Genesis of Resting Membrane Potential (RMP)

Prerequisites for a Membrane Potential

1. Unequal ion distribution across the membrane (a concentration gradient)
2. Selective membrane permeability - the membrane must have ion channels permeable to those ions

Step 1 - The Na⁺-K⁺ ATPase Pump Creates the Ion Gradients

• 3 Na⁺ OUT of the cell
• 2 K⁺ IN to the cell

Step 2 - K⁺ Diffusion Dominates (The Major Contribution)

• K⁺ (inside 140 mEq/L) diffuses outward down its concentration gradient through leak channels.
• This movement of positive charge outward leaves excess negative charges inside.
• The resulting electrical gradient (inside negative) opposes further K⁺ efflux.
• At equilibrium for K⁺ alone, the Nernst potential = -94 mV (using a 35:1 K⁺ inside:outside ratio).

Step 3 - Small Na⁺ Diffusion Partially Offsets K⁺ Effect

Em = -86 mV (from K⁺ and Na⁺ diffusion combined)

Step 4 - Na⁺-K⁺ Pump Adds the Final Electrogenic Contribution

Final RMP ≈ -90 mV (in nerve/muscle)

Summary Table of Contributors

Key Equations

E = -(61/z) × log [ion]inside / [ion]outside

Em = -61 × log [ (PK[K⁺]i + PNa[Na⁺]i + PCl[Cl⁻]o) / (PK[K⁺]o + PNa[Na⁺]o + PCl[Cl⁻]i) ]

Em = (gK / gT)EK + (gNa / gT)ENa + (gCl / gT)ECl

Role of the Na⁺-K⁺ Pump - Two Distinct Contributions

1. Direct electrogenic contribution - small (-4 mV), due to unequal charge transport
2. Indirect contribution - far more important; maintains the K⁺ concentration gradient that drives the K⁺ diffusion potential, which is the main determinant of the RMP

Enteric Nervous System (ENS)

Definition and Overview

Structural Organization - The Two Major Plexuses

Neural Components

• Sensory (afferent) neurons - innervate receptors in the mucosa responding to mechanical, thermal, osmotic, and chemical stimuli
• Interneurons - integrate sensory information and relay it to motor neurons
• Motor (efferent) neurons - control smooth muscle (motility) and secretory cells

Myenteric Plexus - Functions in Detail

1. Increased tonic contraction of the gut wall
2. Increased intensity of rhythmic contractions
3. Increased rate of contraction
4. Increased velocity of conduction of excitatory waves along the gut

Submucosal Plexus - Functions in Detail

• Integrates sensory signals from the GI epithelium
• Controls local intestinal secretion and absorption
• Regulates local contraction of submucosal muscle causing mucosal infolding
• Regulates gastrointestinal blood flow

Neurotransmitters of the ENS

Extrinsic Autonomic Control of the ENS

Parasympathetic (enhances ENS activity)

• Cranial division - vagus nerve (CN X); innervates esophagus, stomach, pancreas, intestines to the proximal half of the large intestine
• Sacral division - S2-S4 via pelvic nerves; innervates the distal half of the large intestine, sigmoid, rectum, and anus (important for defecation reflexes)
• Postganglionic neurons located within the myenteric and submucosal plexuses
• Net effect: increases activity of the entire ENS; enhances motility and secretion

Sympathetic (inhibits ENS activity)

• Preganglionic fibers from spinal cord segments T5-L2
• Synapse in prevertebral ganglia (celiac, superior/inferior mesenteric ganglia)
• Postganglionic fibers release norepinephrine
• Inhibits ENS in two ways: (1) direct inhibition of intestinal smooth muscle; (2) inhibitory effect on neurons of the ENS
• Strong sympathetic stimulation can block food movement through the GI tract entirely

Gastrointestinal Reflexes Mediated by the ENS

1. Entirely intramural (gut wall only) - peristalsis, mixing contractions, local secretion, local inhibitory effects
2. Gut → prevertebral ganglia → gut - long-distance reflexes e.g.:
   • Gastrocolic reflex (stomach → colon evacuation)
   • Enterogastric reflex (small intestine/colon → inhibit gastric motility)
   • Colonoileal reflex (colon → inhibit ileal emptying)
3. Gut → spinal cord/brain stem → gut - e.g., gastric motor/secretory control via vagus; pain reflexes; defecation reflexes

Afferent Signals from the ENS

Embryological Origin

• Vagal + truncal neural crest: enter the foregut mesenchyme and colonize the intestine in a cephalocaudal direction, complete by ~13 weeks of embryonic development
• Sacral neural crest: forms extraintestinal pelvic ganglia that colonize the hindgut

