Gastrointestinal Physiology

Most images courtesy Joe Haeberle, UVM

Splanchnic Circulation
Vasoconstrictors- Ang II, endothelin, NE (a2-agonists), PGF2a, Vasopressin Vasodilators- Ach, Adenosine, Bradykinin, CGRP, histamine, NO, VIP, b2-agonists
Vasorelaxation cGMP GPCR

dilator
Gs AC Vascular Smooth Muscle Cell cAMP Decreased free Ca++

Splanchnic Circulation (contd)

Myogenic Control- resistance vessels can close themselves off in times of high MAP
a mechanism for autoregulation

Postprandial Hyperemia- increases in blood flow to organs in response to a meal

mediated through intrinsic VIP release

Villar countercurrent mechanisms- make villi susceptible to ischemic necrosis

oxygen is shunted between arteriole and venule

Intrinsic Nervous System (gut brain)

Nerves that interconnect within GI organs and plexuses, independent of the autonomic system.
Auerbachs, Meissners plexus contribute!

Receptor neurons are sensory (detect stretch, damage), effector neurons are motor (cause SM contraction) Excitatory NTs- Ach, Subst. P Inhibitory NTs- VIP, NO
what causes contraction/relaxation of smooth muscle?

Gastrointestinal Smooth Muscle

Single-unit (gap junctions, coordinated contraction) Activated/inhibited by many neurotransmitters, hormones Contraction can be tonic or phasic depending on location/purpose of muscle cells
GI Wall vs. Sphincter

Smooth Muscle Excitation/Contraction Coupling

Slow Waves cause Spike Potentials during Ach stimulation Spike Potentials lead to increased [Ca++] [Ca], hormones
activate MLCK phosphorylates MLC

Slow Waves and SM Contraction

Slow Waves are regular changes in SM VM. They do not cause SM contraction unless they reach a threshold and cause action potentials. They are propagated along the GI tract. Parasympathetic Stimulation and other inputs increase the probability that VM will reach threshold.

Questions: 1. Where are the slow waves the most frequent Orad in the GI system? 2. Which cells initiate slow Interstitial Cells of wave activity?
Cajal

Slow Waves vs. MMCs

In fasting individuals, slow waves persist, but contractions diminish, until an MMC. MMC (migrating motor complex) is a set of strong contractions that lasts a few minutes in one section of the digestive tract, then moves aborally. These complexes last 90 minutes and will restart in the stomach approximately every 90 minutes as long as youre fasting. Their roles
to flush remaining food and bacteria into the large intestine. to tell you that youre hungry!

GI Smooth Muscle (contd)

Less-obvious differences between Skeletal/Cardiac and Smooth muscle:
1. Primary site of activation is thick filament (myosin light chain) instead of thin (TnC) 2. Smooth muscle undergoes pharmacomechanical coupling (hormones can contract SM without changing VM.)
e.g. agents that induce MLC phosphorylation directly

Similarities:
1. Both have actin/myosin and use cross-bridging to contract
SM has 15:1 ratio of thin:thick filaments

2. Both are activated by intracellular [Ca++]

Smooth Muscle Activators and Inhibitors:

Activators: Ach, Histamine Inhibitors: NO, VIP

Saliva!
Salivary Amylase (ptyalin) Lingual Lipase Mucins (glyco-proteins) Fluid
Hypotonic High [K+]

With increased salivary flow, [HCO3-]and osmolarity increase Secretion is inhibited by sleep

Saliva Secretion Control

Esophageal Peristalsis
1o Peristalsis:
Initiated by swallowing (not after vagotomy)

2o Peristalsis:
Caused by residual food in esophagus

Vagal nuclei run the show (ambiguus, DMN) SM Peristalsis persists after vagotomy (enteric NS takes over)

Diseases of the Esophagus

Achalasia:
Stenosis of LES, dilation of body of esophagus
bird-beak appearance on barium study

Hiatal Hernia
LES protrudes into thoracic cavity
LES tends to be patent due to negative pressure in thoracic cavity

LES Tone:
Increased by Ach, Gastrin Decreased by Sympathetics, PGE1

Acid Regulation in the Stomach

More Acid Regulation

Gastric Emptying
Contraction in the stomach
Orad <<<< Caudad (3/minute) Primarily peristaltic

Solid food is usually forced back into stomach for mixing Duodenum contracts much more often but is phasic (pseudosphincter)

Regulation of Gastric Emptying

Chyme entering the duodenum activates intestinal receptors. This leads to increased contraction of the duodenum and decreased contraction of the stomach (Delayed Gastric Emptying) Secretin, CCK, and GIP (enterogastrone) are released by the duodenum and feed back on the stomach to slow down.

