LECTURE 5

Gastric secretion comes from:

Mucus-secreting cells:

Simple mucous cells that line the entiresurface of the stomach,

The Gastric glands or theoxyntic(acid-forming)

Located on the inside surfaces of the body and fundus of the stomach, constituting the proximal 80 per cent of the stomach and secrete:

  • hydrochloric acid,
  • pepsinogen,
  • intrinsic factor, and
  • mucus.

The pyloricglands located in the antral portion of the stomach, the distal 20 per cent of the stomach.

  • secrete mainly mucus for protection of thepyloric mucosa from the stomach acid.
  • They alsosecrete the hormone gastrin.

Secretions from Surface Mucous Cells

The entire surface of the stomach mucosa between glands has a continuous layer of a special type of mucous cells called simply “surface mucous cells.” They secrete large quantities of very viscid mucus that coats the stomach mucosa with a gel layer of mucus often more than 1 millimeter thick, thus providing a major shell of protection for the stomach wall as well as contributing to lubrication of food transport.

Another characteristic of this mucus is that it is alkaline.

Therefore, the normal underlying stomach wall is not directly exposed to the highly acidic, proteolytic stomach secretion.

Even the slightest contact with food or any irritation of the mucosa directly stimulates the surfacemucous cells to secrete additional quantities of this thick, alkaline, viscid mucus.

As mentioned before, mucus is strongly resistant to digestion by the gastrointestinal enzymes.

Secretions from the Oxyntic (Gastric) Glands

A typical stomach oxyntic gland is composed of three types of cells:

(1)mucousneck cells, which secrete mainly mucus;

(2)peptic(or chief) cells, which secrete large quantities ofpepsinogen; and

(3)parietal (or oxyntic) cells, which secrete hydrochloric acidandintrinsic factor.

Secretion of Hydrochloric Acid

  • Whenstimulated, the parietal cells secrete an acid solutionthat contains about 160 millimoles of hydrochloric acidper liter, which is almost exactly isotonic with the bodyfluids.
  • The pH of this acid is about 0.8, demonstratingits extreme acidity. At this pH, the hydrogen ion concentrationis about 3 million times that of the arterialblood.
  • To concentrate the hydrogen ions this tremendousamount requires more than 1500 calories ofenergy per liter of gastric juice.

  • Figure 64–5 shows schematically the functionalstructure of a parietal cell (also called oxyntic cell),demonstrating that it contains large branching intracellularcanaliculi.
  • The hydrochloric acid is formed atthe villus-like projections inside these canaliculi and isthen conducted through the canaliculi to the secretoryend of the cell.

Different suggestions for the chemical mechanismof hydrochloric acid formation have been offered.General principles of one of these:

  • The apical membranes contain:

H+-K+ ATPase (proton pump)

Cl- channels.

  • The basolateral membranes contain:

Na+-K+ ATPase

Cl--HCO3- exchangers.

  • The cellscontain:

Carbonic anhydrase.

  1. In intracellular fluid, carbon dioxide (CO2), produced from aerobic metabolism and other sources, combines with H2O to form H2CO3, catalyzed by carbonic anhydrase. H2CO3 dissociates into H+ and HCO3-. The H+ is secreted with Cl- into the lumen of the stomach, and the HCO3- is absorbed into the blood, as described in steps 2 and 3, respectively.
  2. At the apical membrane, H+ is secreted into the lumen of the stomach via the H+-K+ ATPase. The H+-K+ ATPase is a primary active process that transports H+ and K+ against their electrochemical gradients (uphill). H+-K+ ATPase is inhibited by the drug omeprazole, which is used in the treatment of ulcers to reduce H+ secretion.

Cl- follows H+ into the lumen by diffusing through Cl- channels in the apical membrane.

  1. At the basolateral membrane, HCO3- is absorbed from the cell into the blood via a Cl--HCO3- exchanger. The absorbed HCO3- is responsible for the "alkaline tide" (high pH) that can be observed in gastric venous blood after a meal. Eventually, this HCO3- will be secreted back into the gastrointestinal tract in pancreatic secretions.
  2. In combination, the events occurring at the apical and basolateral membranes of gastric parietal cells result in net secretion of HCl and net absorption of HCO3-.

Secretion and Activation of Pepsinogen.

Several slightly different types of pepsinogen are secreted by the peptic and mucous cells of the gastric glands. Even so, all the pepsinogens perform the same functions.

When pepsinogen is first secreted, it has no digestive activity. However, as soon as it comes in contact with hydrochloric acid, it is activated to form active pepsin.

