GI secretion ebook

GASTROINTESTINAL PHYSIOLOGY SECRETION Feb. 10 & 11, 2014 The amount of material handled by the intestine is considerably greater than the volume of the ingested food and drink. Secretion occurs all along the GI tract. By volume, water is the largest contributor. Water is secreted in the upper portion of the tract and reabsorbed in the lower portion. Another major contributor is mucus, which serves a protective function for the epithelial surface all along the tract. Most of the mucus and some neutralizing fluids are secreted by cells or glands in the epithelial surface itself. Mixtures of digestive enzymes, basic fluids, inorganic and organic substances, and water are secreted at specific sites in the tract by the accessory glands and organs. All the major secretions are mixtures of substances from different cells or glands. A small portion of these secretions is destined for excretion. In general, enzymes are secreted via 2 nd messenger activated fusion of granules with the luminal membrane. Non-granule secretion also occurs, but the mechanism is not well understood. Secretion of most electrolyte solutions is initiated by active transport, primary or secondary, of one ion through the basolateral membrane and diffusion through the apical membrane or by active transport of one ion through the apical membrane. Other ions and water passively move into the lumen to maintain electroneutrality and iso-osmolarity. The composition of this primary fluid may be altered by active transport of specific ions along the duct leading to the tract. A. SALIVARY SECRETIONS - The composition of saliva varies: it is always hypotonic and contains a higher concentration of K + than plasma. The volume varies depending on the stimuli and the number of secreting acinar cells. In general, volume decreases with age. In young adults, approximately 1 - 1.5 L are secreted daily (most at meals, resting secretory rate is 25 l/min). 1. Functions: a. Lubricate the bolus for easy swallowing. b. Dissolve substances for tasting. Figure 1. Overall fluid balance in the human gastrointestinal tract. Approximately 2 L of water is ingested each day, and 7 L of various secretions enters the GI tract. Of this total of 9 L, about 8.5 L is absorbed in the small intestine. Approximately 500 ml is passed on to the colon, which normally absorbs 80% to 90% of the water presented to it (Berne & Levy, Physiology, 4 th Ed, p.655,Fig 39-9, St. Louis, 1998, Mosby). GI-Secretion-2014_HF 2 c. Protect the oral cavity, teeth and esophagus (alkaline pH, lysozyme, lactoferrin and secretory Ig). d. Facilitate speech and oral comfort. e. Initiate carbohydrate digestion and provide lingual lipase for subsequent fat digestion. 2. Characteristics of fluid component o saliva a. Concentrations of electrolytes vary with the rate of secretion, but it is always hypotonic b. Is always lower in sodium and chloride than serum c. Is always higher in potassium than serum d. Is rich in bicarbonate most of the time. 3. Two-stage secretion model - Primary secretions by the acinar cells is followed by modifications of the luminal fluid by the ductular cells. Secretory rate (ml/minute) Io n c o n ce n tr at io n ( m E q /L ) o r to ta l o sm o la ri ty ( m O sm /L ) Na+: 143.3 Cl-: 100.9 HCO3 -: 27.5 K+: 4.1 Plasma Total: 300 160 140 120 100 80 60 40 20 0 0 1 2 3 4 Na+ Cl- HCO3 - K+ Saliva 320 300 280 260 240 220 200 180 Total Figure 2. Composition of the parotid saliva as a function of the secretion rate. Note the ion concentration differences between the salivary and plasma. Secretory