Stomach Pathophysiology
Dumping Syndrome
Uncontrolled gastric emptying due to lack of feedback inhibition by duodenum
post-surgical neurological deficit

Un-digested food makes it to the colon Patient barely makes it to the bathroom

Pyloric Stenosis
Projectile vomiting Pediatric disease
failure to thrive projectile vomiting after breast feeding (walls sign) caused by atresia, improper formation of duodenum

Gastric and Duodenal UlcersH. pylori

Gastric-stomach. Duodenal-obvious. Peptic- hydrochloric acid/pepsin present 80% of gastric, 90% of duodenal ulcers are due to H. pylori infection weakens mucus barrier causes acid production (decreased Bicarb) NSAIDs can also contribute (COX-1) Gastrin Carcinomas- secrete gastrin
cause excessive acid secretion

Treatment? triple therapy (2 antibiotics, one antacid or bismuth) vagotomy

Pancreatic and Bile Secretions

Acid in Duodenum activates Secretion of Secretin to initiate HCO3- secretion AA, Lipids stimulate Gastrin (quick response) and CCK (prolonged response) to initiate pancreatic enzyme secretion. CCK also causes GB contraction, Sphincter of Oddi relaxation, and increased Bile Salt excretion by the liver.

Components of Bile
50% Bile Acids (Cholic, chenodeoxycholic, deoxycholic, and lithocholic acid
Product of Cholesterol + 7aHydroxylase, most is recycled from distal ileum Form micelles- amphipathic pK= approx. 7 if unconjugated conjugated to taurine or glycine- pK goes down, allows them to be soluble in the intestine

Phospholipids (lecithin)
solubilized by bile salts

Cholesterol Bile pigments

bilirubin glucuronide

Bilirubin Metabolism
senescent RBC

heme

Macrophages (spleen) Bilirubin (indirect)

BilirubinAlbumin Adduct

Feces (stercobilin)

Urine Systemic Circulation (urobilin)

Bilirubin Glucuronide

Portal Circ. Urobilinogen

Bile Duct Intestinal Flora

Hepatocyte

Enterohepatic Circulation
Most ile acids are taken up by distal ileum epithelial cells by 2o active transport when they are no longer needed for digestion. They travel to the liver via the portal vein and are taken up by hepatocytes through the NTCP channel for recycling. They re-enter the bile canaliculus through the BSEP (bile salt exchange pump) Other pumps exist for bilirubin glucuronide (MDR2), cations (MDR1) and phospholipids (MDR3). Bile acid-dependent bile secretion involves osmotic gradients created by the transport of bile acids.

Liver Pathophysiology- Cholestasis

Cholestasis is the absence of bile flow
2 Main Causes:
Failure to secrete bile acids and salts (no osmotic gradient) Obstruction of the biliary tree (cholelithiasis, cholangitis, tumor)

Cholestasis leads to jaundice (yellow skin/sclera) due to bilirubin backup in plasma

Indirect Bilirubin- unconjugated Direct Bilirubin- conjugated

Intestinal Reflexes
Vagovagal - Vagal sensory nerves relay stretch information to the brainstem, releasing vagal efferents to (e.g.) parietal and G cells in the stomach. Intestinointestinal- distention of one portion of the intestine leads to decreased contractions caudad of the bolus. Gastroileal, gastrocolic - Stomach activity leads to ileocecal relaxation and increased mass movements in the colon
These reflexes are mediated through both long and short nervous pathways (extrinsic and intrinsic) and hormones (CCK, gastrin)

Absorption of Sugars
Polysaccharides are broken down in the mouth, stomach, and small intestine Disaccharidases (e.g. sucrase) further digest them into monosaccharides, which are taken up by special transporters:

2 AT

fac. diffusion fac. diffusion

Absorption of Water/ Lytes

Most water is absorbed in the small intestine (approx. 7-9 L/ 24 hours!), another 600 mL/day is absorbed in the colon. Small intestine- water follows nutrients Large intestine- water follows electrolytes!
Na+ enters via its concentration gradient, pumped out the basolateral side by ATPase Cl- is exchanged for HCO3-, which is excreted.

Absorption of Proteins/ Lipids

SCFAs
Good bacteria in the colon produce Short Chain Fatty Acids from carbohydrates. These acids have been shown to kill harmful bacteria and nourish colon epithelial cells.

The End