretes sterilizes food Stomach regulates how much food enters the SI → benefit to someone who is obese and has had gastric bypass surgery -​ SI will not be as efficient at digesting because it is going to receive a larger amount of food from the stomach rather than the stomach regulating the entry of food into SI -​ Large intestine does not receive a lot of nutrients (SI does) -​ Huge microbial population will digest the nutrients Lecture 4 recording 20: The Pancreas ∙ The Pancreas: ▪ An exocrine and endocrine gland ▪ Exocrine pancreas: o Important for digestion o Produces secretions that go into the GIT o Source of the majority of enzymes required for digestion of carbohydrates,  proteins, fats and nucleic acids -​ Enzymes are produced in excess by the pancreas o Problems with digestion and absorption will not be noticed until the organ function falls below 10% – will not notice any problems until 90% of pancreas is affected by tumor o Secretes bicarbonate into the duodenum for neutralization of stomach acid Digestive enzymes produced by the pancreas are completely inactive under acidic pH The stomach acid must be neutralized by bicarbonate for these enzymes to be functional ▪ Endocrine pancreas: o Not involved in digestion but it is important for producing hormones that regulate the entire body (eg. Insulin) ∙ Functional Anatomy of the Pancreas: ▪ Main pancreatic duct drains the exocrine secretions into the SI o Main pancreatic duct joins common bile duct from the liver just before entering duodenum ▪ Sphincter of Oddi (hepatopancreatic sphincter) → sphincter common to the bile duct and to the main pancreatic duct o Regulates the release of both liver and pancreatic contents into the SI ▪ Exocrine pancreas → secrete substances into ducts that drain onto the epithelial surface, or the apical surface, and converge into the pancreatic duct o Secretions ultimately enter the SI ▪ Endocrine pancreas → is a ductless gland o Secretion occurs across the epithelial basolateral surface for diffusion into blood o Endocrine cells surround capillaries o Eg. Insulin Pancreatic islets (Islets of Langerhans) produce the hormone insulin ∙ Pancreatic Ducts: -​ Very similar to salivary gland ▪ Acinar cells: o Pancreatic ducts have acinar cells at the end portion of the duct o Produce and secrete digestive enzymes Exocytosis of vesicles within the acinar cells ▪ Ductal cells: o Secrete bicarbonate for neutralization of acid o Water is also secreted  ∙ Pancreatic Juices: ▪ Pancreatic juices: o Isotonic and alkaline, 1-2L/day Alkaline because of bicarbonate (HCO3-) o Electrolytes: High in HCO3- and low in Cl- Na+ and K+concentrations are the same as in plasma (this is why pancreatic juice is isotonic; iso = same) HCO3- and water are secreted by ductal cells HCO3- neutralizes gastric acid in duodenum o Contain digestive enzymes: Essential for the digestion of proteins, carbohydrates, fats and nucleic acids Secreted by acinar cells Proteolytic enzymes (break down proteins into amino acids) are stored and secreted in inactive forms ❖ Activated in the duodenum Lecture 4 recording 21: Production of HC03-in the Pancreas and Tides ∙ Production of HCO3- by Pancreatic Duct Cells: ▪ How do the ductal cells of the pancreas produce the alkaline, watery solution? o Cl channel: Apical (luminal) surface of the ductal epithelium CFTR ❖ Cl channel ❖ Cystic fibrosis transmembrane conductance regulator ❖ Allows Cl to diffuse out of the duct cell into the lumen o Cl that has diffused out of the channel is then exchanged for HCO3-: In the pancreas HCO3-(base) leaves the cell Carbonic anhydrase catalyzes the formation of carbonic acid (H2CO3) from CO2 and water ❖ H2CO3dissociates into HCO3- and H+. and this HCO3-is the base that is moved into the duct lumen o Neutral pH of cytosol is maintained by exchange of H+(Exported from cell) for Na+(Imported) Na+/H+ exchanger ❖ Secondary active transport pathway where Na+ moving down its concentration gradient provides the energy to efflux H+from the cell ❖ Na+gradient is provided by the Na+/K+ ATPase o Cl gradient into the duct lumen draws Na+ and water paracellularly, or between the cells ∙ Ductular Cell Secretion of HCO3-: (Summary of previous slide) 1.​ Chloride channel (CFTR) opens a.