Function of the GI system 4 basic digestive processes • MOTILITY • SECRETION • DIGESTION • ABSORPTION
Delay of 3 seconds 3
4 Lymph node Villus Epithelium Lamina propria Muscularis mucosae Submucosa Circular muscle Longitudinal muscle Serosa Myenteric plexus Submucosal plexus Gland in submucosa Muscularis externa Mucosa • epithelium • lamina propria: • muscularis mucosae • exocrine cells • endocrine/paracrine cells Submucosa • connective tissue, blood vessels, glands • submucosal nerve plexus (Meissner’s plexus) Muscularis externa • smooth muscle cell layer inner circular layer outer longitudinal layer • myenteric nerve plexus (Auerbach’s plexus) Serosa (adventitia)
Regulation of GI function Autonomous Neural regulation smooth muscle extrinsic NS (CNS) function intrinsic NS pacemaker activity electrical coupling GI hormones Paracrine mediators humoral regulation 5
3 Lymph node Villus Epithelium Lamina propria Muscularis mucosae Submucosa Circular muscle Longitudinal muscle Serosa Myenteric plexus Submucosal plexus Gland in submucosa Muscularis externa Autonomous smooth muscle function Intestinal smooth muscle cells: effector organ of GI motility Pacemaker activity: Thin layer of interstitial cells (interstitial cells of Cajal) between circular and longitudinal cell layer. Conduction through gap junctions.
Excitation-contraction coupling intestinal smooth muscle Contraction requires an increase of cytosolic calcium ([Ca2+]i) Electro-mechanical coupling: Contractions are triggered by action potentials (APs) that travel from cell to cell through gap junctions. Pharmaco-mechanical coupling: Contraction occur in the absence of action potentials e.g. in response to neurotransmitter or hormones. 5
3 Lymph node Villus Epithelium Lamina propria Muscularis mucosae Submucosa Circular muscle Longitudinal muscle Serosa Myenteric plexus Submucosal plexus Gland in submucosa Muscularis externa Pacemaker activity: Thin layer of interstitial cells (interstitial cells of Cajal) between circular and longitudinal cell layer. Conduction through gap junctions.
GI smooth muscle electrophysiology and contraction 6 Resting membrane potential -40 to -80 mV. membrane potential oscillations Na+/K+-ATPase. Slow waves Pacemaker activity Ionic events during slow waves: Na-, Ca- and K-currents Modulation by enteric neurons Action potentials when slow-waves reach electrical threshold: burst of APs (10-20 ms, rising phase is carried by Na+ and Ca2+ ions)
Smooth muscle tone and contraction • Contraction begins when depolarizing phase reaches mechanical threshold. • Development of muscle tone and contraction correlate with the degree of depolarization • can occur in the absence of APs. • Baseline tension is ‘non-zero’ (constant basal tone). • Tonic contractions: contractile tension that is maintained for prolonged periods of time. • Phasic contraction: “twitch-like” contraction evoked by action potentials. Triggering of APs increases strength of contraction. Frequency and number of APs grade the degree and duration of contraction.
Neurotransmitters of the autonomic nervous system sympathetic 2 parasympathetic 10
Integration of sympathetic, parasympathetic and enteric nervous system 12
Sympathetic efferent innervation • Primarily via postganglionic adrenergic fibers with cell bodies in prevertebral and paravertebral plexuses (celiac plexus, superior and inferior mesenteric plexus, superior and inferior hypogastric plexus) terminate in submucosal and myenteric plexus. • Typically inhibitory effect on synaptic transmission in the enteric plexuses. • Effects of sympathetic activity - vasoconstriction of gastrointestinal blood vessels - inhibition of glandular function - muscularis externa: inhibition of motor activity - contraction of muscularis mucosae and certain sphincters
Parasympathetic efferent innervation • Vagus nerve (upper gastrointestinal tract to transverse colon) and parasympathetic fibers of pelvic nerves from the hypogastric plexus Predominantly cholinergic fibers that terminate on ganglion cells of intramural plexuses. • Stimulation of motor (smooth muscle cells) and secretory activity.
