Gastrointestinal Physiology

1. Gastrointestinal Physiology Most images courtesy Joe Haeberle, UVM

2. 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 cAMP Decreased free Ca++ AC Vascular Smooth Muscle Cell

3. Splanchnic Circulation (cont’d) • 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

4. Intrinsic Nervous System (gut brain) • Nerves that interconnect within GI organs and plexuses, independent of the autonomic system. • Auerbach’s, Meissner’s plexus contribute! • Receptor neurons are sensory (detect stretch, damage), effector neurons are motor (cause SM contraction) • Excitatory NT’s- Ach, Subst. P • Inhibitory NT’s- VIP, NO • what causes contraction/relaxation of smooth muscle?

5. 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

6. 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

7. Slow Waves and SM Contraction Questions: 1. Where are the slow waves the most frequent in the GI system? 2. Which cells initiate slow wave activity? • 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. Orad Interstitial Cells of Cajal

8. Slow Waves vs. MMC’s • 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 re-start in the stomach approximately every 90 minutes as long as you’re fasting. • Their roles • to flush remaining food and bacteria into the large intestine. • to tell you that you’re hungry!

9. GI Smooth Muscle (cont’d) • 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

10. 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

11. Saliva Secretion Control

12. 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)

13. 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

14. Acid Regulation in the Stomach

15. More Acid Regulation

16. 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)

17. 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.

18. 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 (wall’s sign) • caused by atresia, improper formation of duodenum

19. Gastric and Duodenal Ulcers-H. 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

20. 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.

21. Components of Bile • 50% Bile Acids (Cholic, chenodeoxycholic, deoxycholic, and lithocholic acid • Product of Cholesterol + 7a-Hydroxylase, 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

22. Bilirubin Metabolism senescent RBC Bilirubin- Albumin Adduct Plasma Macrophages (spleen) heme Bilirubin (indirect) Systemic Circulation Urine (urobilin) Feces (stercobilin) Bilirubin Glucuronide Portal Circ. Urobilinogen Bile Duct Hepatocyte Intestinal Flora

23. 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.

24. 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

25. 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)

26. 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

27. 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.

28. Absorption of Proteins/ Lipids

29. SCFA’s • 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