Physiology Gastrointestinal System Dr. LL Wang E-mail: wanglinlin@zju.edu.cn

INTRODUCTION Gastrointestinal System includes GI tract plus the accessory organs. Digestion of food and absorption of nutrients are accomplished in a long tube connected to the external world at both ends; secretion and motility of “the tube” are major themes in understanding the gut.

Functions of Gastrointestinal System Four processes carried out by the GI tract Moisten food Lubrication Polysaccharide-digesting enzyme Move food and lubricate Store, mix, dissolve, digestion;emptyof dissolved food Secretion of enzyme and bicarbonate Digest carbohydrates ,fats, proteins and nucleic acids Elimination in feces propulsion defecation Amylase Chemoreceptor React with chemoreceptor, sensation of taste lysozyme Functions of Gastrointestinal System .

Smooth Muscle of the Gut (1) General properties Low excitability High extensibility Tonic contraction Autorhythmicity High sensitivity to temperature, stretch & chemical stimulation Distensibility Musculature Insensitive to electrical stimuli Tonic contraction:weak and contiunal contraction, 1)makes pressure in the tublar tract 2) Maintain the shape and location of GI tract 3)basis of other movement

(2) Electrophysiological properties (a) Resting potential: between -50 and -60 Mv Ionic basis Em (selective membrane permeability to K+) Electrogenic Na+-K+ pump Like other excitable cells, gastrointestinal smooth muscle cells maintain a electrical potential difference across their membranes. The resting membrane potential of smooth muscle cells is between -50 and -60 mV. In contrast to nerves and other types of muscle cells, the membrane potential of smooth muscle cells fluctuates spontaneously. These partial depolarizations are equivalent to fluctuations in membrane potential of 5 to 15 mV. Fluctuation [ 7flQktju5eiFEn ] n.波动, 起伏 Fluctuate [ 5flQktjueit ] vi.变动, 波动, 涨落, 上下, 动摇 Basal [ 5beisl ] adj.基础的, 基本的, 基部的, 构成基部的

(b) Slow wave (basic electrical rhythm,BER) The spontaneous rhythmic, subthreshold depolarizations of the cell membrane (slow wave) of the gastrointestinal tract Initiated in the interstitial cells of Cajal (ICC) (pacemaker cell)

Intensity: 5~15 mV Frequency: 3~12 cpm Ionic mechanism Slow wave (basic electrical rhythm) Intensity: 5~15 mV Frequency: 3~12 cpm Ionic mechanism spontaneous rhythmic changes in Na+-K+ pump activity

Frequencies: 3-12 per minute cpm: cycles per minute The figure below depicts the varying frequencies throughout the stomach and bowel. BER varies in resting membrane potential 3-12 cycles per minute depending on area of GI tract: stomach = 3/min, small intestine = 12/min Jejunum [ dVi5dVu:nEm ] n.[解]空肠 Ileum [ 5iliEm ] n.[解]回肠

BER not generated by nervous activity Mechanisms BER might be due to spontaneous rhythmic changes in Na+-K+ pump activity BER not generated by nervous activity Mechanisms Its important to remember that slow waves are electrical activity in muscle and are not generated by nervous activity. origins of fluctuations unknown – may be differential activity of pumps and differential factors gating channels in pacemaker cells

always present but do not always cause contraction Features of slow waves always present but do not always cause contraction dictate frequency of contractions frequency and height modulated by body temp & metabolic activity intrinsic & extrinsic nerves circulating hormones It’s important to note that slow waves do not produce contractions unless action potentials are triggered EXCEPT in the stomach, where slow wave depolarization can cause contraction without action potentials. So slow waves Always present but do not always cause contractions. The important feature of the BER is that it regulates the frequency of contractile waves in different parts of the gastrointestinal tract.   Slow wave frequency and height modulated by body temp& metabolic activity intrinsic & extrinsic nerves (increased by Ach,SP; decreased by noradrenaline, NO, VIP) circulating hormones (CCK, motilin)

(c) Spike potentials (action potentials) only at the peaks of slow waves Threshold: –40 mV

