Gastrointestinal Physiology

ENTERIC NERVOUS SYSTEM

SMOOTH MUSCLE: All smooth muscle is innervated by the autonomic nervous system.

General Properties:

• Caveolae: Micro-pits allow for increased surface area on smooth muscle.
• No Striations: Thin and thick filaments run through in a random order. Smooth muscle has relatively more thin filaments than thick.
• Plasticity: Smooth muscle is able to stretch to a greater length and compress to a shorter length than skeletal.
• Calcium supply comes more from outside the cell rather than inside (in the SR), as compared to skeletal.
• Slow, Sustained contraction as compared to skeletal muscle.

MULTI-UNIT SMOOTH MUSCLE: Has high innervation density. This is the type of smooth muscle found in Ciliary Muscle and Ductus Deferens.

UNITARY SMOOTH MUSCLE: The type of smooth muscle found in gut. Sparse innervation compared to multi-unit muscle Functional Syncytium: Gap junctions allow intercellular communication. Shows spontaneous (basal) electrical activity even in the absence of innervation.

• High basal resting potential (-57 mV -vs- -80 mV) as compared to skeletal muscle. Smooth muscle is more permeable to Na+ which accounts for spontaneous electrical activity.

SMOOTH MUSCLE CHANNELS:

Electromechanical Channels: Channels that transduce electrical activity, in one form or another, to mechanical activity of actin and myosin.

• Slow-Leaking Ca⁺²-Channels
• Ligand-Gated Channels
• Voltage-Gated Na⁺-Channels

Pharmaco-mechanical Channels: Channels that employ a second messenger, causing contractility without a change in the cell's electrical potential.

SMOOTH MUSCLE CONTRACTION:

• Ca⁺² enters cell --> Calmodulin then activates Myosin Light-Chain Kinase (MLCK) --> MLCK then phosphorylates myosin, enabling it to interact with actin --> contraction
• Regulatory step is binding of Ca⁺² with Calmodulin.

SLOW-WAVES: The basal electrical tone of smooth muscle. No contraction occurs with slow-waves.

• Also called the Basal Electrical Rhythm (BER)
• Magnitude of change is 5 - 15 mV, caused by entrance of Na⁺ into cell. No Ca⁺² is associated with these waves so no contraction occurs with them.
• Basal Rhythm in Different Regions: Remember these waves are only electrical -- not mechanical.
  • STOMACH: 3 waves per minute
  • DUODENUM: 12 waves per minute. In the duodenum, 30-40% of slow-waves are associated with Ca⁺² as Ca⁺² is added to the cells.

ENTERIC NERVOUS SYSTEM: The GI nervous system is independent of the CNS. Activity can go on without any CNS input.

GI Plexus(es):

• MYENTERIC PLEXUS: Outermost plexus located between the two layers of musculature -- between the muscularis circularis and muscularis longitudinalis.
• SUBMUCOSAL PLEXUS: Located in the submucosa, just outside the Muscularis Mucosae.

EXTRINSIC REGULATORY INPUT:

• Chemoreceptors and mechanoreceptors from the GI-Lumen are an important source of input. They are the origin of short reflexes (not involving the CNS) that go through the two GI plexes in the enteric NS.
• VAGO-VAGAL (long) REFLEX: Generally stimulatory (increase motility, secretomotor, vasodilatory). The Vagus carries both afferents (70%!) and efferents. Luminal receptors send afferent signal back to the CNS via the Vagus.
• INTESTINO-INTESTINAL (short) REFLEX: Generally inhibitory, involving only the Enteric NS, and completely independent of the Autonomic NS.
• SYMPATHETICS are inhibitory to the GI-Tract. They work primarily by presynaptic inhibition, thus inhibiting release of ACh. In this way we get smooth muscle relaxation. Norepinephrine binds to alpha1-Adrenoreceptors on parasympathetic nerve terminals and thereby inhibit the release of ACh.

  NEUROTRANSMITTERS:

• Acetylcholine increases GI-Motility when it acts on smooth muscle.
• Norepinephrine decreases GI-Motility when it acts on smooth muscle.
• Enkephalin (Opioid) decreases GI-motility by inhibiting the release of ACh.
• VASOACTIVE INTESTINAL PEPTIDE (VIP): Acts directly on smooth muscle to cause smooth muscle relaxation.
  • It is localized with ACh in the Vagus Nerve.
  • VIP is in local neurons, and is released when Vagal Fibers excite these inhibitory neurons to cause relaxation: Vagus (Excitatory synapse) ------> Turn on VIP neurons (Inhibitory synapse) ------> Relaxation.
• COLOCALIZATION: Enkephalins, VIP, NO, Serotonin, and a whole bunch of other transmitters are localized along with ACh and NorE in the autonomic nervous system. Depending on the nerve, when ACh and NorE are released, various other substances will also be released.

MYOGENIC CONTRACTILITY: The gut has some contractility without any nervous input whatsoever.

• Luminal contents will cause basal contractility without any nervous influence at all.
• Thus there is a constant inhibitory tone of VIP and NO on the gut, to prevent / slow down this contractility.

PARALYTIC ILEUS: Loss of GI contractility.

• It can occur chronically from overproduction of Sympathetics.
• Post-Operative (Physiologic) Ileus is a very common occurrence with abdominal surgeries

TYPES OF MOTILITY:

PERISTALSIS: Propulsion of material in the aboral (away from mouth) direction.

