Basic Mechanism of Secretion1. Secrete substance – nervous or hormonal

stimuli increase iCa2+ → exocytosis2. Secrete water and electrolytes to move

substance into target area (osmosis)

Chemical & Electrical Gradients Drive Secretionof Water

cAMP causes Cl- channels to

open

Na+ follows electrical gradient

H2O moves along osmoticgradient

Cl -Na+

Cl - Na+

PNa+ Na+

K+ K+

Na+

H2 0

Na+

H2 0

Cl -

CFTR

cAMP

-----

-----

lumen blood

++

++

++

Types of Secretory Glands

• Single Cell - mucous cells or goblet cells

• Simple - indentations in epithelium in S.I.and colon

(e.g. crypts of Lieberkühn inS.I.)

• Tubular - stomach, duodenum

• Complex - salivary, pancreas, liver

Control of Secretion• Local - tactile, distention, irritation that comes

from direct contact with food/chyme

• Reflex - nervous input, activated by local inputor sensory input

• Hormonal - G.I. hormones (more so in stomach& S.I.)

PNS Stim. - secretion of substance & waterSNS Stim. - blood flow to gland & cAMP

in acinar cells

Mucus Composition - Properties

• Thick secretion that is mainly water,

electrolytes and glycoproteins -

• Essential for digestion because -Adherent - sticks to foodBody - coats wellLow resistance - lubricationSelf adherent - sticks togetherResistant to digestionBuffering capacity

Functions of Saliva

• Lubrication and binding of foodtogether

• Solubilizes dry food

• Initiates starch digestion

• Oral hygieneDestroys bacteria - proteolytic enzymes (lysozyme)

- thiocyanate- antibodies

Saliva

• Two types of secretion -

- Serous - watery secretion, contains an

-amylase (ptyalin)

- Mucous - contains mucin - lubrication

• Secrete 800-1000 mL/day of saliva• Maximum rate of secretion: 4 ml/min

Salivary Glands

Type of % of totalGland saliva Secreted

Parotid Serous

Submandibular Mucous/ Serous

Sublingual Mucous 10%/ Serous

90%

Formation and Secretion of Saliva

• Two Stages -

- Acini: - primary secretion similar toplasma

- Salivary Ducts: modified as it passesthrough ducts

- Na+ is actively reabsorbed- K+ is secreted, but not equal to

the Na+ that’s reabsorbed- increased electronegative forceleads to passive Cl- reabsorption- HCO3- secreted

Ionic Composition of Saliva

• Hypotonic

• Ionic composition depends upon rate ofsecretion. Resting composition is:

- Na+ - 0.1 x plasma (15 mEq/L)- Cl- - 0.15 x plasma (15 mEq/L)- K+ - 7 x plasma (30 mEq/L)- HCO

-3 - 3 x plasma (70 mEq/L)

• Increased secretion increases the [Na+] and[Cl-] & decreases the [K+] & [HCO3-]

• Aldosterone increases K+ secretion

Salivation is under neural control

Cl- actively transported into acinar cells across basolateral membrane. Cl- and HCO3-transported across apical side by anion transporter. (Est. lumen negative transepithelialpotential)

Sympathetic stimulation leads to increasedblood flow to glands

Parasympathetic stimulation leads tosecretion from acini

NucleiiSalvatorii

in theMedulla

SleepFatigueDehydrationRough objectsFear

Conditionedreflexes

ChewingTaste/SmellSmooth objectsNausea

+ -

Parasympathetics(CN - IX and VII)

SALIVARYGLAND

Ach

Sympathetics(T1-T3)

SCG

NE

SecretionMyoepithelial cell

contractionVasodilation

Nervous Regulation of Salivation

B2 AR: leads to ↑ cAMP

M1: leads to ↑ iCa2+M3: myoepithelial

contraction

kallikrein → bradykinin

Clinical

• Xerostomia - dry mouth.- Causes: -- lack of sleep or dehydration- drug related, e.g. diuretics

- insufficient capillary perfusion- radiation treatment (aplasia of glands)

- destruction of glands- autoimmune disease

• Drooling- Treatment: - anticholinergics

- surgical removal of the sublingualglands and retropositioning

submandibular ducts.

