Fluid balance in the GI tract & control of motility

Question 1

What is the driver of absorption of water?

Answer 1

movement of electrolytes (mainly Na) from the lumen of the intestines to the bloodstream

Question 2

What is diarrhoea defined as?

Answer 2

loss of fluid and solutes from the GI tract in excess of 500 ml per day

Question 3

What does the reabsorption of Na provide?

Answer 3

provides a (local) osmotic force for reabsorption of water

Question 4

What are the principle mechanisms of absorption of water?

Answer 4

Na+/glucose co-transport
Na+/amino acid co-transport
Na+/H+ exchange
Parallel Na+/H+ and Cl-/HCO3- exchange
Epithelial Na+ channels (ENaC)

Question 5

Describe where and when the Na+/glucose co-transport and Na+/amino acid co-transport occur?

Answer 5

throughout the small intestine and is most important in the postprandial period (fed state)
- major mechanism of fed state

Question 6

Describe where and when the Na+/H+ exchange occurs?

Answer 6

Occurs in the duodenum and jejunum and is stimulated by luminal HCO3-

Question 7

Describe where and when the parallel Na+/H+ and Cl-/HCO3- exchange occurs?

Answer 7

Occurs in the ileum and colon most important in the interdigestive period

Question 8

Describe where and when the Epithelial Na+ channels (ENaC) occurs?

Answer 8

In the colon (distal particularly) and is regulated by aldosterone
- is an ION CHANNEL instead of a transporter

Question 9

Describe the function of the Na+/glucose co-transport and Na+/amino acid co-transport?

Answer 9

secondary active transport
are electrogenic (like the Na+/K+ ATPase)
collectively the overall transport of Na+ generates a transepithelial potential (VTE) in which the lumen is negative – this drives the parallel absorption of Cl-

Question 10

Which membranes do the Na+/H+ exchange occur? What is the role of each transporter?

Answer 10

both the apical (NHE2 and NHE3) and basolateral (NHE1) membranes
but only NHE2 and NHE3 contribute to transepithelial movement of Na+
NHE1 is a ‘cellular pH housekeeper’

Question 11

What is exchange at apical membranes in the jejunum stimulated by?

Answer 11

alkaline environment of the lumen

Question 12

What do intracellular cAMP, cGMP and Ca2+ all reduce ?

Answer 12

NaCl absorption

Question 13

What change in NaCl causes diarrhoea?

Answer 13

Reduction in NaCl absorption

Question 14

What are the 3 mechanisms of aldosterone?

Answer 14

1. opens ENaC (seconds)
2. inserts more ENaC into membrane from intracellular vesicle pool (minutes)
3. increases synthesis of ENaC and Na+/K+-ATPase (hours)

Question 15

What are Epithelial Na+ channels (ENaC) regulated by?

Answer 15

aldosterone

Question 16

How is Cl absorbed?

Answer 16

Can occur passively via transcellular or paracellular routes

Question 17

How is Cl absorbed in the small intestine?

Answer 17

driving force provided by lumen negative potential due to electrogenic transport of Na+ (Na+/glucose and Na+/amino acid)

Question 18

How is Cl absorbed in the large intestine?

Answer 18

driving force provided by lumen negative potential due to electrogenic movement of Na+ through ENaC

Question 19

True or false - there is a higher rate of Cl absorption than secretion?

Answer 19

TRUE

Question 20

Where does Cl secretion occur?

Answer 20

crypt cells

Question 21

What 3 processes are involved in Cl secretion?

Answer 21

Na+/K+ATPase
Na+/K+/2Cl- co-transporter (NKCC1)
K+ channels (IK1 and BK)
(all on the basolateral membrane)

Question 22

How does Cl exit the cell?

Answer 22

via CFTR on the apical membrane

Question 23

What does activation of the CFTR result in?

Answer 23

secretory diarrhoea

Question 24

What is the role of Misoprostol?

Answer 24

enhances secretion - drug used to start labour, cause diarrhoea by opening the CFTR

Question 25

What secondary messagers can cause activation of the CFTR?

Answer 25

cAMP (e.g. cholera toxin, VIP, histamine)
cGMP (e.g. heat stable enterotoxin, guanylin)
Ca2+ (e.g. acetylcholine, bradykinin, 5-HT)

Question 26

What other things can cause activation of the CFTR?

Answer 26

bacterial enterotoxins [e.g. cholera toxin (V. cholerae), heat stable enterotoxin (E. coli), C. difficile toxin]
hormones and neurotransmitters [e.g. vasoactive intestinal peptide (VIP), guanylin, acetylcholine, bradykinin, 5-HT (serotonin)]
immune cells products (e.g. prostaglandins*, histamine)
some laxatives (e.g. bile acids)

Question 27

What can cause Diarrhoea?

Answer 27

Impaired absorption of NaCl
Non-absorbable, or poorly absorbable, solutes in intestinal lumen (lactase deficiency)
Hypermotility
Excessive secretion - cholera (blocks GTPase which causes an irrevesible increase of cAMP which stimulates CFTR)

Question 28

How does SGLT1 work?

Answer 28

1. 2 Na+ bind
2. Affinity for glucose increases, glucose binds
3. Na+ and glucose translocate from extracellular to intracellular
4. 2 Na+ dissociate, affinity for glucose falls
5. Glucose dissociates
6. Cycle is repeated

Question 29

What does SGLT1 also transport?

Answer 29

water

Question 30

How do opiods treat diarrhoea?

Answer 30

inhibition of enteric neurones
decreased peristalis, increased segmentation
increased fluid absorption
constriction of pyloric, ileocaecal and anal sphincters
increased tone of large intestine

Question 31

What is the best anti-diarrhoea drug?

Answer 31

loperamide