Enteric nervous system 11 semi-autonomous nervous system in the wall of the GI tract ("the little brain in the gut"): major network of ganglia and interconnecting neurons (about 108 neurons!) 2 major plexuses • myenteric plexus (Auerbach’s plexus) • submucosal plexus (Meissner’s plexus)
Example of enteric reflex: The neural circuit for peristaltic propulsion of GI (the”law of intestine”). 14 Stretching a segment of the GI tract is sensed by sensory enteric neurons. This signal is transmitted via excitatory and inhibitory interneurons to excitatory (proximal) and inhibitory (distal) motor neurons, causing ascending excitation and descending inhibition of smooth muscle cells -->GI content is transported in aboral direction VIP = vasoactive intestinal peptide
Intestinal reflexes Short range reflexes: Food bolus causes aboral relaxation and proximal contraction --> food transport in orthograde direction (law of the intestine). Regulated by intrinsic nerves.
• Gastro intestinal hormones are released from distant endocrine cells and transported by blood streamto activate secretion (e.g. gastrin from G cells activate HCl secretion) • Paracrine mediators are released into the neighborhood of secretory cell and reaches target cells by diffusion (e.g. histamine = paracrine agonist for gastric HCl secretion). 58
Important actions of GI hormones (compare with table 15) Action Gastrin CCK Secretin GIP Acid secretion S I I Pancreatic HCO3- secretion S S Pancreatic enzyme secretion S Bile HCO3- S Gallbladder contraction S Gastric emptying I Mucosal growth S Pancreatic growth S S S = stimulates; I = inhibits
Additional GI hormones Hormones are produced by enteroendocrine cells in the GI tract in stomach, small and large intestine Motilin Serotonin Substance P Vasoactive intestinal peptide (VIP) Neurotensin increases intestinal motility increases intestinal motility increases intestinal motility neurotransmitter for intestinal smooth muscle stimulates secretion of water and ions decreases intestinal motility increases blood flow to ileum 16
Additional GI hormones (cont.) stimulate hepatic glycogenolysis stimulates hepatic glycogenolysis local inhibition of other endocrine cells (e.g. G-cells) inhibits secretion of HCl increases epithelial growth increases secretion of HCl Glucagon Entero-glucagon Glicentin (glucagon-like substance) Somatostatin Urogastrone (Epidermal Growth Factor) Histamine
Gastrointestinal paracrine mediators Paracrine agonists released by: - paracrine cells - GI immune system - antibodies - inflammaory mediators (prostaglandins, leukotrienes, cytokines, histamine, others) 4 Lymph node Villus Epithelium Lamina propria Muscularis mucosae Submucosa Circular muscle Longitudinal muscle Serosa Myenteric plexus Submucosal plexus Gland in submucosa 3 Muscularis externa
GI immune system - half of the mass of immune cells in the body are in the GI tract - antibody secretion to specific food antigens - immunologic defense against pathogenic microorganisms
Pancreatic Hormones Pancreatic hormones: insulin glucagon somatostatin produced and secreted (endocrine pancreatic secretion) by the islets of Langerhans essential for the regulation of metabolism
Regulation of GI function Autonomous Neural regulation smooth muscle extrinsic NS (CNS) function intrinsic NS pacemaker activity electrical coupling GI hormones Paracrine mediators humoral regulation > high degree of integration > high degree of autonomy 5
Example: acid secretion by gastric parietal cell.... cholinergic nerve terminals G-cells + gastric motility enhances mixing of food and disgestive juices 71 H+
MOTILITY muscular contractions that mix and move the contents of the gastro-intestinal tract to the appropriate sites of digestion and absorption
Patterns of GI motility Type of contraction Organ/structure • Tonic contractions upper and lower esophageal sphincters pyloric valve sphincter of Oddi ileocecal valve internal anal sphincter • Propulsive peristalsis esophagus lower 2 thirds of stomach small intestine rectum
Patterns of GI motility (cont) Type of contraction Organ/structure • Reverse peristalsis (antipropulsion) proximal colon • Mass movements ascending, transverse and descending colon • Nonpropulsive segmentation small intestine • Haustration ascending, transverse and descending colon
Patterns of GI motility (cont) • Migrating motor complex = migrating myoelectric complex fasting/empty small intestine
Esophagus Tubular conduit (about 20 cm long) for food transport from mouth to stomach. Structural and regulatory aspects: • Upper third of the esophagus: circular and longitudinal muscle layers are striated; innervation via cranial nerve. • Middle third: coexistence of skeletal and smooth muscle. Primary innervation from vagus nerve; nerve input from neurons of myenteric plexus • Lower third: smooth muscle, enteric nerve system (input from vagus nerve to enteric nerve system).