​ Allows diffusion of Cl- into duct lumen 2.​ Cl- in lumen is exchanged for HCO3- in cell 3.​ H2O and Na+ follow paracellularly in response to electrochemical gradient across epithelium 4.​ Neutral pH of cytosol in maintained by exchange of H+ (exported from cell) for Na+ (imported) a.​ Secondary active transport dependent upon the electrochemical gradient generated by the Na+/K+ ATPase b.​ Resulting watery alkaline secretion neutralizes gastric acid and washed digestive enzymes through ∙ Alkaline and Acid Tide: ▪ After a meal: o Acid is being produced by the parietal cell and enters the lumen of the stomach o Base leaves the cell into the bloodstream as bicarbonate (HCO3-) o Whatever is moving into the blood is referred to as the tide In the stomach, a large amount of bicarbonate (alkaline) is pumped across the basolateral surface into the blood ❖ Alkaline tide  ∙ Alkaline and Acid Tide: After a big meal ▪ In the pancreas, the duct cells are producing base as bicarbonate, which is moving into the lumen of the pancreatic ducts ▪ Large amounts of acid are being pumped across the basolateral surface into the blood stream o Acid tide ∙ Alkaline and Acid Tide: ▪ In the stomach, acid is produced by the parietal cells and secreted into the stomach lumen, resulting in base moving into the blood ▪ In the pancreas base moves into the lumen while acid moves into the blood ▪ While the process is first initiated in the stomach, the two processes occur simultaneously o Eventually, HCO3- which is released into the blood from the stomach and the acid that is released into the blood from the pancreas meet up in the portal vein o Thesetwo separate processes will compensate for each other and maintain the acid-base balance in the bloodstream Lecture 5 recording 22: Digestive Function of the Pancreas ∙ Digestive Function of the Pancreas: ▪ Pancreas: o Source of the major enzymes required for digesting carbohydrates, proteins, fats and nucleic acids  Starve without pancreas because you cannot digest food or move nutrients around Proteases → enzymes that digest proteins into peptides and amino acids -​ Pepsin and trypsin are types of proteases Amylolytic enzymes → digest starches into sugars Lipases → digest triglycerides into free fatty acids and monoglycerides Nucleases → digest nucleic acids into free nucleotides Enzymes are synthesized and packaged into vesicles by pancreatic acinar cells ❖ Enzymes are packaged as proenzymes into zymogen granules that are stored at the apical pole of the acinar cell until appropriate stimuli causes exocytosis ❖ Zymogens = proenzymes or inactive precursor enzymes ∙ Secretion of Digestive Enzymes: ▪ Most pancreatic enzymes secreted as inactive forms o Activated in the duodenum Enterokinase: ❖ Enzyme ❖ Enterokinase is attached to the apical, or luminal, surface of the epithelial cells in the duodenum ❖ Cleaves a pro-protease called trypsinogen into the protease trypsin ✔Trypsinogen is an inactive precursor molecule ✔Trypsin activates other enzymes ∙ Prevention of Autodigestion Under Normal Conditions: ▪ Pancreas produces and stores proenzymes: o Proenzymes are not activated until they reach the SI ▪ Pancreas secretes a variety of trypsin inhibitors to prevent any premature activation of trypsin ▪ Trypsin can also degrade itself if it is activated prior to reaching the SI -​ Prevents autodigestion of pancreas ∙ The Major Proteases Secreted by the Pancreas: ▪ Enzymes which form a mixture of peptides and amino acids:  o Endopeptidases: Trypsinogen (inactive enzyme) → activated by enterokinase in the duodenum to trypsin ❖ Trypsin (active enzyme) important as it activates other enzymes Chymotrypsinogen → activated by trypsin to the active enzyme chymotrypsin Pro-elastase → activated by trypsin to the active enzyme elastase o Exopeptidase: Pro-carboxypeptidase A and B → activated by trypsin to the active enzyme carboxypeptidase A and B ∙ Amylolytic and Lipolytic Enzymes: ▪ Amylolytic enzymes: o Pancreatic amylase cleaves starches to sugars End product of this digestion is disaccharides and trisaccharides, maltose, maltotriose and alpha-limit dextrins ▪ Lipolytic enzymes: o Lipase → hydrolyzes triglycerides into free fatty acids and monoglycerides o Phospholipase A2 → hydrolyzes phospholipids into