Duration: 10~20 ms Ionic mechanism: Depolarization: Ca2+ influx Spike potential (Action potential) Duration: 10~20 ms Ionic mechanism: Depolarization: Ca2+ influx Repolarization: K+ efflux

The higher the slow wave potential rises, the greater the frequency of the spike potentials "spike potentials" - which occur only at the crests of slow waves It occur when membrane potential rises above –40 mV (a threshold) The higher the potential rises above threshold, the greater the number of spike potentials Spike potentials are true action potentials that elicit muscle contraction. Mechanism: induces movement of Ca2+ into the cell (calcium-sodium channel), and can thereby lead to vigorous muscle contraction.

(3) muscle contraction Ca2+ binds to calmodulin (intracellular protein)  activates myosin light chain kinase  phosphorylates myosin light chain  phosphorylated myosin then (in the presence of ATP) binds to actin in smooth muscle regulation of contraction occurs by the phosphorylation state of the myosin molecule: Ca++ binds to calmodulin (intracellular protein)  activates myosin light chain kinase  phosphorylates myosin light chain  phosphorylated myosin then (in the presence of ATP) binds to actin smooth muscle has little troponin, so contraction occurs by the action of calmodulin on smooth muscle myosin. Calcium binds to calmodulin, which then acts to activate an protein kinase which can act on myosin, myosin kinase. This kinase phosphorylates myosin, resulting in muscle contraction. SMC remain contracted while Ca concentration is high in the cells (>10-6M), and only relaxes when Ca falls (<10-6M).

Innervation of the Gut Enteric nervous system Extrinsic nervous system Control over gastrointestinal function is provided by nervous and endocrine systems. The innervation of the GI tract is mainly through the autonomic nervous system i.e. it is generally not under conscious control. The motor innervation of the gut consists of two major parts, the intrinsic or enteric nervous system, and the extrinsic nervous system. Intrinsic [ in5trinsik ] Extrinsic [ eks5trinsik ] Enteric [ en5terik ] adj.肠的

Myenteric plexus : control over GI motility Function Myenteric plexus : control over GI motility Submucous plexus: regulate gastrointestinal blood flow and control GI secretion The principal components of the enteric nervous system are two networks or plexuses of neurons, both of which are embedded in the wall of the digestive tract and extend from esophagus to anus: The myenteric plexus is located between the longitudinal and circular layers of muscle in the tunica muscularis and, appropriately, exerts control primarily over digestive tract motility. The submucous plexus, as its name implies, is buried in the submucosa. Its principal role is in sensing the environment within the lumen, regulating gastrointestinal blood flow and controlling GI secretion. ( In regions where these functions are minimal, such as the esophagus, the submucous plexus is sparse and may actually be missing in sections. ) Myenteric Submucous

Local reflex

Ach: Stimulatory NE: inhibitory Neurotransmitters secreted by enteric neurons Ach: Stimulatory NE: inhibitory Others: Substance P, Nitric oxide , Vasoactive intestinal polypeptide (VIP), Opioid peptide, serotonin, histamine, ATP… The intrinsic nervous system signals through multiple different transmitters, the primary ones being acetylcholine and vasoactive intestinal polypeptide. For example: acetylcholine (Ach), norepinephine (NorEpi) and epinephrine (Epi), nitric oxide (NO), vasointestinal peptide (VIP), ATP, substance P, seratonin, dopamine, cholecystokinin (CCK), somatostatin, effects of many unknown Ach = excitatory in gut NorEpi and Epi = inhibitory in gut NO, VIP, ATP act locally to relax smooth muscle (decrease peristalsis) and increase local blood flow – promotes absorption Substance P – increases peristalsis Serotonin [ 7siErE5tEunin ] n.含于血液中的复合胺

Gastrointestinal Hormone The hormones synthesized by a large number of endocrine cells within the gastrointestinal tract Brain-gut peptides: a number of the classical GI hormones are also synthesized in the brain There are a bunch of hormones, neuropeptides and neurotransmitters that affect gastrointestinal function. Interestingly, a number of the classical GI hormones are also synthesized in the brain, and sometimes referred to as "brain-gut peptides". The significance of this pattern of expression is not clear.