Pepsin functions as an active proteolytic enzyme in a highly acid medium (optimum pH 1.8 to 3.5), but above a pH of about 5 it has almost no proteolytic activity and becomes completely inactivated in a short time.

Hydrochloric acid is as necessary as pepsin for protein digestion in the stomach;

Secretion of Intrinsic Factor.

The substance intrinsic factor, essential for absorption of vitamin B12 in the ileum, is secreted by the parietal cellsalong with the secretion of hydrochloric acid. When the acid-producing parietal cells of the stomach are destroyed, which frequently occurs in chronic gastritis (atrophic gastritis), the person develops not onlydigestive problems andachlorhydria but often also pernicious anemiabecause of failure of maturation of the red blood cells in the absence of vitamin B12 stimulation of the bone marrow.

Secretions from thePyloric Glands

The pyloric glands are structurally similar to the oxyntic glands but

  • contain few peptic cells
  • almost no parietal cells.
  • mostly mucous cells
  • secrete the hormone gastrin

Regulation of Gastric Acid Secretion

The gastric acid secretion is under continuouscontrol by both endocrine and nervous signals. Furthermore, the parietal cells operate in close associationwith another type of cell called enterochromaffin-like cells (ECL cells), the primary function of whichis to secrete histamine.

The ECL cells lie in the deep recesses of the oxynticglands and therefore release histamine in directcontact with the parietal cells of the glands. The rate of formation and secretion of hydrochloric acid by the parietal cells is directly related to the amount of histamine secreted by the ECL cells. In turn, the ECLcells can be stimulated to secrete histamine in severaldifferent ways:

(1)Probably the most potent mechanismfor stimulating histamine secretion is by the hormonalsubstance gastrin, which is formed almostentirely in the antral portion of the stomach mucosain response to proteins in the foods being digested.

(2) In addition, the ECL cells can be stimulated by:

(a) acetylcholine released from stomach vagal nerveendings and

(b) probably also by hormonal substancessecreted by the enteric nervous system of the stomachwall.

Stimulation of Acid Secretion by Gastrin.

When meats or other protein-containing foodsreach the antral end of the stomach, some of the proteinsfrom these foods have a special stimulatory effecton the gastrin cells in the pyloric glands to causerelease of gastrin into the digestive juices of thestomach. The vigorous mixing of the gastric juicestransports the gastrin rapidly to the ECL cells in thebody of the stomach, causing release of histaminedirectly into the deep oxyntic glands. The histaminethen acts quickly to stimulate gastric hydrochloric acidsecretion.

Regulation of Pepsinogen Secretion

It occurs in response to twotypes of signals:

(1)Stimulation of the peptic cells byacetylcholine released from the vagus nervesor fromthe gastric enteric nervous plexus, and

(2)Stimulationof peptic cell secretion in response to acid in thestomach.

The acid probably does not stimulate thepeptic cells directly but instead elicits additionalenteric nervous reflexes that support the originalnervous signals to the peptic cells.

Therefore, the rateof secretion of pepsinogen isstrongly influenced by the amount of acid in thestomach. In people who have lost the ability to secretenormal amounts of acid, secretion of pepsinogen isalso decreased, even though the peptic cells mayotherwise appear to be normal.

Phases of Gastric Secretion

Gastric secretion is said to occur in three “phases” (asshown in Figure 64–7):

cephalic phase,

gastric phase,

intestinal phase.

Cephalic Phase.

Thisphase of secretion normally accounts for about 20 percent of the gastric secretion associated with eating ameal.

Gastric Phase

Once food enters the stomach, it excites

  • long vagovagal reflexes from the stomach to thebrain and back to the stomach
  • local enteric reflexes
  • the gastrin mechanism

all of which in turn causesecretion of gastric juice during several hours while foodremains in the stomach.

The gastric phase of secretionaccounts for about 70 per cent of the total gastric secretionassociated with eating a meal and thereforeaccounts for most of the total daily gastric secretion ofabout 1500 ml.

Intestinal Phase. The presence of food in the upperportion of the small intestine, particularly in the duodenum,will continue to cause stomach secretion ofsmall amounts of gastric juice, probably partly becauseof small amounts of gastrin released by the duodenalmucosa.

Inhibition of Gastric Secretion

by Intestinal Factors

1.Reverse enterogastric reflex.