free fatty acids and lysophospholipids o Cholesterolesterase →hydrolyzes cholesterol-esters into free fatty acids and cholesterol ▪ Some enzymes are secreted as active enzymes while others are secreted as inactive forms Lecture 5 recording 23: More on Pancreatic Secretions ∙ Regulation of Pancreatic Juice Secretion: ▪ Pancreatic juice secretion: o Primarily mediated by food and acid entering the SI o Cells in the epithelial layer of the duodenum: S-cells → acid entering the duodenum from the stomach stimulates S cells to produce the hormone secretin  ❖ Secretin → hormone released into the blood and finds its way to the pancreatic duct cells where it stimulates the release of HCO3- I-cells → digested fats and protein are entering into the upper SI from the stomach stimulate I-cells to release the hormone cholecystokinin (CCK) ❖ CCK → released into the blood and acts on the acinar cells in the pancreatic duct to stimulate the zymogen granules to release the digestive enzymes ▪ Activity in parasympathetic nerves will also cause the release of digestive enzymes o When you are hungry and you smell food ∙ CCK As an Example: ▪ Fatty acids and amino acids in the SI trigger the secretion of CCK from cells in SI into the blood → I Cells ▪ CCK: o Stimulates the pancreas to increase the secretion of digestive enzymes o Stimulates the gallbladder to contract Release of bile acids for fat breakdown Sphincter of Oddi relaxes allowing secretions from the liver and pancreas to flow into the SI ▪ As the fats and amino acids are absorbed, the stimuli for CCK release is removed, as it is the fats and amino acids themselves in the SI that trigger CCK secretion o A negative feedback control system ∙ Secretin Regulation of Pancreatic HCO3-Secretion: ▪ Acid entering the duodenum from the stomach stimulates secretin secretion from cells in the SI into the blood (reduced pH trigger secretin secretion) o Circulating secretin stimulates: Pancreas (Duct cells) to increase HCO3-secretion Liver (Duct cells) to increase HCO3-secretion o The stomach acid is neutralized and the stimulation of secretin release is stopped A negative feedback control system ∙ Secretin and CCK Influence on the Stomach: ▪ Secretin and CCK both inhibit gastrin secretion o Results in reduced stomach motility (slows stomach emptying) and reduced acid secretion ∙ The Phases of Pancreatic Secretion: ▪ Cephalic phase → involves stimulation that is occurring in the brain o Sight, smell, and taste of food stimulate pancreatic secretion via the parasympathetic nerves (minor phase) ▪ Gastric → distension of the stomach will stimulate the pancreatic secretion via the parasympathetic nerves (minor phase) ▪ Intestinal phase → major regulatory phase of pancreatic secretion  o Acid from the stomach in the duodenum stimulates secretin release and digested fat and protein in the duodenum stimulate CCK release -​ Inhibitory phase ∙ Pancreas and Cystic Fibrosis: ▪ The Cl channel involved in HCO3-secretion in the pancreas is the channel that is mutated in the disease cystic fibrosis ▪ Cystic fibrosis: o A defective chloride channel is produced o Patients suffer from pancreatic insufficiency Produce all of the digestive enzymes HCO3- and water secretion is so minimal that these enzymes do not get flushed from the ducts and do not reach the intestines ❖ The retained proteolytic enzymes, which break down proteins, can result in pancreatic autodigestion ❖ The cystic ducts in the pancreas are fibrotic because of constant autodigestion and inflammation ❖ Patients must receive supplements of digestive enzymes and antacids to allow for adequate nutrition Lecture 5 recording 24: The Liver ∙ The Liver and Biliary System Components: ▪ Gall bladder → a small sac located underneath a lobule of the liver ▪ Bile ducts run from the liver and join to form the common hepatic duct, which then joins with the common bile duct ▪ Main pancreatic duct and the common bile duct join and release their contents into the duodenum o Sphincter of Oddi controls the release of contents into the SI ∙ Blood Flow in the Liver: ▪ Liver: o Receives blood by 2 distinct circulatory routes: the systemic circulation and the hepatic portal circulation Systemic supply = arterial blood ❖ Hepatic artery contribute