rate (ml/minute) Io n c o n ce n tr at io n ( m E q /L ) o r to ta l o sm o la ri ty ( m O sm /L ) Na+: 143.3 Cl-: 100.9 HCO3 -: 27.5 K+: 4.1 Plasma Total: 300 160 140 120 100 80 60 40 20 0 0 1 2 3 4 Na+ Cl- HCO3 - K+ Saliva 320 300 280 260 240 220 200 180 Total Secretory rate (ml/minute) Io n c o n ce n tr at io n ( m E q /L ) o r to ta l o sm o la ri ty ( m O sm /L ) Na+: 143.3 Cl-: 100.9 HCO3 -: 27.5 K+: 4.1 Plasma Total: 300 160 140 120 100 80 60 40 20 0 0 1 2 3 4 Na+ Cl- HCO3 - K+ Saliva 320 300 280 260 240 220 200 180 Total Figure 2. Composition of the parotid saliva as a function of the secretion rate. Note the ion concentration differences between the salivary and plasma. Figure 4. Mechanisms for ion and water movements in acinar and duct cells of the salivary glands Figure 3. Movements of ions and water in the acinus and duct of the salivon. Na+ Cl- K+ HCO3 - Cl- K+ HCO3 - Na+ H2O H2O 12 3 3 H2O 1 2 3 H2O + CO2 HCO3 - + H+ Na+ HCO3 - Cl- Cl- Na+ Na+ HCO3 - H2O + CO2 HCO3 - + H- Cl- Cl- K+ K+ K+ H+ Na+ Na+ Na+ Cl- K+~ K+ K+ K+ ~ Acinus Duct cell Lumen Serosal side 4 5 Channels 2,3 are stimulated by Ca2+ Figure 4. Mechanisms for ion and water movements in acinar and duct cells of the salivary glands Figure 3. Movements of ions and water in the acinus and duct of the salivon. Na+ Cl- K+ HCO3 - Cl- K+ HCO3 - Na+ H2O H2O 12 3 3 H2O 1 2 3 H2O + CO2 HCO3 - + H+ Na+ HCO3 - Cl- Cl- Na+ Na+ HCO3 - H2O + CO2 HCO3 - + H- Cl- Cl- K+ K+ K+ H+ Na+ Na+ Na+ Cl- K+~ K+ K+ K+ ~~ Acinus Duct cell Lumen Serosal side 4 5 Channels 2,3 are stimulated by Ca2+ GI-Secretion-2014_HF 3 a. Primary secretion is an isotonic ultrafiltrate of plasma that is secreted by the acinar cells. These cells also secrete organic material. b. Ductule epithelial cells modify the primary secretion fluid by reabsorbing Na + and C1 - and secreting K + and HCO3 - . There is a greater amount of Na + and C1 - reabsorbed than K + and HCO3 - secreted. This reduction in the number of ions in the tubular fluid plus the impermeability of ducts leads to a hypotonic saliva. c. Metabolic hyperemia and vasodilation increase during active secretion. Both provide the required plasma to support the secretory process. Metabolic hyperemia is due to a local increase in the concentrations of metabolic end products. Vasodilation is mediated by vasoactive intestinal polypeptide (VIP) from non-cholinergic parasympathetic fibers and by bradykinin. 4. Neural control (little hormonal effect) B. SPLANCHNIC CIRCULATION (for your reference, not to be covered in the lecture). The splanchnic circulation supplies blood to most of the tract. Under resting conditions, 25% - 33% of the cardiac output goes to this area. Within the hollow organs the majority of the blood is directed to the mucosa. Figure 5. Control of saliva secretion Figure 6. Schematic presentation of the splanchnic circulation Conditioned reflex Smell Taste Pressure Nausea Salivary nucleus of the medulla Parasympathetics, CN IX, X and FN VII Sympathetics T1 - T3 Fatigue Lack of sleep Fear Dehydration Superior Cervical Ganglion NE Fluid, enzymes, mucus Ach, VIP Vasodilation acinar cell metabolism channel activation glandular growth myoepithelial cell contraction GI-Secretion-2014_HF 4 Increasing motility, secretion, and absorption causes a rapid increase in the local blood flow and may lead to a redistribution of blood within the gut wall. For example, upon stimulating gastric secretion, the blood flow increases in parallel with secretion. Reducing blood flow, such as occurs with strong sympathetic activity, limits gastric secretion. C. GASTRIC SECRETIONS - The composition of gastric juice depends on the number and type of secreting cells, and their secretory rates. It is higher in K + than plasma and usually much higher in H + . Approximately 2 L are secreted daily (most at meals). Continued loss of saliva and gastric juice (vomiting or aspiration) can lead to water and electrolyte losses that result in dehydration, metabolic alkalosis and severe electrolyte imbalances. Replacement requires water, H + , K + , Na + and Cl - . 