The presence of food in the small intestine initiatesa reverse enterogastric reflex, transmitted through:

  • The myenteric nervous system
  • Extrinsic sympathetic and
  • Vagus nerves,

that inhibitsstomach secretion. This reflex can be initiated by:

  • distending the small bowel,
  • the presence of acidin the upper intestine,
  • the presence of protein breakdown products,
  • irritation of intestinal mucosa.

2.Intestinal hormones

The presence of

  • acid,
  • fat,
  • protein breakdownproducts,
  • hyperosmotic or hypo-osmotic fluids, or
  • any irritating factor in the upper small intestine

causes release of several intestinal hormones namely:

  • secretin
  • gastric inhibitory peptide, (secretin-like action)
  • vasoactiveintestinal polypeptide (VIP), and
  • somatostatin

Secretin is the main hormone to oppose stomach secretion. The others have slight to moderate inhibiting effects.

In fact, the enterogastricinhibitory reflexes plus inhibitory hormonesusually also reduce stomach motility at the same timethat they reduce gastric secretion.

Gastric Secretion During the Interdigestive Period.

Thestomach secretes a few milliliters of gastric juice eachhour during the “interdigestive period”, when little orno digestion is occurring anywhere in the gut.

The secretionthat does occur usually is almost entirely of thenonoxyntic type,

composed mainly of mucus

but littlepepsin

and almost no acid.

Unfortunately, emotional stimuli frequently increaseinterdigestive gastric secretion (highly peptic andacidic) to 50 milliliters or more per hour.

Pancreatic Secretion

The pancreas, which lies parallel to and beneath thestomach, is a large compoundgland with most of its internal structure similarto that of the salivary glands.

Thepancreatic digestive enzymes are secreted bypancreaticacini, and large volumesof sodium bicarbonatesolution are secreted by the small ductules and largerducts leading from the acini.

The combined product ofenzymes and sodium bicarbonate then flows througha long pancreatic duct that normally joins the hepaticduct immediately before it empties into the duodenumthrough the papilla of Vater, surrounded by the sphincterof Oddi.

Pancreatic juice is secreted most abundantly inresponse to the presence of chyme in the upper portionsof the small intestine.

The characteristics ofthe pancreatic juice are determined to some extent bythe types of food in the chyme.

Pancreatic Digestive Enzymes

Pancreatic secretion contains multiple enzymes fordigesting all of the three major types of food: proteins,carbohydrates, and fats. It also contains large quantitiesof bicarbonate ions, which play an important rolein neutralizing the acidity of the chyme emptied fromthe stomach into the duodenum.

Enzymes for Digesting proteins are:

Trypsin

Chymotrypsin

Carboxypolypeptidase.

By far the most abundant of theseis trypsin.

Trypsin and chymotrypsin split whole and partiallydigested proteins into peptides of various sizes but donot cause release of individual amino acids.

However,carboxypolypeptidase does split some peptides intoindividual amino acids, thus completing digestion ofsome proteins all the way to the amino acid state.

Enzyme for digesting carbohydrates

pancreatic amylase,

which hydrolyzes starches, glycogen,and most other carbohydrates (except cellulose)to formmostly disaccharides and a few trisaccharides.

Enzymes for digesting fat

(1)pancreaticlipase, which is capable of hydrolyzing neutral fat(Triglycerides) into fatty acids and monoglycerides;

(2)cholesterolesterase, which causes hydrolysis of cholesterol esters;and

(3) phospholipase, which splits fatty acids fromphospholipids.

When first synthesized in the pancreatic cells, theproteolytic digestive enzymes are in the inactiveforms:

trypsinogen,

chymotrypsinogen,

procarboxypolypeptidase,

which are all inactive enzymatically.They become activated only after they aresecreted into the intestinal tract.

Trypsinogen isactivated by an enzyme calledenteropeptidaseor enterokinase, which issecreted by the intestinal mucosa when chyme comesin contact with the mucosa. Also,trypsinogen can beautocatalytically activated by trypsin that has alreadybeen formed from previously secreted trypsinogen.

Chymotrypsinogenand procarboxypolypeptidase are activated by trypsin to form chymotrypsin and carboxypolypeptidase.

Secretion of Trypsin Inhibitor Prevents Digestion of thePancreas Itself.

It is important that the proteolyticenzymes of the pancreatic juice not become activateduntil after they have been secreted into the intestinebecause the trypsin and the other enzymes woulddigest the pancreas itself.

Fortunately, the same cellsthat secrete proteolytic enzymes into the acini of thepancreas secrete simultaneously another substancecalled trypsin inhibitor.This substance is formed in thecytoplasm of the glandular cells, and it prevents activationof trypsin both inside the secretory cells and inthe acini and ducts of the pancreas.