• Rate of peristalsis varies in region, but peristaltic generally gets slower as we move down the tract.
• Peristalsis occurs by segmental hyperpolarization followed by depolarization of muscle.
• Mechanism: Bolus of food in a particular location stimulates mechanoreceptors and chemoreceptors in the GI lumen, ultimately resulting in peristalsis:
  • Relaxation of the muscle occurs distal to the bolus, so that the food can go forward. This is mediated by VIP / NO.
  • Contraction of Longitudinal Muscle layer also occurs distal to bolus, because longitudinal contraction causes widening of the GI lumen.
  • Contraction of the muscle occurs proximal to the bolus, in order to propel the bolus forward.
  • There is a basal level of VIP inhibition in the muscle, and a bolus of food turns off this inhibition: distension of lumen by a bolus will cause inhibition of release of VIP / NO --> contraction of proximal region.

  RHYTHMIC SEGMENTATION: Mixing and churning of materials without propelling them forward in the tract.

• Only involves circular muscle -- not longitudinal
• Common in small and large intestine
  TONIC CONTRACTION: Blocking of the passage of material, as in sphincters.
• Tonic Contraction is myogenic -- it doesn't depend on innervation.

Gastrointestinal Hormones

NEUROENDOCRINE HORMONES: All hormones listed below are either exclusively endocrine (glandular secretions into bloodstream), exclusively neural (neurotransmitter) or both. All serve regulatory (as opposed to digestive) functions.

GASTRIN:

• Endocrine hormone


Structure: Active part of peptide is at carboxy-end. Last four residues same as CCK (Trp-Met-Asp-Phe), with a protective NH₂ group on the carboxy end to help prevent degradation.
• PENTAGASTRIN: Drug that mimics Gastrin, containing the last four residues in gastrin, and therefore containing similar biological activity.

Distribution: Gastrin is made by G-CELLS in the ANTRUM of the Stomach.

Fxns:

• Stimulates release of HCl from Parietal cells.
• Also stimulates growth of gastric mucosa and proliferation of intestinal enterocytes.
• Intestinal Resection: Cutting out part of the intestine results in higher levels of gastrin.

  Regulation:

• Gastrin release is inhibited by acid in the stomach. Primary negative feedback mechanism.
• Gastrin release is stimulated by digested proteins and by Acetylcholine.

CHOLECYSTOKININ (CCK):

• Endocrine hormone and neural transmitter


Strucure: Biological activity is contained in last seven residues on carboxy-end, with last four residues in common with Gastrin, and with a protective NH₂ on the carboxy terminus.
• Activity on parietal cells: CCK in the stomach can bind to Gastrin receptors to BLOCK the effects of Gastrin.

Distribution: CCK is synthesized in I-cells

Fxns:

• Stimulates contraction of the gall bladder
• Stimulates secretion of pancreatic enzymes.
• Inhibits gastric emptying as part of the Entero-Gastric Reflex.
  • Presence of CCK indicates that the duodenum is currently full and gastric emptying should be slowed.

Regulation: CCK release stimulated by presence of peptides w/in duodenum.

SECRETIN:

• Endocrine hormone and neurotransmitter

Distribution: Secretin comes from S-CELLS in the duodenum.

Fxns:

• Inhibits stomach motility when released in duodenum via Entero-Gastric Reflex.

Regulation: Secretin-release is stimulated by acid in the duodenum.

SOMATOSTATIN: The universal inhibitory substance. It acts in endocrine, neural, and paracrine fashion.

Distribution: Somatostatin is all over the place.

GASTRIC INHIBITORY PEPTIDE (GIP):

• Endocrine hormone

Fxns:

• Inhibits the release of Gastrin by a pharmacological mechanism. Thus the effect is dose-dependent, and a large (non-physiological) dose is required to elicit a response.
Dr. Greenwald thinks this effect is secondary importance because it is only pharmacological.

Major fxn: stimulates release of Insulin from Pancreas

Distribution: Antrum of stomach + duodenum.

VASOACTIVE INTESTINAL PEPTIDE (VIP): Primarily neural

MOTILIN

• Endocrine hormone

Fxn: It elicits the Migrating Motor Complex in the small intestine, to propel bacteria aborally.

GASTRIC RELEASING PEPTIDE (GRP) (Bombesin)

• Neurotransmitter
• Involved in the release of Gastrin
• Its release is Non-Adrenergic Non-Cholinergic

Regulation: Its release stimulated during the Cephalic Phase of gastric secretion.

ENKEPHALIN (an Opioid)

Fxn: Decreases GI-motility by inhibiting the release of ACh.

PREGNANCY:

• Pregnant women tend to gain weight because they have increased levels of CCK (higher fat and protein absorption) and lower levels of Somatostatin.
• Higher CCK is especially marked during first trimester.
• INFANTS have very high levels of Gastrin to accompany their very high calorie-per-body-weight intake. Gastrin interacts with hypothalamus to somehow promote anabolic growth in infants.

Motility

The Esophagus:

ANATOMY and PRESSURES:

• Upper Esophageal Sphincter (UES): Skeletal muscle, essentially comprising the cricopharyngeus muscle.
  • Resting pressure = 50-60 mm Hg to prevent swallowing of air.
  • Muscle tone is neurogenic and depends on CNS neural input from swallowing center to remain active.
• Body: Combination of skeletal and smooth muscle.
  • Resting pressure = -5 mm Hg
• Lower Esophageal Sphincter (LES): Smooth muscle, normally closed in order to prevent gastric reflux.
• Resting pressure = 30 mm Hg
• LES contractility is myogenic. LES relaxation results from tonal amounts of VIP / NO on the sphincter.
• VIP inhibition of LES is Non-Adrenergic, Non-Cholinergic (NANC). We know this because atropine does not prevent the inhibition:
  • Give atropine, and the LES will still relax because VIP is not stopped.
  • Give a VIP-Antibody and the LES will no longer relax because inhibition has been removed.