1. Functions a. Liquefy the bolus and form chyme. b. Initiate protein (and fat) digestion. c. Provide Intrinsic Factor for vitamin B12 absorption. d. Stabilize an absorbable form of some minerals (Ca +2 , Fe +2 ). e. Maintain a relatively sterile environment in the small intestine. f. Protect the gastric mucosa from acid and other damage. 2. Sources a. Surface columnar mucous and epithelial cells secrete mucus and an alkaline fluid (paracellular fluid flux also occurs). b. Cardiac glands secrete mucous. c. Fundic glands (straight): i Chief cells in the body secrete pepsinogens (peptic). ii Parietal cells secrete HCl & IF (oxyntic). iii Neck chief cells secrete mucus & are the progenitors of luminal cells. d. Pyloric glands (branched): i Mucous cells secrete mucus & pepsinogens. ii G cells - release gastrin (to blood not lumen). 3. Two component hypothesis - Two different secretions from different cells with different controls. Figure Factors that regulate splanchnic blood flow General Hemodynamics Cardiac output Arterial pressure Blood volume Fluidity of blood Autonomic Nerves Sympathetics Parasympathetics Intrinsic enterics Local Vascular Properties Autoregulation Escape Redistribution O 2 countercurrent exchange Bloodborne Substances Catecholamines Angiotensin II Vasopressin GI peptides Local Metabolism Decreased PO 2 Dilator metabolites - adenosine - prostaglandins - amines - peptides GI Blood Flow Figure 7. Factors that regulate splanchnic blood flow General Hemodynamics Cardiac output Arterial pressure Blood volume Fluidity of blood Autonomic Nerves Sympathetics Parasympathetics Intrinsic enterics Local Vascular Properties Autoregulation Escape Redistribution O 2 countercurrent exchange Bloodborne Substances Catecholamines Angiotensin II Vasopressin GI peptides Local Metabolism Decreased PO 2 Dilator metabolites - adenosine - prostaglandins - amines - peptides GI Blood Flow GI-Secretion-2014_HF 5 a. Oxyntic component (isotonic HCl) i In the resting oxyntic cell and the surface epithelial cell, Cl - is transported into the lumen. This movement is by HCO3 - /Cl - exchangers in the basolateral membrane and Cl - channels in the luminal membrane. This is a major contributor to the negative electrical potential (-70 to - 80 mV) between the stomach lumen and blood (lumen negative). ii Upon stimulation, oxyntic cells undergo structural changes and actively secrete isotonic HCl into the lumen and HCO3 - into the interstitial area. The Figure 10. Diagrammatic representations of electron micrographs of human gastric parietal (oxyntic) cells. In a resting cell (left) there are numerous tubulovesicles that are rich in the H+/K+-ATPase. In response to stimulation (right) the tubulovesicles fuse with canaliculi leading to the gastric lumen, enableing the H+/K+-ATPase to secrete H+. iii Proposed secretion mechanism. RestingResting SecretingSecretingRestingResting SecretingSecreting Potential Difference (PD):-70 ~ -80 mV -30 ~ -50 mV ATP Metabolism CO2 + H2O HCO3 -+ H+ Na+ Cl- K+ Cl- H+ATP Cl - Secreting Ca2+, cAMP ATP Metabolism CO2 + H2O HCO3 -+ H+ Na+ Cl- K+ Cl- Cl - Resting H+ATP Stimulus Lumen of gland Lumen of gland Potential Difference (PD):-70 ~ -80 mV -30 ~ -50 mV ATP Metabolism CO2 + H2O HCO3 -+ H+ Na+ Cl- K+ Cl- H+ATP Cl - Secreting Ca2+, cAMP ATP Metabolism CO2 + H2O HCO3 -+ H+ Na+ Cl- K+ Cl- Cl - Resting H+ATP Stimulus Lumen of gland Lumen of gland Figure 8. Gastric Juice is a mixture of oxyntic cell and non - oxyntic secretions Figure 9. The oxyntic component predominates at high rates of secretions Figure Gastric Juice is a mixture of oxyntic - oxyntic secretions Figure . The oxyntic component predominates at high rates of secretions GI-Secretion-2014_HF 6 Figure 11. Postulated model of the major ionic transport processes involved in the secretion of H+ and Cl- by parietal cells. Cl- enters the cell across the basolateral membrane against an electrochemical gradient. Cl- entry is powered by the downhill efflux of HCO3 -. H+ is pumped into the secretory canaliculus by the H+/K+-ATPase. Cl- enters the canalicular fluid by an electrogenic ion channel. Resting cells secrete few H+ ions because of low metabolic activity and the largely absence of H+/K+-ATPase in the canalicular membranes, as illustrated in Fig. 14. Stimulated cells generate more H+, which are readily secreted by the H+/K+-ATPase in the canalicular membranes. The Cl- conductance of the luminal membrane and the conductance of basolateral K+ channels increase in response to elevated cytosolic Ca2+ and cAMP concentrations. The K+ efflux increases the electronegativity of the cytosol and increases the driving force for efflux of Cl- across the apical membrane. iv Control of acid secretion  At the whole body level, stimulation is normally associated with meals. Inhibition is associated with loss of stimuli + specific inhibition of secretion.  At the cellular level (isolated cell work) 160 140 120 100 80 60 40 20 0 Secretory rate (ml/minute) C o n c e n tr a ti o n ( m E q v /L ) [Na+] [Cl-] 0 31 2 [K+] [H+] Figure 12. Relationship of the electrolyte concentrations in gastric juice to the rate of gastric secretion. 160 140 120 100 80 60 40 20 0 Secretory rate (ml/minute) C o n c e n tr a ti o n ( m E q v /L ) [Na+] [Cl-] 0 31 2 [K+] [H+] 160 140 120 100 80 60 40 20 0 Secretory rate (ml/minute) C o n c e n tr a ti o n ( m E q v /L ) [Na+] [Cl-] 0 31 20 31 2 [K+] [H+] Figure 12. Relationship of the electrolyte concentrations in gastric juice to the rate of gastric secretion. Self-selected Time (min.) -30 0 30 60 90 Bland Regular Sham feeding A ci d O u tp u t (m E q /h o u r) 0 4 8 12 16 Figure 13. Influence of types of meals on human sham feeding: acid output Self-selected Time (min.) -30 0 30 60 90 Bland Regular Sham feeding A ci d O u tp u t (m E q /h o u r) 0 4 8 12 16 Figure 13. Influence of types of meals on human sham feeding: acid output PhasePhase StimulusStimulus % daily % daily HClHCl InterdigestiveInterdigestive None (basal)None (basal) 1515 CephalicCephalic Sight of foodSight of food SmellingSmelling ChewingChewing TastingTasting SwallowingSwallowing 3030 GastricGastric Food in stomachFood in stomach 5050 IntestinalIntestinal Digestion productDigestion product 55 Mediator (or inhibitor) PSPS,, gastrin, histaminegastrin, histamine PSPS,, gastrin, histaminegastrin, histamine PS, gastrin, histaminePS, gastrin, histamine ((SecretinSecretin, CCK, GIP), CCK, GIP) GI-Secretion-2014_HF 7 b. Non-oxyntic component (mucosal barrier) i Paracellular movement and cellular secretion of an isotonic ultrafiltrate of plasma that is high in K + (10-20 mM) and HCO3 - (45 mM). HCO3 - is produced in the epithelial cells, and transported from the blood into the cell by a basolateral HCO3 - transporter. It is secreted at the luminal membrane by several mechanisms.  