Lecture 2

Chemical Messenger Regulation

• Four principal categories governing inter-cellular communication in the GIT and elsewhere:
  • Endocrine regulation
  • A hormone-secreting gland cell releases its product across the basolateral membrane directly into the blood.
  • Hormone travels via circulation to one or many distant target cells.
  • Neurocrine regulation
  • Neuron generates an action potential; at axon terminal releases a neurotransmitter.
  • Transmitter diffuses across a synapse and binds receptors on a post-synaptic neuron or effector cell.
  • Paracrine regulation
  • A local epithelial or gland cell releases a paracrine substance across its apical surface.
  • Substance diffuses through interstitial fluid to neighboring targets in close proximity.
  • Autocrine regulation
  • Cell releases messenger that binds to receptors on the very same cell, modulating its own activity.

Hormonal Control of GI Activity

• Endocrine (enteroendocrine) cells
  • Embedded within stomach & small-intestinal epithelium.
  • Secrete hormones basolaterally into lamina-propria capillaries.
• Shared features of GI hormones (e.g., secretin, cholecystokinin (\text{CCK}), gastrin)
  • All are peptide hormones.
  • Operate within negative-feedback loops.
  • Each may act on multiple distinct target tissues.
• Example: (\textbf{CCK})
  • Stimulus for release: fatty acids & amino acids in small intestine (SI).
  • Circulates to:
  • Pancreas → ↑ digestive enzyme secretion.
  • Gallbladder → contraction → bile acid ejection → lipid emulsification.
  • Absorption of fats/AA removes the initial stimulus → ↓ CCK (classic negative feedback).

Intestinal Motility

• Propulsion & mixing arise from coordinated contraction/relaxation of two smooth-muscle layers (circular & longitudinal).
• Peristalsis (primary propulsion)
  • Circular muscle contracts oral to bolus while longitudinal layer relaxes.
  • Contraction ring migrates aborally, pushing contents toward anus; region ahead relaxes.
• Segmentation (primary mixing)
  • Rhythmic contractions at multiple intestinal segments with minimal net propulsion.
  • Major in SI.
  • Functions:
  • Mixes chyme with enzymes.
  • Slows transit → optimizes nutrient & water absorption.

Basic Electrical Rhythm (BER)

• Generated by GI pacemaker (Interstitial Cells of Cajal) interspersed among smooth-muscle cells.
• Characteristics of slow waves
  • Spontaneous depolarization–repolarization cycles (no external input required).
  • Propagate via gap junctions through circular & longitudinal layers.
  • Baseline slow waves do \emph{not} cross threshold → no contraction without superimposed excitatory input.
  • Excitatory neurotransmitter/hormone depolarizes membrane further → reach threshold → action potentials → contraction.
  • Number of spikes ∝ force of contraction; frequency dictated by inherent BER.

Phases of Gastrointestinal Control

• Distinguished by location of initiating stimulus, not by effector site.
• Cephalic phase ("head")
  • Initiated by sight, smell, taste, chewing, emotional state.
  • Predominantly mediated by parasympathetic (vagal) efferents → enteric plexuses.
• Gastric phase ("stomach")
  • Stimuli: gastric distension, acidity, peptides, amino acids.
  • Mediators: short reflexes (gastrin) & long vagovagal reflexes (acetylcholine).
• Intestinal phase ("intestine")
  • Stimuli: intestinal distension, luminal acidity, hyper-osmolarity & digestive products.
  • Mediators: short & long reflexes plus hormones secretin, CCK, gastric inhibitory peptide ((\text{GIP})).