Clinical complications

• Cystic Fibrosis - salivary Ca++, Na+, and protein are elevated(also true for bronchial secretions, pancreatic juice, andsweat).- Cl- secretion is essential for cell secretion- CF patients have dysfunctional or no (CFTR )

CFTR = cystic fibrosis transmembrane

conductance regulator

• Primary aldosteronism - (Conn’s syndrome)

- salivary NaCl close to zero

- salivary K+ increases to high levels

Esophageal Secretion

• Mucosal

• Simple mucos glands

• Compound mucos glands in proximal &distal ends secrete mucos that– Prevents food from scraping epithelia

– Protects in case of stomach reflux

Functions of Stomach

• Short-term storage reservoir

• Secretion of intrinsic factor

• Chemical and enzymatic digestion isinitiated, particularly of proteins

• Liquefaction of food

• Slowly released into the small intestine forfurther processing

Gastric Secretions• Two types glands -

- Gastric - HCl(oxyntic) pepsinogen

intrinsic factormucusrennin (chymosin)

- Pyloric - gastrinmucus(sm. amountspepsinogen)

Figure 64-4; Guyton & Hall

Gastric (oxyntic) Gland

• Four cell types -

- Enterochromaffin likecells

- histamine- Mucous neck cells

- mucus

- Chief cells- pepsinogen- rennin

- Parietal cells- HCl- intrinsic factor

80%

Figure 64-5; Guyton & Hall

Parietal Cell• HCl is formed at the villus-

like membranes of thecanaliculi which arecontinuous with the lumen

• H+ concentration in parietalcell secretions is 3 million-fold higher compared toblood

• H+-K+ATPase or "protonpump" in cannalicularmembrane is key player

ATPase is Mg++-dependent

Gastric Acid

• Three major functions -

- Bacteriostatic- Converts pepsinogen to pepsin- Begins protein digestion (with pepsin)

• Composition-

- HCl 155 mEq/L pH = 0.8!- KCl 15 mEq/L to concentrate this- NaCl 3 mEq/L much acid requires

- 1500 cal/L gastricjuice

Mechanism of Acid Secretion

Regulation of Gastric Secretion

• Secretion occurs in 3 phases: cephalic, gastric,intestinal

• Gastric secretion is stimulated by neural,paracrine and endocrine mechanisms- Acetylcholine - HCl secretion

- mucus, pepsinogen, and gastrin

- Histamine - HCl secretion

- Gastrin - HCl secretion (1500x more

powerful compared to histamine)

Phases of Gastric Secretion

Figure 64-7; Guyton & Hall

Cephalic Phase

• Seeing, smelling and anticipating food is perceived in brain. Brain tells stomach toprepare for receipt of meal

• Accounts for 30% of acid response to meal -

Stimuli - MechanoreceptorsChemoreceptors (smell and taste)Central pathway (thought)Hypoglycemia

Blocked entirely by vagotomy

Gastric Phase

• Accounts for 60% of acid response to a meal• When meal enters stomach, several factors

come into play•

Increased pH - gastrin release ** Distention - gastrin release **

Ach stimulation of HCl * Peptides / AA - gastrin release **

* blocked by atropine** blocked by acidification of antrum

Intestinal Phase

• Accounts for 10% of acid response to a meal

Distention of small intestine - stimulates acid secretion(enterooxyntin - postulated hormone)

Amino acids - circulating amino acids stimulate acidsecretion via direct effect on parietal cell

Table 16-4, p. 609

Stimulation of Gastric Secretion

Table 16-5, p. 610

Inhibition of Gastric Secretion

Fig. 16-10, p. 608

Mechanism ofpepsin production

Pepsinogen

• Pepsinogen is an inactive, secreted form ofpepsin -

Acid converts pepsinogen to pepsin

Pepsin (35 kDa) converts more pepsinogen to pepsin

- proteolytic enzyme- optimal pH 1.8 - 3.5- reversibly inactivated > pH 5.0- irreversibly inactivated > pH 7-8