an electroneutral Cl-/HCO3 - exchanger, stimulated by glucagon.  an electrogenic HCO3 - transporter, stimulated by prostaglandin E2. ii Mucus is secreted in response to several stimuli.  Soluble mucus is released from the mucous neck cells in response to parasympathetic stimulation via the ENS.  Visible mucus is released from the surface cells in response to mechanical irritation, chemical stimulation. Local reflex, and both sympathetic and parasympathetic activity via the ENS play a minor role.  Containing and neutralizing gastric acid. i The non-oxyntic component secretions create the mucosal barrier. This barrier can neutralize about 20 mM acid. ii H + ions are "held" in the stomach lumen by the negative charge created by the Cl - current. pH ? 1.0 [H + ] = 140 mM pH ? 7.4 [H + ] = 50 nM 140 mM 50 nM = 3 x 10 The maintenance of the gradient depends on: 1) Gastric musosal barrier to the back - diffusion of H + 2) Negative lumenal PD Figure 15. The H + gradient across the gastric mucosa Figure 16. Mucus and HCO3 - produce pH profile adjacent to the epithelium pH ~ 1.0 [H + ] = 140 mM pH ~ 7.4 [H + ] = 50 nM 140 mM 50 nM = 3 x 10 6 The maintenance of the gradient depends on: 1) Gastric musosal barrier to the back - diffusion of H + 2) Negative lumenal PD Figure 1 + gradient across the gastric mucosa Figure - produce pH profile adjacent to the epithelium Figure 14. Secretagogues and antagonists of acid secretion from parietal cells and signaling mechanisms. Binding of acetylcholine (ACh) and gastrin to their receptors causes increases in cytosolic Ca2+ concentration Histamine, through its receptor, activates adenylyl cyclase and increases the intracellular level of cAMP. The secretagogues activate protein kinase C (PKC), cAMP- dependent protein kinase (PKA), and Ca2+-calmodulin-dependent kinases. There is synergism among secretagogues. Somatostatin, GIP, CCK and secretin inhibit acid secretion by decreasing gastrin production and/or the cAMP level. Prostaglandins of the E class inhibit acid secretion by decreasing cAMP production. There is also synergism among three inhibitors, somatostatin, GIP and secretin. Gastrin is the major trophic factor for parietal cells. Maintenance of Maintenance of cell functioncell function HClHCl ECLECL CCKCCK--BB M3M3 H2H2 HistamineHistaminePLCPLC srsr PRPR ProstaglandinsProstaglandins GastrinGastrin CaCa2+2+ AChACh cAMPcAMP SomatostatinSomatostatin + ++ + +++ - - + + + + + + GIPGIP CCKCCK+ - SecretinSecretin Figure 14. Secretagogues and antagonists of acid secretion from parietal cells and signaling mechanisms. Binding of acetylcholine (ACh) and gastrin to their receptors causes increases in cytosolic Ca2+ concentration Histamine, through its receptor, activates adenylyl cyclase and increases the intracellular level of cAMP. The secretagogues activate protein kinase C (PKC), cAMP- dependent protein kinase (PKA), and Ca2+-calmodulin-dependent kinases. There is synergism among secretagogues. Somatostatin, GIP, CCK and secretin inhibit acid secretion by decreasing gastrin production and/or the cAMP level. Prostaglandins of the E class inhibit acid secretion by decreasing cAMP production. There is also synergism among three inhibitors, somatostatin, GIP and secretin. Gastrin is the major trophic factor for parietal cells. Maintenance of Maintenance of cell functioncell function HClHCl ECLECL CCKCCK--BB M3M3 H2H2 HistamineHistami