Physiological functions control of the digestive function the release of other hormones trophic action Trophic [ 5trCfik ] adj.营养的, 有关营养的

Five major GI hormones Gastrin Cholecystokinin Secretin Gastric inhibitory polypeptide (GIP) motilin Gastrin - Synthesized in G cells Cholecystokinin - Synthesized in I cells Secretin – Synthesized in S cells Gastrin [ 5^Astrin ] n.[医]胃泌激素 Cholecystokinin [`kClI9sIstE`kaInIn] n.[生化]缩胆囊素,缩胆囊肽, 肠促胰酶肽 Secretin [ si5kri:tin ] n.分泌素 Polypeptide [ 7pCli5peptaid ] n.[生化]多肽

DIGESTION IN STOMACH

Gastric Secretion Specialized cells in the stomach synthesize and secrete mucous fluid, enzyme precursors, hydrochloric acid, and hormones. Note esophageal sphincter correction. The abundant smooth muscle in the stomach is responsible for gastric motility.

Chief cells synthesize and secrete the protease precursor known as pepsinogen. Parietal cells synthesize and secrete the hydrochloric acid responsible for the acidic pH in the gastric lumen.

(i)Composition and Function Properties pH 0.9~1.5 1~2.5 L/day Major components Hydrochloric acid Pepsinogen Mucus Intrinsic factor

(1) Hydrochloric acid Secreted by the parietal cells Output Basal: 0~5 mmol/h Maximal: 20~25 mmol/h

Mechanism of HCl secretion HCl is actively secreted against a huge concentration gradient H+/K+ ATPase or "proton pump"

Four chemical messengers regulate HCl secretion One inhibitory and three stimulatory signals that alter acid secretion by parietal cells in the stomach. p595

Role of HCl Acid sterilization Activation of pepsinogen Promotion of secretin secretion Assisted effect of iron and calcium absorption

(2) Pepsinogen Secreted by the chief cells as an inactive precursor of pepsin Activated in the stomach, initially by H+ ions and then by active pepsin, autocatalytic activation Active pepsin (MW: 35,000)

The acidity in the gastric lumen converts the protease precursor pepsinogen to pepsin; subsequent conversions occur quickly as a result of pepsin’s protease activity.

Effect of pepsin Pepsin is an endopeptidase, which attacks peptide bonds in the interior of large protein molecules Proteins Proteoses Peptones Polypeptides Pepsin

(3) Mucus Secreted by the epithelial cells all over the mucosa and by the neck mucus cells in the upper portion of the gastric glands and pyloric glands

Role Lubrication of the mucosal surface Protection of the tissue from mechanical damage by food particles Mucus: Mucus is secreted by the epithelial cells all over the mucosa of mlumenal surface and by the “neck mucus cells” in the upper portion of the gastric glands & pyloric glands. It is deposited as a layer ~500 m thick on the surface of the mucosa. MUCUS is composed chiefly of mucins and inorganic salts suspended in water a layer ~500 m thick composed chiefly of mucins

Mucus-HCO3- barrier Epithelial cells and neck mucus cells secrete a bicarbonate-rich mucus that coats and lubricates the gastric surface Serves an important role in protecting the epithelium from acid and other chemical insults. The mucus layer also traps HCO3- secreted by the mucosal cells and this buffers, or chemically insulates, the mucosa from the acidic stomach contents.

