5-Mark Short Notes: Guyton & Hall Medical Physiology

1. Excitation-Contraction Coupling

1. Terminal cisternae - large chambers that abut the T tubules
2. Longitudinal tubules - surround the surfaces of the myofibrils

2. Action Potential - Definition; Ionic Basis: Large Myelinated Nerve Fibre vs. SAN

• Resting stage: Membrane potential = -70 mV (polarized)
• Depolarization: Stimulus brings membrane to threshold (~-55 mV); voltage-gated Na+ channels open rapidly; Na+ rushes in; potential rises to +35 mV
• Repolarization: Na+ channels inactivate; delayed-rectifier K+ channels open; K+ exits; membrane returns toward -70 mV
• After-hyperpolarization (undershoot): K+ channels remain open briefly, causing slight overshoot below -70 mV, then close

3. Neuromuscular Junction (NMJ) - Diagram, Myasthenia Gravis, End Plate Potential

Myelinated Motor Nerve
        |
   [Axon Terminal]
   - Mitochondria
   - ~300,000 ACh vesicles
   - Dense bars with voltage-gated Ca2+ channels
        |
   [Synaptic cleft] ← 20-30 nm wide; contains AChE
        |
   [Muscle Membrane]
   - Nicotinic ACh receptors (at mouths of subneural clefts)
   - Voltage-gated Na+ channels
   - Subneural clefts (increase surface area)

1. Nerve AP arrives at terminal
2. Voltage-gated Ca2+ channels open; Ca2+ enters
3. Ca2+ activates Ca2+-calmodulin kinase, phosphorylates synapsin, releasing ACh vesicles
4. ~125 vesicles fuse with membrane (exocytosis), releasing ACh into cleft
5. ACh binds nicotinic receptors, opens cation channels (Na+/K+), producing depolarization
6. AChE in cleft rapidly degrades ACh (within milliseconds)

• Block ACh binding
• Accelerate receptor degradation
• Activate complement-mediated damage to the end plate

4. Properties of Nerve Fibres

1. Excitability (Irritability): Ability to respond to an adequate stimulus by generating an action potential. Depends on a threshold - the membrane must depolarize to ~-55 mV. A stimulus below threshold produces only a subthreshold (local) potential; above threshold triggers the explosive AP.
2. Conductivity: Ability to propagate an action potential along the entire length of the fibre without decrement. The AP at one point produces local currents that depolarize adjacent regions, propagating the signal. Once initiated, the AP propagates at a fixed velocity characteristic of that fibre type.
3. All-or-None Law: If the stimulus is strong enough to reach threshold, a full AP is generated; if below threshold, no AP occurs. The AP amplitude and shape are constant regardless of stimulus strength.
4. Refractoriness: After an AP, the fibre enters an absolute refractory period (no AP possible, ~1 ms in large myelinated fibres) followed by a relative refractory period (AP possible only with stronger stimulus, 2-4 ms). This limits the maximum firing frequency.
5. Accommodation: If a slowly rising stimulus is applied, the threshold gradually rises as Na+ channels become inactivated - the fibre "accommodates" and may not fire even when the potential reaches the original threshold.
6. Fatigue: With repetitive stimulation, the fibre's response decrements due to metabolic depletion (though pure nerve fibres show minimal fatigue; the NMJ fatigue is more important clinically).
7. Unidirectional Conduction (physiological): In reflex arcs, conduction is effectively unidirectional because of synaptic/NMJ directionality; pure nerve fibres can conduct in both directions.
8. Metabolism and Ion Pumps: Na+-K+ ATPase continuously pumps 3 Na+ out and 2 K+ in, maintaining the resting ionic gradients necessary for excitability.

5. Factors Regulating Force of Skeletal Muscle Contraction; Motor Unit

1. Multiple Fibre (Spatial) Summation: The CNS recruits more motor units to increase force. Small motor units are recruited first (size principle - smaller motoneurons are more excitable). As force requirement increases, progressively larger motor units are recruited, providing graded force. Different motor units are activated asynchronously, ensuring smooth contraction.
2. Frequency Summation and Tetanization: Increasing the rate of AP discharge to a motor unit increases force. When individual twitches follow each other so rapidly that Ca2+ does not fully return to SR before the next AP, the contractions summate. At a critical frequency, complete tetanus occurs: sustained, smooth, maximal contraction because Ca2+ stays elevated continuously.
3. Initial Length of Muscle (Length-Tension Relationship): Maximum force is produced when the sarcomere is ~2.0-2.2 µm (optimal overlap of actin and myosin filaments with all cross-bridges engaged). Over-stretching (>3.6 µm) or excessive shortening reduces force due to reduced cross-bridge overlap.
4. Degree of Muscle Stretch / Stretch Reflex: Stretching the muscle activates muscle spindles, reflexly increasing alpha motoneuron discharge, boosting force.
5. Blood Supply: Adequate O2 and glucose delivery sustains ATP production, which is essential for cross-bridge cycling and Ca2+ reuptake.
6. Body Temperature: Increased temperature speeds enzyme kinetics and cross-bridge cycling, increasing contraction velocity and, to a degree, peak force.