Swallowing center Neuronal control of esophagus Pharynx 1 UES Innervation afferent: sensory feedback to swallowing center efferent: • vagal somatic motor neurons to striated muscle • vagal visceral motoneurons to smooth muscle, terminating at neurons of myenteric plexus 2 3 1 2 3 18
32 Esophageal sphincters • Upper esophageal sphincter(UES): prevents entry of air • Lower esophageal sphincter(LES): LES = zone of elevated resting pressure (~ 30 mm Hg) prevents reflux of corrosive acidic stomach content. LES tone is regulated by extrinsic and intrinsic nerves, hormones and neuromodulators. Contraction: vagal cholinergic nerves (nicotinic, i.e. atropine insensitive) and sympathetic nerves (-adrenergic). Relaxation: primary peristalsis --> inhibitory vagal nerve input to circular muscle of LES (neurotransmitters (VIP and NO) and reduced activity of vagal excitatory fibers (cholinergic, nicotinic).
Swallowing Swallowing can be initiated voluntarily, but then it is under reflex control. Swallowing reflex= sequence of events that result in propulsion of food from the mouth to the stomach 1. Oral/voluntary phase 2. Pharyngeal phase 3. Esophageal phase
Control of esophageal motility Local and central circuits 31
Intraluminal esophageal pressure profile Pressure in the body of esophagus is negative, reflecting intrathoracic pressure pressure wave during swallowing 0 mm Hg = ambient pressure
Functions of stomach motility • reservoir for large volumes of food • fragmentation of food and mixing with gastric secretion --> digestion • controlled emptying of gastric content into duodenum
Fundus Stomach smooth muscle electrical activity 35 Reservoir Mixing + Transport Sphincter
• Gastric filling Empty stomach (volume approx. 50 ml) can expand to > 1 liter; volume increase is n o t paralleled by similar increase of intragastric tension because of • Plasticity: stomach smooth muscle cells can be stretched (within limits) without a change in tension (developed force). • Receptive relaxation: Filling (gastric distension) causes reflective relaxation of the fundus and body of the stomach; reflex is mediated by vagus nerve (VIP and NO as neurotransmitters).
• Gastric mixing Chyme = mixture of gastric secretion and food content 36
• Gastric emptying • antral peristaltic contractions • pylorus regulates emptying • neural and humoral/hormonal fine regulation gastric duodenum/jejunum factors outside GI system
Pyloric valve - regulates emptying of gastric content - prevents regurgitation of duodenal content 37 Pyloric relaxation: inhibitory vagal fibers (mediated by VIP and NO). Pyloric constriction: excitatory cholinergic vagal fibers, sympathetic fibers and hormones cholecystokinin, gastrin, gastric inhibitory peptide and secretin.
• Gastric factors Volume of chyme: increased volume (distension) stimulates motility Fluidity: increased fluidity allows more rapid emptying
• Duodenal/jejunal factors 37 CNS