Hypothalamic Control of Food Intake

• Hypothalamus = homeostatic command center; contains discrete nuclei:
  • Feeding center (lateral hypothalamus) → activation increases hunger; lesions cause anorexia/weight loss.
  • Satiety center (ventromedial hypothalamus) → activation promotes fullness; lesions cause hyperphagia/obesity.
• Orexigenic signals (↑ intake)
  • Neuropeptide Y (NPY) released within hypothalamus.
  • Ghrelin from gastric endocrine cells during fasting → bloodstream → stimulates NPY neurons.
• Anorexigenic signals (↓ intake)
  • Leptin from adipose tissue; insulin from pancreas; peptide YY from intestine; melanocortin from hypothalamus itself.
• Leptin feedback loop
  • Positive energy balance → ↑ adiposity → ↑ plasma leptin.
  • Leptin acts on hypothalamus → inhibits NPY release → ↓ appetite, ↑ metabolic rate.
  • Absence/deficiency of leptin → uncontrolled eating → obesity.

Regulation of Water Intake (Thirst)

• Thirst center located in hypothalamus; stimulated by:
  1. ↑ Plasma osmolarity (most potent)
  • Detected by osmoreceptors → triggers thirst & vasopressin (ADH) release → renal water conservation.
  1. ↓ Plasma volume
  • Large volume loss (hemorrhage, diarrhea, vomiting) → ↓ arterial pressure.
  • Activates arterial baroreceptors & intrarenal baroreceptors (juxtaglomerular cells) → renin–angiotensin cascade → \text{angiotensin II} → direct dip to hypothalamus → thirst.
  1. Dry mouth & throat sensations.
  2. Pre-absorptive satiety (prevents over-hydration)
  • Oral, pharyngeal & GI signals terminate drinking before blood variables normalize.

Salivary Glands: Anatomy, Composition & Functions

• Three paired exocrine glands: parotid, submandibular, sublingual.
• Ductal anatomy: many microscopic ducts converge into main ducts.
• Cell types
  • Acinar cells → form primary secretion.
  • Ductal (striated) cells → modify secretion.
  • Myoepithelial cells → contractile wrap; expel saliva.
• Saliva characteristics
  • Hypotonic; slightly alkaline (pH > 7).
  • Components:
  • Water (~99%).
  • Electrolytes: ↑ K^+, ↑ HCO_3^-; ↓ Na^+, ↓ Cl^-.
  • Enzymes: amylase (starch → di/tri-saccharides), lipase (triglyceride → fatty acids).
  • Glycoproteins: mucin → mucus upon hydration.
  • Antimicrobials: lysozyme (bacterial cell-wall lysis), lactoferrin (chelates Fe^{2+}).
• Functions
  • Lubricates & compacts food bolus; facilitates swallowing.
  • Begins carbohydrate & lipid digestion.
  • Solubilizes tastants for gustatory receptors.
  • Limits oral microbial growth.
  • Aids phonation & buffers acidic challenges via HCO_3^-.

Formation of Saliva

• Step 1: Primary isotonic secretion (acinar region)
  • Active secretion of Cl^-, HCO_3^-, K^+ into lumen.
  • Na^+ & H_2O follow paracellularly through leaky tight junctions → isotonic fluid similar to plasma.
  • Proteins (enzymes, mucin) released via exocytosis.
  • Myoepithelial contraction propels fluid into duct.
• Step 2: Ductal modification
  • Duct cells have tight junctions (impermeable to water) → produce hypotonicity.
  • Net reabsorption: Na^+ & Cl^- (active).
  • Net secretion: K^+ & HCO_3^- (active, smaller magnitude).
  • Result: final saliva = hypotonic, alkaline (rich in HCO_3^-, K^+; poor in Na^+, Cl^-; water unchanged).

Regulation of Salivary Gland Function

• Purely neural (no hormonal control).
• Parasympathetic (dominant)
  • Stimuli: taste/smell of food, oral mechanoreceptors, nausea.
  • Effects:
  • ↑ glandular blood flow (vasodilation) → sustains secretion volume.
  • ↑ acinar protein secretion.
  • Contraction of myoepithelial cells → ↑ flow rate.
  • Inhibitors: fatigue, sleep, fear, dehydration; anticholinergic drugs (e.g., some psychotropics) cause xerostomia.
• Sympathetic
  • Minor but stimulatory; augments protein output & myoepithelial contraction.
  • Also increases flow, yet less pronounced than parasympathetic.