(4) Intrinsic factor A high molecular weight glycoprotein, synthesized and secreted by the parietal cells The intrinsic factor binds to Vit B12 and facilitates its absorption

(5) Secretion of other enzymes Gastric lipase Gastric amylase Gelatinase

(ii) Regulation of Gastric Secretion (1) Basic factors that stimulate gastric secretion Acetylcholine (+ all secretory cells) Gastrin (+ parietal cells) Histamine (+ parietal cells)

‘Short’ reflex pathways (2) Nervous regulation ‘Short’ reflex pathways ‘Short’ excitatory reflexes: mediated by cholinergic neurons in the plexuses ‘Short’ inhibitory reflexes: mediated by non-adrenergic non-cholinergic (NANC) neurons

‘Long’ autonomic pathways (2) Nervous regulation ‘Long’ autonomic pathways ‘Long’ excitatory reflexes: parasympathetic ‘Long’ inhibitory pathways: sympathetic

5-hydroxytryptamine (5-HT) Prostaglandin (3) Humoral regulation Excitatory ACh Histamine Gastrin Inhibitory Somatostatin Secretin 5-hydroxytryptamine (5-HT) Prostaglandin

(4) Phases of gastric secretion Cephalic phase Gastric phase Intestinal phase

(5) Inhibition of gastric secretion The functional purpose of the inhibition of gastric secretion by intestinal factors is presumably to slow the release of chyme from the stomach when the small intestine is already filled or overactive

Gastric Motility Proximal stomach cardia Distal stomach antrum fundus corpus (body) Distal stomach antrum pylorus pyloric sphincter

Receptive relaxation Storage function (1.0~1.5 L) Vago-vagal reflex Peristalsis BER in the stomach

Waves of smooth muscle contraction mix and propel the ingested contents of the gastric lumen, but only a small amount of the material enters the small intestine (duodenum) as a result of each wave cycle.

Emptying of the stomach Emptying rate Fluid > viscous Small particle > large particle Isosmotic > hyper- & hypo-osmotic Carbohydrates > Protein > Fat Regular meal 4～6 hrs

Regulation of stomach emptying Gastric factors that promote emptying Gastric food volume Gastrin Duodenal factors that inhibit stomach emptying Enterogastric nervous reflexes Fat Cholecystokinin

Pancreatic Secretion

The exocrine cells in the pancreas play a central role in the production of digestive enzymes; the endocrine functions of the pancreas will be discussed at length in Chapter 16.

(I) Pancreatic Secretion pH 7.8~8.4 ~1500 ml/day Isosmotic Components: Pancreatic digestive enzymes: secreted by pancreatic acini Sodium bicarbonate: secreted by small ductules and larger ducts

Were digestive enzymes synthesized in their active form, they would digest the very cells that make them. Hence, inactive precursors (e.g., trypsinogen) become activated (trypsin).

Secretion of bicarbonate ions Secreted by the epithelial cells of the ductules and ducts that lead from acini Up to 145mmol/L in pancreatic juice (5 times that in the plasma) Neutralizing acid entering the duodenum from the stomach

Secretion of pancreatic digestive enzymes Carbohydrates -- Pancreatic amylase Pancreatic lipase (coplipase) Fat Cholesterol esterase Phospholipase Trypsinogen Proteins Chymotrypsinogen Procarboxypolypeptidase Proelastase -RNAase -DNAase

Starches Pancreatic amylase Maltose and glucose polymers

Trypsin Inhibitor Inhibits the activity of trypsin and thus guards against the possible activation of trypsin and the subsequent autodigestion of the pancreas

Acute pancreatitis

(II) Regulation of pancreatic secretion Basic stimuli that cause pancreatic secretion Ach Cholecystokinin: Secreted by I cells Stimulates the acinar cells to secrete large amounts of enzymes Secretin: Released by S cells Acts primarily on the duct cells to stimulate the secretion of a large volume of solution with a high HCO3- concentration

Phases of pancreatic secretion Cephalic Phase: taste of food- ‘long’ parasympathetic pathways Gastric Phase: distension of stomach- ‘long’ parasympathetic reflex pathways Intestinal Phase The most important regulators are CCK and secretin Acid, fats, amino acids, peptides and protein are the main stimulus for pancreatic production and secretion

Bile Secretion

Composition of bile HCO3- Bile salts Lecithin Cholesterol Bile pigments Trace metals … The bile is funneled into the gallbladder and then delivered into the duodenum upon stimulation from CCK.