6. Refractory Period

• No AP can be elicited, no matter how strong the stimulus
• Corresponds to the period of depolarization and most of repolarization when Na+ channels are inactivated
• Duration: ~1 ms in large myelinated nerve fibres
• Significance: Sets the maximum firing frequency (~1000 impulses/sec for myelinated fibres)

• Follows the ARP; lasts approximately 2-4 ms
• Corresponds to the after-hyperpolarization (undershoot) phase when delayed K+ channels are still open
• An AP can be elicited but requires a stronger-than-normal stimulus
• The generated AP may have a reduced amplitude and slower propagation velocity

• Ensures one-way propagation of the AP (the region just activated is refractory, so only the forward direction conducts)
• Determines maximum impulse frequency in neurons (important for sensory coding)
• Cardiac ARP (0.25-0.30 s in ventricle) prevents summation and tetanus of heart muscle - crucial for rhythmic pumping

7. Sarcotubular System

• Invaginations of the sarcolemma running transversely (perpendicular to myofibrils) deep into the muscle fibre
• Open to extracellular fluid, contain extracellular fluid in their lumens - they are internal extensions of the cell membrane
• Located at the junction of A and I bands (two per sarcomere in skeletal muscle; one per sarcomere in cardiac muscle, at Z discs)
• Carry the AP from the surface into the fibre interior

• Smooth ER specialized for Ca2+ storage and release
• Two parts:
  • Terminal cisternae (lateral sacs): Large Ca2+-filled chambers that abut and flank the T tubules
  • Longitudinal tubules: Run along the long axis, surrounding the myofibrils; actively resequester Ca2+ via SERCA pumps

• One T tubule flanked by two terminal cisternae forms the "triad"
• At the triad, voltage sensors (L-type Ca2+ channels / DHPR) on the T tubule wall are physically linked to RyR1 (ryanodine receptor) Ca2+ release channels on the SR

• AP in T tubule → DHPR conformational change → opens RyR1 → Ca2+ floods into cytoplasm
• Ca2+ binds troponin C → muscle contraction
• Relaxation: SERCA pumps Ca2+ back into SR; Ca2+ dissociates from troponin; tropomyosin re-blocks actin active sites

8. Red Muscle and Pale Muscle; Isotonic and Isometric Contraction

Red Muscle vs. Pale (White) Muscle

Isotonic Contraction

Isometric Contraction

9. Saltatory Conduction; Factors Affecting Conduction Velocity

Saltatory Conduction

1. Speed: AP transmission velocity is 5 to 50 times faster than in unmyelinated fibres of the same axon diameter (up to 120 m/s in large myelinated Aα fibres vs. ~0.5-2 m/s in unmyelinated C fibres)
2. Energy efficiency: Only nodes depolarize, so ion exchange is ~100 times less than in continuous conduction; Na+-K+ pump expends far less energy to restore gradients

Factors Affecting Conduction Velocity

1. Myelin sheath (most important): Myelination increases velocity dramatically (saltatory conduction). Demyelination (as in multiple sclerosis) slows or blocks conduction.
2. Fibre diameter: Larger diameter = less internal resistance = faster conduction. Velocity (m/s) ≈ 6 × diameter (µm) for myelinated fibres.
3. Temperature: Higher temperature increases ion channel kinetics and speeds conduction. Cooling slows conduction (used in cryoanalgesia).
4. Ion concentrations: Hypercalcemia stabilizes the membrane and can slow conduction; hypocalcemia increases excitability.
5. Local anesthetics: Block Na+ channels, reducing safety factor, slowing or stopping conduction.
6. Metabolic state: Ischemia, hypoxia, or metabolic poisons reduce Na+-K+ pump activity, alter resting potential, and impair conduction.