Pepsinogen Secretion

• Signals stimulating secretion of pepsinogen-

- Vagal stimulation as mediated byacetylcholine

- Direct response to gastric acid- Stimulation by secretin, CCK

Intrinsic Factor

• Stomach - Dietary vitamin B12 bound by B12-binding proteins present in gastric juice

• Duodenum - pancreatic proteases digest bindingproteins, releasing vitamin B12 which binds tointrinsic factor

• Ileum - intrinsic factor- vitamin B12 complexabsorbed

• Only indispensable substance in gastric juice

• Ileal disease, resection, atrophic gastritis- Lack of B12 - pernicious anemia

Rennin (Chymosin)

• Proteolytic enzyme - causes milk to curdle instomach

• Milk retained in stomach and released moreslowly

• Rennin secretion - maximal first few days afterbirth. Replaced by secretion of pepsin as majorgastric protease

• Secreted as inactive proenzyme (prochymosin)that is activated on exposure to acid

Pyloric Gland

• Three cell types -

G-cells - release gastrin D-cells – release somatostatin Mucus neck cells

- mucous- Few peptic cells

20%

Role of Vagus in Gastric Secretion

Stomach MucosaEnteric nervous system

Vagus Nerve

Gastric gland

HCl

Pyloric gland

Gastrin

Regulation of Gastrin Secretion

• Vagal control Gastrin secretion not blocked by atropine Gastrin releasing peptide - stimulates gastrin release

from G-cell Somatostatin - inhibits gastrin release

from G-cell

• Antrum acidification - pH <3 inhibits gastrinrelease

• Sm peptides and amino acids - directlystimulate gastrin release from G-cell

Regulation of Gastrin SecretionVagus Nerve

AChACh

GRP ACh

Somatostatin CellGastrin CellSS

Gastrin

peptides, amino acids H+

+ -

Regulation of Histamine Secretion

• Gastrin and acetylcholine stimulate histaminerelease from enterochromaffin-like (ECL) cells

• ECL cells are a specialized endocrine cell ingastric mucosa

• Proliferation of ECL cells occurs in associationwith hypergastrinemic states -

Gastrin-secreting tumors Long term therapy with drugs that block acid secretion

Multiplicative Effect of Secretagogues

• Gastrin, acetylcholine and histamine potentiate the effects of theothers- Histamine potentiates effects of gastrin and acetylcholine. H2 blockers

attenuate secretory responses to both acetylcholine and gastrin.

- Acetylcholine potentiates effects of gastrin and histamine. Atropineattenuates secretory effects of histamine and gastrin.

H+

Histamine

Cm

Cm CmAt

Cm, CimetidineAt, Atropine

Acid Response to a Meal

• Duration of gastric acid response to mealis a function of -

1. Intragastric pH2. Nature of chyme entering duodenum

• Before meal - pH is low - acid secretion issuppressed Acid stimulates somatostatin release (which

decreases gastrin secretion)

Acid has direct effect to suppress parietal cellsecretion

Acid Response to a Meal (cont’d)

Meal (early) - acid secretion increases because - Cephalic phase (vagal) Gastric pH rises (disinhibition of somatostatin effect) Chemical nature of food (protein, etc.)

Meal (late) - acid secretion decreases because - Buffering capacity of food is saturated As pH falls, acid inhibits further secretion of gastrin and acid

secretion wanes (negative feedback) Chyme entering duo further inhibits acid secretion (acid, osmolarity,

fat - same as inhibits gastric emptying)

Copyright © 2006 by Elsevier, Inc.