Function of bile Bile salts are facial amphipathic (1) Bile are critical for digestion and absorption of fats and fat-soluble vitamins Bile salts are facial amphipathic There are two fundamentally important functions of bile in all species: Bile contains bile acids, which are critical for digestion and absorption of fats and fat-soluble vitamins in the small intestine. Because: Bile salts are derivatives of cholesterol synthesized in the hepatocyte. The most abundant of the bile salts in humans are cholate and deoxycholate, They are then conjugated to an amino acid (glycine or taurine) to yield the conjugated form that is actively secreted into cannaliculi. Bile acids are facial amphipathic, that is, they contain both hydrophobic (lipid soluble) and polar (hydrophilic) faces.

"Looking at you with a jaundiced eye" (2) Eliminate many waste products Excrete bile pigments or drug metabolites "Looking at you with a jaundiced eye" 2. Many waste products are eliminated from the body by secretion into bile and elimination in feces. The liver is well known to metabolize and excrete into bile many compounds and toxins, thus eliminating them (usually) from the body. One of the most important and clinically relevant examples of waste elimination via bile is that of bilirubin. is a useless and toxic breakdown product of hemoglobin. The dead and damaged red blood cells are picked up by phagocytic cells throughout the body (including Kuppfer cells in the liver) and digested. Within the phagocytic cells, heme is converted through a series of steps into free bilirubin, which is released into plasma where it is carried around bound to albumin, itself a secretory product of the liver. Free bilirubin is stripped off albumin and absorbed by - you guessed it - hepatocytes. Within hepatocytes, free bilirubin is conjugated to either glucuronic acid or sulfate - it is then called conjugated bilirubin Conjugated bilirubin is secreted into the bile canaliculus as part of bile and thus delivered to the small intestine. Bacteria in the intestinal lumen metabolize bilirubin to a series of other compounds which are ultimately eliminated either in feces or, after reabsortion, in urine. The major metabolite of bilirubin in feces is sterobilin, which gives feces their characteristic brown color. If excessive quantities of either free or conjugated bilirubin accumulate in extracellular fluid, a yellow discoloration of the skin, sclera and mucous membranes is observed - this condition is called icterus or jaundice. Determining whether the excessive bilirubin is free or conjugated can aid in diagnosing the cause of the problem. Bilirubin (useless and toxic breakdown product of hemoglobin)

90% of gallstones are of cholesterol stones (3) Prevent the precipitation of cholesterol in the gallbladder and eliminate excess cholesterol Secretion into bile is a major route for eliminating cholesterol. Free cholesterol is virtually insoluble in aqueous solutions, but in bile, it is made soluble by bile acids and lipids like lethicin. In humans, roughly 500 mg of cholesterol are converted to bile acids and eliminated in bile every day. This route for elimination of excess cholesterol is probably important in all animals, but particularly in situations of massive cholesterol ingestion. Bile Preventing the cholesterol precipitation Gallstones Gallstones are concretions that form in the biliary system, usually the gallbladder. About 90% of gallstones are of cholesterol stones. These stones can be almost pure cholesterol or mixtures of cholesterol and substances such as mucin. The key event leading to formation and progression of cholesterol stones is precipitation of cholesterol in bile 90% of gallstones are of cholesterol stones

(4) Increasing bile synthesis & secretion Up to 95% of the cholesterol-based bile salts are “recycled” by reabsorption along the intestine. -------Enterohepatic circulation (5) neutralize the stomach acid

Regulation of bile secretion Substances increasing bile production Bile salts Secretin Cholecystokinin parasympathetic input The flow of bile is lowest during fasting, and a majority of that is diverted into the gallbladder for concentration. When chyme from an ingested meal enters the small intestine, acid and partially digested fats and proteins stimulate secretion of and.

Absorption in the gastrointestinal tract

(I) Basic principle of absorption Almost all absorption of nutrients occurs in the small intestine

1. Absorptive surface of small intestinal mucosa Total area of 250 m2: Folds: 3-fold Villi: 10-fold Microvilli: 20-fold

2. Absorption pathways transcellular route paracellular route There are two routes for transport across the epithelium of the gut: Across the plasma membrane of the epithelial cells (transcellular route) Across tight junctions between epithelial cells (paracellular route)

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