Regulation of gastrointestinal function

1. Regulation of gastrointestinal function Lecture 24 Friday, March 2, 2007 Refs. Ross Chapter 17, Wheater’s Chapter 14 and 17 p326-327, Moore and Dalley Chapter 2, More and Agur, Medical Physiology Chapter 40, Ganong Chapter 26, and Berne and Levy

2. General features of digestive tube • Muscular tube lined by mucosa • Regional variations in mucosa • Regional variations in muscular tunic • Regional variations in outer layer • Peristalsis • Involuntary waves of smooth muscle contraction • 2 layers of smooth muscle: • circular inner and longitudinal outer • Borborygmus- a rumbling noise caused by the propulsion of gas through the gut • Sphincters/junctions • Esophageal • Pyloric sphincter • Ileocecal valve • Anal sphincter

3. Anatomy of nerves of the GI tract • Autonomic • Parasympathetic preganglionic fibers: • Vagus supplies esophagus through ascending colon • S2, 3, 4 supply descending colon to anal canal • Sympathetic preganglionic fibers come from spinal segments and postganglionic neurons are in prevertebral ganglia: • Celiac ganglion from spinal segments T6 - T10; postsynaptic fibers supply the stomach, small intestine, pancreas and liver. • Superior mesenteric ganglion from segments T6-T8; supplies colon • Inferior mesenteric ganglion has input from L1-3 and supplies colon/rectum.

4. Sympathetic ganglia and plexuses M/A 3.29b

5. Simplified schematic of innervation of intestine Moore and Agur 3.20

6. Visceral pain • Viscera are mainly sensitive to distension and chemical stimuli. • Pain varies from dull to severe. • Often poorly localized or referred. • Referred-- perceived as originating in the dermatome supplied by somatic nerves that enter the same spinal segment as the afferent nerves from the visceral organ.

7. Referred pain. Snell 5-17

8. Nervous networks in gut wall gan 26-1

9. Nerve networks in the wall of the digestive tract • Submucosal plexus • Located in submucosa; supplies glands, blood vessels, muscularis mucosae • Myenteric plexus • Located between the circular and longitudinal layers of the muscularis externa • Both networks contain • Postganglionic parasympathetic neurons • Both sympathetic and parasympathetic fibers • Neurons of enteric nervous system

10. Enteric nervous system • Contains~100 million sensory neurons, interneurons, and motor neurons • Considered a third division of the autonomic system by authors of Medical Physiology. • Neurotransmitters • Acetylcholine • Norepinephrine • Serotonin, GABA, ATP, NO, CO, and many peptides and polypeptides that can also act as hormones or in a paracrine fashion.

11. Enteric nervous systemNeurons of the ENS are shown here in black and include sensory neurons, interneurons, and secretomotor neurons MP 40-3b

12. Peptides found in the enteric nervous system • CGRP calcitonin gene-related peptide • CCK cholecystokinin • Endothelin-2 • Enkephalins • Galanin • GRP gastrin releasing peptide • Neuropeptide Y • Neurotensin • Peptide YY • PACAP pituitary adenylyl cyclase-activating polypeptide • Somatostatin • Substance P • TRH thyrotropin-releasing hormone • VIP vasoactive intestinal peptide

13. Effects of nerve stimulation • Parasympathetic stimulation • Increases secretion • Increases smooth muscle activity • ? Cholinergic innervation to blood vessels is uncertain • Sympathetic • Noradrenergic activity decreases muscle activity but contracts sphincters • Postganglionic fibers end on parasympathetic neurons and inhibit them by activating a2 presynaptic receptors • Postganglionic fibers end on blood vessels and produce vasoconstriction • Intrinsic • Blood vessels are also innervated by enteric fibers • VIP and NO are mediators of hyperemia

14. Smooth muscle in gut wall is unitary MP 9-2

15. Unitary smooth muscle • Arranged in large sheets or bundles • Walls of hollow viscera • Most blood vessels • Low level of rhythmic contraction • ± action potential • Transmission through gap junctions • Autonomic modulation

16. Unitary smooth muscle contraction • Stretch stimulates contraction. • Slow initiation, slow “walking” on actin, and slow relaxation • Energy requirement is low compared to skeletal muscle • 1/10 to 1/300 • Maximum force greater than skeletal muscle • Latch phenomenon • Adapts to stretch • Energy required to maintain contraction can be minimal

17. Action potentials in smooth muscle • May occur in unitary muscle • 30 to 40 cells must depolarize simultaneously to generate a self-propagating action potential • Can be spontaneous associated with slow waves • Can be stimulated • Neurotransmitters, hormones, stretch • Spikes or plateaus

18. Calcium in smooth muscle contraction • Initiates contraction • Source is mainly extracellular • Many voltage-gated calcium channels • Hormone-activated calcium channels

19. Basic electrical rhythm • Rhythmic fluctuations in membrane potential • -65 to -45 mV • Initiated by interstitial cells of Cajal • Stellate mesenchymal pacemaker cells located near the mesenteric plexus in stomach and small intestine • In the colon located at the submucosal border of circular muscle. • BER itself does not cause contractions • Spike potentials superimposed on depolarized part of cycle increase muscle tension • Contractions occur only during depolarizing part of wave.

20. BER (slow wave) and contractionsBerne and Levy 33-6

21. Electrical and tension recordings in gut gan 26-2

22. Motility • Peristalsis • A reflex: the stimulus is distension of lumen • Contraction orad of bolus • Relaxation aborad of bolus • Propulsive versus mixing or churning • Migrating motor complex • Occur during fasting periods, about 90 minutes apart • Each MMC has a quiescent period, irregular period, regular activity • Immediately stopped by ingestion • Move indigestible material down tract. • Help prevent bacterial overgrowth in small intestine.

23. MMCs move down GI tract at regular rate gan 26-3

24. Neuroendocrine cells • Found in epithelium throughout GI tract • Open type can sample contents of lumen • Closed type are not in direct contact with lumen • Secrete peptides to basolateral surface • Many different polypeptides (>20) • Usually 1 peptide/cell • Endocrine (carried by blood to target), paracrine, and neurocrine (act as neurotransmitters) • Identify secretory product by immunostaining or nucleotide sequence.

25. Open type mucosal neuroendocrine cell W 17.23a

26. Closed type mucosal neuroendocrine cell W 17.23b

27. Neuroendocrine cells in colon W 17.23c

28. EM of pylorus: gastrin and somatostatin neuroendocrine cells W 17.24

29. Distribution of peptides along GI tract gan 26-4