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2 Gastrointestinal physiology for medical students

3 General principal of gastrointestinal function Motility, nervous control and blood circulation

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5 Physiological processes in the GI tract: Motility Secretion Digestion Absorption

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7 Gastrointestinal (GI) Motility Characteristic of the GI wall * Smooth muscles in GI function as syncytium

8 Characteristic of the GI wall Mucosa: Epithelium; varies at different part of GI Lamina propria; connective tissue Glands, lymph node, capillaries Muscularis mucosa; mucosal fold and ridges Submucosa: connective tissue Glands, large nerve trunks, blood vessels Muscularis externa: mix & propel content of the lumen Inner circular layer Outer longitudinal layer Serosa: connective tissue covered by squamous mesothelial cells

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10 Villus Microvillus Crypt

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13 Electrical activity of GI smooth muscle* Slow waves: oscillation of RMP Fr: 3-12/min Generated by interstitial cells of Cajal Amplitude and frequency of SW modified by ANS Spike potential: due to slow Na-Ca entry, Fr: 1-10/sec Calcium ions and muscle contraction Changes in RMP: Depolarizing (distension, Ach) Hyperpolarizing (epinephrine) Tonic contraction of some GI muscles: Repeated spike potential or Hormonal

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15 REGULATORY MECHANISMS IN THE Neural GASTROINTESTINAL TRACT Extrinsic component (sympathetic and parasympathetic) Intrinsic component (Enteric nervous system) Endocrine Entroendocrine cell (EEC) Paracrine

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17 Endocrine control

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19 In The Clinic Glucagon-like peptide 1 (GLP-1) is a regulatory peptide released from EC cells in the gut wall in response to the presence of luminal carbohydrate and lipids. GLP-1 arises from differential processing of the glucagon gene, the same gene that is expressed in the pancreas and that gives rise to glucagon. GLP-1 is involved in regulation of the blood glucose level via stimulation of insulin secretion and also insulin biosynthesis. Agonists of the GLP-1 receptor improve insulin sensitivity in diabetic animal models and human subjects. Administration of GLP-1 also reduces appetite and food intake and delays gastric emptying, responses that may contribute to improving glucose tolerance. Long-acting agonists for the GLP-1 receptor, such as exanatide, have been approved for the treatment of type 2 diabetes.

20 Endocrine cell in GI tract: Open type Close type

21 Paracrine Regulation Histamine: by ECL cells. Serotonin: by enteric neurons, mucosal mast cells, enterochromaffin cells, regulates smooth muscle function & water absorption. Prostaglandins Adenosine Nitric oxide (NO)

22 Neural control Extrinsic component (sympathetic & parasympathetic) Intrinsic component (Enteric nervous system)

23 The Enteric nervous system (ENS) Myenteric Auerbach's) (Auerbach's plexus: motor Submucosal Meissner's) (Meissner's plexus: secretory Neurotransmitters on ENS: Excitatory: Ach, VIP Inhibitory: NO ENS (minibrain) consists of: Sensory neurons Interneurons Motor neurons

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25 Neurotransmitters/neuromodulatorsneuromodulators in the ENS Acetylcholine (ACh): Excitatory transmitter to smooth muscle, intestinal epithelial cells, parietal cells, certain endocrine cells, and at neuroneuronal synapses Adenosine triphosphate (ATP): Inhibitory transmitter to smooth muscle Calcitonin gene-related peptide (CGRP): Released by enteric sensory neurons onto interneurons in enteric ganglia and central ganglia Gastric-releasing peptide: Released by secretomotor neurons onto G cells Nitric oxide (NO): Inhibitory transmitter to smooth muscle cells Substance P: Excitatory transmitter to smooth muscle cells Vasoactive intestinal peptide (VIP): Inhibitory transmitter to smooth muscle cells, excitatory secretomotor transmitter to epithelial and gland cells, vasodilator.

26 Autonomic control of GI tract Parasympathetic innervation Cranial (vagus n) Sacral (S 2 -S 4 ): pelvic n

27 - Sympathetic innervation (T5 - L2) : celiac and mesenteric ganglions

28 Afferent sensory nerve fiber from To: 1. ENS 2. Prevertebral ganglion 3. Spinal cord 4. Brain stem Osmoreceptors Chemoreceptors mechanoreceptors GI reflexes: 1. local reflex 2. Gastrocolic, enterogastric, colonoileal reflexes 3. Vagovagal reflex, defecation reflex

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30 Three types of afferent signals that originate from the GI tract by: - hormones - immune system - neurons

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33 In The Clinic Hirschsprung's disease is a congenital disorder of the enteric nervous system characterized by failure to pass meconium at birth or severe chronic constipation in infancy. The typical features are absence of myenteric and submucosal neurons in the distal part of the colon and rectum. It is a polygenic disorder with characteristic mutations in at least three different classes of genes involved in neuronal development and differentiation

34 A hierarchy of neural integrative centers Brain-gut axis

35 In The Clinic Neurogenic secretory diarrhea Secretomotor neurons excite secretion of H2O, electrolytes, and mucus from the crypts of Lieberkühn. Ach and VIP are the principal excitatory neurotransmitters. The cell bodies of secretomotor neurons are in the submucosal plexus. Excitation of these neurons, for example, by histamine release from mast cells during allergic responses, can lead to neurogenic secretory diarrhea. Suppression of excitability e.g. by morphine or other opiates, can lead to constipation.

36 Gastrointestinal blood flow Anatomy of GI blood supply Sup & inf mesenteric arteries* Effect of gut activity and metabolic factors on GI blood flow Increased blood flow during activity Role of vasodilators: CCK, VIP, Gastrin, Secretin Bradykinin, Kallidin O 2 -Adenosin Nervous control of GI blood flow: Hemorrhagic shock, exercise End

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