And, because it istrypsin that activates the other pancreatic proteolyticenzymes, trypsin inhibitor prevents activation of theothers as well.

When the pancreas becomes severely damaged orwhen a duct becomes blocked, large quantities of pancreaticsecretion sometimes become pooled in thedamaged areas of the pancreas. Under these conditions,the effect of trypsin inhibitor is often overwhelmed,in which case the pancreatic secretionsrapidly become activated and can literally digest theentire pancreas within a few hours, giving rise to thecondition called acute pancreatitis. This sometimes islethal because of accompanying circulatory shock;even if not lethal, it usually leads to a subsequent lifetimeof pancreatic insufficiency.

Secretion of Bicarbonate Ions

Bicarbonate ions and water are secreted mainlyby the epithelial cells of the ductules and ducts thatlead from the acini.

When the pancreas is stimulatedto secrete copious quantities of pancreatic juice, thebicarbonate ion concentration can rise to as high as145 mEq/L, a value about five times that of bicarbonateions in the plasma. This provides a large quantityof alkali in the pancreatic juice that serves to neutralizethe hydrochloric acid emptied into the duodenumfrom the stomach.

The basic steps in the cellular mechanism for secretingsodium bicarbonate solution into the pancreaticductules and ducts are:

1. Carbon dioxide diffuses to the interior of thecell from the blood and, under the influence ofcarbonic anhydrase, combines with water to formcarbonic acid (H2CO3). The carbonic acid in turndissociates into bicarbonate ions and hydrogenions. Then the bicarbonate ionsare actively transported in association withsodium ions (Na+) through the luminal border ofthe cell into the lumen of the duct.

2. The hydrogen ions formed by dissociation ofcarbonic acid inside the cell are exchanged forsodium ions through the blood border of thecell by a secondary active transport process.This supplies the sodium ions (Na+) that aretransported through the luminal border into thepancreatic duct lumen to provide electricalneutrality for the secreted bicarbonate ions.

3. The overall movement of sodium and bicarbonateions from the blood into the duct lumen createsan osmotic pressure gradient that causes osmosisof water also into the pancreatic duct, thusforming an almost completely isosmotic

bicarbonate solution.

Regulation of Pancreatic Secretion

Basic Stimuli That Cause Pancreatic Secretion

Three basic stimuli are important in causing pancreaticsecretion:

1. Acetylcholine, which is released from theparasympathetic vagus nerve endings and fromother cholinergic nerves in the enteric nervoussystem

2. Cholecystokinin, which is secreted by theduodenal and upper jejunal mucosa when foodenters the small intestine

3. Secretin, which is also secreted by the duodenaland jejunal mucosa when highly acid food entersthe small intestine

The first two of these stimuli, acetylcholine andcholecystokinin, stimulate the acinar cells of thepancreas, causing production of large quantities ofpancreatic digestive enzymes but relatively smallquantities of water and electrolytes to go with theenzymes. Without the water, most of the enzymesremain temporarily stored in the acini and ducts untilmore fluid secretion comes along to wash them intothe duodenum.

Secretinstimulates secretion of large quantities ofwater solution of sodium bicarbonate by the pancreaticductal epithelium.

Multiplicative Effects of Different Stimuli.

When all the differentstimuli of pancreatic secretion occur at once, thetotal secretion is far greater than the sum of the secretionscaused by each one separately. Therefore, thevarious stimuli are said to “multiply,” or “potentiate,”one another. Thus, pancreatic secretion normallyresults from the combined effects of the multiple basicstimuli, not from one alone.

Phases of Pancreatic Secretion

Cephalic Phases

During the cephalic phaseof pancreatic secretion, the same nervous signals fromthe brain that cause secretion in the stomach alsocause acetylcholine release by the vagal nerve endingsin the pancreas. This causes moderate amounts ofenzymes to be secreted into the pancreatic acini,accounting for about 20 per cent of the total secretionof pancreatic enzymes after a meal. But little of thesecretion flows immediately through the pancreaticducts into the intestine because only small amounts ofwater and electrolytes are secreted along with theenzymes.

Gastric Phases

During the gastric phase, the nervous stimulation ofenzyme secretion continues, accounting for another 5to 10 per cent of pancreatic enzymes secreted after ameal. But, again, only small amounts reach the duodenumbecause of continued lack of significant fluidsecretion.

Intestinal Phase.

After chyme leaves the stomach andenters the small intestine, pancreatic secretionbecomes copious, mainly in response to the hormonesecretin.

Secretin