L19 - GI Motility

Question 1

What facilitates mechanical digestion in the small intestine?

Answer 1

SEGMENTATION:

• Rhythmic contraction and relaxation of the intestine
• Mixing of:
• Chyme
• Bile
• Pancreatic enzymes
• Pancreatic fluid
• Intestinal fluid
• Anterograde + retrograde movements (back and forth motion) for mixing
• Increases contact time with chyme with the intestinal juices for digestion and mucosal surface for absorption
• Distension in the intestine stimulates stretch receptors, which stimulates myenteric plexus.
• Myenteric plexus (via nagal innervation) stimulates circular smooth muscles to contract to produce segmentation contractions

Question 2

Skeletal muscle in the GI tract

Answer 2

• Striated muscle - muscle fibre
• Attached to bones by bundles of connective tissue - tendons
• Only found in the upper third of the oesophagus + lower part of the large intestine (rectum)
• Voluntary control
• Stimulated by motor neurons
• Neurotransmitter used = acetylcholine

Question 3

How is excitation-contraction (E-C) coupling achieved? (skeletal muscle)

Answer 3

• After ACh binds to receipts on motor-end plate of the muscle plasma membrane under axon terminal - opening of ion channels => depolarisation
• Propagation of action potential over the surface of muscle fibre (in both directions)

E-C coupling steps:
1. Action potential propagated along muscle cell and into T-tubule protein - triggers opening of voltage-gated Ca++ channels - influx of Ca++ into cell

2. Ca++ ions released from sarcoplasmic reticulum into cytosol inside cell
3. Ca++ ions bind to troponin - removing blocking action of tropomyosin
4. Cross-bridges bind, rotate, and generate force (ATP) => CONTRACTION occurs
5. Ca++ ions transported back into sarcoplasmic reticulum via Ca-ATPase pump
6. Ca++ removed from troponin, restoring tropomyosin blocking action => RELAXATION occurs

Question 4

How is excitation-contraction (E-C) coupling achieved? (smooth muscle)

Answer 4

• Different to than in skeletal muscle
• No Ca-binding troponin involved, hence no blocking action of tropomyosin

E-C coupling steps:
1. Ca++ binds to calmodulin protein

2. Ca++-calmodulin complex binds to myosin light-chain kinase (MLCK) - activating the MLCK enzyme
3. Active MLCK uses ATP to phosphorylate myosin
4. This drives the cross-bridge away from thick filament backbone - allowing it to bind to actin => CONTRACTION occurs
5. Repeated cycles of force generation through cross-bridges as long as myosin is phosphorylated
6. RELAXATION => myosin must be dephosphorylated (to disable binding to actin) - via myosin light-chain phosphatase enzyme

Question 5

Transit time in the small intestine

Answer 5

• Relatively constant - 3-4 hrs
• Rapid in duodenum but slows down in ileum - most digestion occurs in duodenum + jejunum
• Slow rate of absorption + transit time in ileum — allows digestion of fats, bile, fat soluble vitamins
• Some Pharma agents + excipients affect motility – controlled-release formulations
• Motility also affected by some disorders

Question 6

How is the motility pattern like in a fasted state?

Answer 6

• Interdigestive peristaltic activity occurs — aka Migrating Myoelectric Complex (MMC)
• In MMC - Peristaltic contraction waves begin in the stomach and reaches ileum - ~2hrs then starts all over again (until feeding state)

Why?
- Moves along undigested material towards the large intestine
- Dead cells + residue gets moved along too

• Due to increase in hormone motilin — increases neuronal activity
• There is always a basal level of activity in the GI tract.

Question 7

How is the motility pattern like in a fed state?

Answer 7

• Random motor activity of sequential contractions – segmentation
• Physical nature of food affects number of contractions
• Solid food induces twice as many contractions as equicalorific liquid
• Carbohydrates > protein > lipid

Question 8

Disorders that affect small intestine motility and transit time

Answer 8

Faster SITT:
- Diarrhoea
- Hyperthyroidism
- IBS
- Chronic pancreatitis

Slower SITT:
- Constipation
- Hypothyroidism
- Pseudo-obstruction
- Ileal resection
- Partial gasterctomy
- Jejunal bypass
- Diabtetes

Question 9

Therapy for GI dysmotility

Answer 9

1. Anti-spasmodics (IBS)
   - reduce smooth muscle contraction
   - e.g. anti-muscarinic antagonists (hyoscine, mebeverine
2. Anti-motility (diarrhoea)
   - reduce transit through GI tract by decreasing activity of myesnteric plexus
   - e.g. loperamide (opioid angonist)
3. Prokinetics (constipation+IBS)
   - stimulate GI tract activity by increasing contraction
   - e.g. drugs that act on 5-HT receptors (Tegaserod, metoclopramide)
4. Laxatives (constipation)
   - stimulate intestinal movement by increasing bulk, adding lubrication or acting as local irritant to mucosal layer