Mechanisms Inhibiting Acid Secretion

Inhibits DirectlyRegion Stimulus Mediation gastrin inhibits acid

release secretion

Oxynticgland area

Antrum

Acid(pH < 3.0) Somatostatin YES YES

SecretinNervous reflex

Unidentifiedenterogasterone

Unidentifiedenterogasterone

GIP

YESYES

YES

YES

YES

YES

YES

Acid

Hyper-osmoticsolutions

Fattyacids

Duodenum

Duodenumand

Jejunum

Fig. 16-11, p. 611

Gastric mucosal barrier

• The gastric mucosa has a physiological and an anatomical basis to preventback-leak of H+ ions

Anatomical - cell membranes and tight

junctions between cellsPhysiological - diffused H+ ions are transported

back to lumen

Integrity of Mucosal Barrier

Barrier HealthyNo Ulcers

BarrierDamagedGastritis,Ulcers

Strengthensmucus, HCO3

-

secretion, gastrin,PGs, epidermalgrowth factor

WeakensH. pylori, aspirin,

ethanol,NSAIDs,bile salts

Damaged Gastric Mucosal Barrier

• H+ back-leaks into mucosa in exchange forNa+. This is a forerunner to gastric ulcer -

Decreased cell pH leads to cell death

Damaged mast cells (ECL cells) leak histamine

Viscous cycle - Histamine .. vascular damage ..

local ischemia .. greater leakage

of H+.. more cell death ...

Treatments for peptic ulcer diseases

Agents Mechanism

Antacids Neutralization of acidAnticholinergics Inhib. of Ach stimulated acid

secretionH2 receptor antag. Inhib. of histamine-dependent

acid secretionOmeprazole Inhib. of H+ K+ ATPaseCoating agents(sucralfate, CBS) Provide protective layerProstaglandins(E series) Inhibit acid secretion & enhance

cytoprotection

Pancreas• As chyme moves into small intestine; two

things must happen:

1. Acid must be neutralized to prevent damage toduodenal mucosa

2. Nutrients – (proteins, fats and starch) must bebroken down much further so their constituentscan be absorbed

• Critical role in accomplishing both objectives

Digestive enzymes for all food types

Bicarbonate solution to neutralize acid chyme

Fig. 16-12, p. 613

Compound gland(structure similar to salivary gland)

Pancreatic Digestive Enzymes• Proteolytic enzymes

- Trypsin- Chymotrypsin

- Carboxypeptidase

Cleaves proteins topolypeptides

Cleaves polypeptidesto AA

• Pancreatic amylase- starches- glycogen to disaccharides

• Pancreatic lipase - fat fatty acids +monoglycerides

• Phospholipase - phospholipids fatty acid

• Cholesterol esterase - cholesterol esters fatty acid

Regulation of pancreatic secretion

Figure 64-10; Guyton & Hall

Vagal stim.

Another view of pancreatic secretion

***AchCCKBombesinSubstance P

SecretinVIP

ACPIP2

cAMPIP3

Ca2+

cGMP

Regulation of acinar cell secretion

NO

Proteinkinases Not well understood,

but 2nd messengers cAMP& cGMP have the oppositeeffect on iCa2+ in secretorycells than it does in smoothmuscle cells

Regulation of pancreatic secretion

Why Doesn’t the Pancreas Digest Itself?

• Proteolytic enzymes stored and secreted in aninactive form - (also, a trypsin inhibitor is presentin cells)

• Trypsin inhib. prevents trypsinogen cleavage inacini & ducts (lack of causes acute pancreatitis)

trypsinogen trypsin

chymotrypsinogen chymotrypsin

procarboxypeptidase carboxypeptidase

Activation of Proteolytic Enzymes

Trypsinogen Trypsin

• Enterokinase – secreted by intestinal mucosalcells

• Trypsin - autocatalytic activation- activates - chymotrypsinogen,

- procarboxypeptidase- trypsinogen

enterokinase

Bicarbonate Neutralizes Acid Chyme

• Secretin induced bicarbonate secretion neutralizes acid chymecreating optimal conditions (pH = 7-8) for digestive enzymes -

isoosmoticHCO3- secretion

Model of Bicarbonate Secretion

1. CO2 combines with H2O in presence of carbonicanyhydrase in cell → H2CO3

2. H2CO3 dissociates into HCO3- and H+

3. H+ exchanged for Na+ across basolateral membrane,active transport (Na+ gradient established by usual Na +K +

ATPase)

4. HCO3- moves out of cell across apical membrane with

Na+

5. Na+ moves down electrochemical gradient. Watermoves into lumen establishing osmotic equilibrium.(Pancreatic juice always isotonic.)