10. Compare and Contrast: Action Potential vs. Excitatory Post-Synaptic Potential (EPSP)

11. Resting Membrane Potential (RMP) - Definition; Ionic Basis in Nerve Fibre

Ionic Basis of RMP

• High intracellular K+ (140 mEq/L inside vs. 4 mEq/L outside)
• High extracellular Na+ (142 mEq/L outside vs. 14 mEq/L inside)
• A net outward movement of positive charge, contributing ~-4 mV directly to RMP (electrogenic contribution)

• Na+: outside 142, inside 14 mEq/L
• K+: outside 4, inside 140 mEq/L
• Cl-: primarily outside; contributes to resting potential in some cells

12. Molecular Basis of Muscle Contraction (Sliding Filament Theory)

• Myosin filaments: 1500 per myofibril; each filament has ~200 myosin molecules; each molecule has two globular heads projecting outward as cross-bridges; the head contains ATPase activity
• Actin filaments: 3000 per myofibril; F-actin (two helical strands); each actin monomer has an active site for myosin binding
• Tropomyosin: Lies in the groove of actin strands; at rest, blocks myosin-binding sites
• Troponin: Complex of TnT, TnI, TnC; TnC binds Ca2+; TnI inhibits actin-myosin interaction at rest

1. Resting state: No Ca2+; tropomyosin blocks actin active sites; myosin head is "cocked" (energized) with ADP + Pi bound, but cannot attach to actin
2. Ca2+ release: AP → T tubule → SR releases Ca2+ → Ca2+ binds TnC → conformational change → tropomyosin moves → actin active sites exposed
3. Cross-bridge attachment: Energized myosin head attaches to exposed actin active site
4. Power stroke: Pi is released → myosin head pivots 45° → pulls actin ~10 nm toward M line; ADP is released; this generates force
5. Detachment: New ATP molecule binds to myosin head → cross-bridge detaches from actin
6. Re-cocking: ATP hydrolysis (by myosin ATPase) → ADP + Pi remain bound → head re-cocks to 90° (high-energy state)
7. Cycle repeats as long as Ca2+ is elevated and ATP is available

13. Neuron - Diagram; Nerve Impulse - Definition

Neuron Diagram

         Dendrites
           |||
    _______________
   /               \
  |   CELL BODY    |  ← Nucleus, Nissl substance, organelles
  |   (Soma)       |
   \_______________/
          |
     [Axon Hillock] ← Site of AP initiation
          |
     ====|====   ← Myelin sheath (Schwann cells)
         |
    [Node of Ranvier]  ← Gap in myelin (~2-3 µm every 1-3 mm)
         |
    ====|====
         |
    [Axon Terminal / Presynaptic Bouton]
   /  /  |  \  \
  ACh vesicles, mitochondria → Synapse with next neuron/muscle

• Cell body (soma): Contains nucleus, rough ER (Nissl bodies - site of protein synthesis), Golgi apparatus, mitochondria
• Dendrites: Branching processes that receive inputs (EPSPs, IPSPs); no myelin
• Axon: Single long process; arises from axon hillock (initial segment); may be myelinated; conducts AP to terminals
• Axon terminals (boutons): Presynaptic endings containing neurotransmitter vesicles and mitochondria

14. Types of Nerve Damage (Seddon's Classification)

• Mildest form; focal demyelination or temporary ionic block with intact axon and connective tissue sheaths (endoneurium, perineurium, epineurium all intact)
• Cause: mild compression, stretch, ischemia
• Result: conduction block - sensory and/or motor deficit at the site; no Wallerian degeneration
• Recovery: complete, days to weeks; no need for surgery

• Axon and myelin sheath disrupted but connective tissue (endoneurium ± perineurium ± epineurium) intact
• Cause: severe crush, stretch
• Result: Wallerian degeneration distal to injury (axon degenerates); proximal axon regenerates along intact endoneurial tubes at ~1 mm/day
• Recovery: possible (guided by intact tubes); may be incomplete if severe

• Complete anatomical division of the nerve (all structures severed) or severe fibrosis
• Cause: sharp laceration, avulsion, severe traction
• Result: complete loss of function; regenerating axons cannot find their correct endoneurial tubes; form neuromas
• Recovery: none without surgical intervention (nerve repair/graft)

15. Classification of Nerve Fibres

Erlanger-Gasser Classification (based on conduction velocity and diameter)

Lloyd-Hunt Classification (for afferent fibres only)

• Myelination is the single most important factor in conduction velocity
• Velocity ≈ 6 × fibre diameter (µm) for myelinated fibres
• C fibres are the most numerous fibre type in peripheral nerves (twice as many unmyelinated as myelinated fibres in an average nerve trunk)
• Clinical importance: differential block by local anaesthetics (small C and Aδ blocked first) and by demyelinating diseases (primarily A fibres affected in multiple sclerosis, Guillain-Barré)

Source: All notes are based on Guyton and Hall Textbook of Medical Physiology (Guyton & Hall, ISBN 9780443111013), Chapters 5, 6, 7, 8, 9, and 46. Chapter references are noted at the end of each short note.