Regulation of Pancreatic Secretion

• Secretion of fluid and HCO3- dependent

upon amount of acid entering duodenum

• Secretion of enzymes dependent uponamount of fat and protein enteringduodenum

Acetylcholine - vagovagal reflexes

Cholecystokinin - fat and protein

Secretin - acid

Phases of Pancreatic Secretion

1. Cephalic (20%)2. Gastric (5-10%)

3. Intestinal (70-80%) acid secretin HCO3

- /H2O fat/protein CCK enzymes acid/fat/protein vagovagal Ach enzymes

• CCK and acetylcholine both potentiate the effects of secretin on water and

bicarbonate secretion.

Both phases mediated by vagus -low volume, mod. enzyme secretion

Pancreatic HCO3- Output (Secretin)

Response to Duodenal Acidification

• Secretin released when pH < 4.5.

• Below pH = 3, secretin release ismaximal in segment of duodenum.Further release of secretin dependsupon area of small intestine affected.(Maximal bicarbonate response is 30mEq/hr)

• During meal pH rarely < 3.5 or 4.0.

Distribution of GI Hormones

• Digestive products are equally effective inreleasing secretin when applied to any partof duodenum or jejunum.

Secretin

Fundus Antrum Duo Jejun Ileum Colon

Pancreatic Failure

• Digestion is abnormal when pancreas failsto secrete normal amounts of enzymes

Pancreatitis Removal of pancreatic head - malignancy

• Without pancreatic enzymes - 60% fat not absorbed (steatorrhea) 30-40% protein and carbohydrates not absorbed

Pancreatitis

• Pancreatitis = inflammation of pancreas. Autodigestiontheory can explain condition.

• Chronic pancreatitis - (multiple shared causes) alcohol - most common cause in adults cystic fibrosis - most common cause in children

• Acute pancreatitis - (multiple shared causes) gallstones - most common cause

Secretion Failure in Cystic Fibrosis

•1/29 Caucasians carry mutation in 1 copy of CFTR gene;CF occurs at about 1/2000 Caucasian births

•CF patients lack chloride transporter at apicalmembrane.

• Watery ductal secretion decreases whichconcentrates acinar secretions in ducts.

• Precipitation of proteinaceous secretions blockducts and can destroy gland by autodigestion.

Bile Composition

Bile Secretion

• Secretion in 2 stages1. Hepatocytes secrete bile acids, cholesterol into bile

canaliculi Bile flows in canaliculi to terminal bileducts, then into the hepatic bile duct & finally thecommon bile duct

2. NaHCO3 & water added by bile duct epithelia,(stim. by secretin) ↑ volume

• Bile concentrated when stored in gallbladder 30-60 mL Active Na+ transport across epithelia 2°

transport of Cl- & water Concentrates bile 5-20 fold

Guyton & Hall Figure 64-11

Fig. 16-16, p. 618

Bile Salts: Fat Digestion & Absorption

• Hepatocytes syn. 6 g bile salts/day

• Cholesterol cholic acid chenodeoxycholic acid

• + glycine (or taurine) glyco- & tauro-conjugated bileacids

• Na+ salts of these acids secreted in bile

• Bile salts are amphipathic

• Surround & emulsify fats (mono- &triglycerides, FA, cholesterol)

• Small particles can be absorbed acrossapical membrane

• FA & monoglycerides triglycerides

• Triglycerides exported to lacteal thenlymphatic vessels

Secretions of Small Intestine

• Brunner’s glands secrete an alkaline mucus. Compound mucus gland in duodenum Protects mucosa from acid chyme Stimulated by local irritation - vagus (Ach) Inhibited by sympathetics (NE)

• Crypts of Lieberkühn - mostly secrete water -like fluid - 1800 ml/day

Crypt of Lieberkuhn in theSmall Intestine

Secretions of the Large Intestine

• Large intestine also contains crypts ofLieberkühn but there are no villi orenzymes.

• Crypts mainly secrete alkaline mucus

• Mucus secretion increased byparasympathetic stimulation