• Congenital absence of ganglion cells in both the submucosal (Meissner) and myenteric (Auerbach) plexuses
• Aganglionosis extends proximally from the internal sphincter
• Most common form: rectosigmoid involvement (80%)
• Incidence: 1 in 5000 live births; male predominance (4:1 in short segment)
• Associated genes: RET (most common, 10q11.2), GDNF, EDNRB, SOX10
• 10% of Down syndrome babies have HD

Clinical Correlates of ENS Dysfunction

• Hirschsprung's disease - absent ganglion cells → functional obstruction
• Achalasia - loss of inhibitory neurons (VIP/NO) in the esophageal myenteric plexus → failure of LES relaxation
• IBS (Irritable Bowel Syndrome) - dysregulation of ENS-mast cell signaling; altered serotonin pathways
• Parkinson's disease - Lewy bodies found in ENS neurons of the large intestinal wall (may enable early gut biopsy diagnosis)
• Alzheimer's disease - amyloid plaques and neurofibrillary tangles found in gut wall neurons

Mechanism of HCl Secretion by Parietal Cells

Cell Structure (Resting vs. Active)

• Resting: H⁺/K⁺-ATPase stored in intracellular tubulovesicles (inactive; impermeable to K⁺)
• Activated: Tubulovesicles fuse with the apical membrane → form an extensive secretory canaliculus with long microvilli → pumps become active
• Mitochondria occupy 30-40% of cell volume to provide ATP energy

The Flowchart

STIMULUS (Acetylcholine / Gastrin / Histamine)
              │
              ▼
     PARIETAL CELL ACTIVATED
              │
    ┌─────────┴──────────────────────────────┐
    │                                        │
    ▼  (CYTOPLASM)                           ▼  (BASOLATERAL MEMBRANE)
                                      
CO₂ + H₂O ──[Carbonic Anhydrase]──▶ H₂CO₃       Na⁺-K⁺-ATPase pump
              │                                    pumps Na⁺ OUT / K⁺ IN
              ▼                                    │
     H₂CO₃ ──▶ H⁺ + HCO₃⁻                        ▼
              │              │              K⁺ accumulates inside cell
              │              │              K⁺ leaks into canaliculus
              │              ▼
              │    HCO₃⁻ exits via          Cl⁻ enters cell from
              │    HCO₃⁻/Cl⁻ exchanger ◀── interstitial fluid
              │    (basolateral)             ("alkaline tide" in blood)
              │
              ▼  (APICAL MEMBRANE - canaliculus)
         H⁺/K⁺-ATPase (Proton Pump)
              │
    H⁺ pumped INTO canaliculus lumen
    K⁺ pumped back INTO cell (recycled)
              │
    Cl⁻ exits through Cl⁻ channels
    (apical uniporters) INTO canaliculus
              │
              ▼
    H⁺ + Cl⁻ ──▶ HCl in canaliculus lumen
              │
    H₂O follows by OSMOSIS
              │
              ▼
    Final secretion into gastric lumen:
    HCl ~150-160 mEq/L
    KCl ~15 mEq/L
    NaCl (small amount)

Classic Diagram (Guyton & Hall)

Step-by-Step Mechanism

Step 1 - H⁺ Generation (Carbonic Anhydrase Reaction)

CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻

• CO₂ diffuses from blood capillaries into the parietal cell
• Carbonic anhydrase (located in cytoplasm AND apical membrane) catalyzes this reaction
• Dissociation produces H⁺ (used for secretion) and HCO₃⁻ (disposed basally)

Step 2 - H⁺ Secretion at the Apical Membrane (H⁺/K⁺-ATPase)

• The H⁺/K⁺-ATPase (proton pump) on the apical secretory canaliculus uses ATP to:
  • Pump H⁺ OUT into the canaliculus lumen
  • Bring K⁺ IN from the canaliculus (K⁺ recycled)
• This is an active, electrogenic, antiport mechanism
• Creates a concentration gradient of 1 million-fold for H⁺ (intracellular pH ~7 vs. luminal pH ~1)

Step 3 - HCO₃⁻ Disposal and Cl⁻ Entry (Basolateral Exchanger)

• The HCO₃⁻ generated in step 1 exits the cell across the basolateral membrane via a Cl⁻/HCO₃⁻ exchanger (Band 3 type)
• In exchange, Cl⁻ enters the parietal cell from the interstitial fluid
• The HCO₃⁻ released into blood creates the post-prandial "alkaline tide" (transient rise in blood/urine pH after a meal)

Step 4 - Cl⁻ Secretion into Canaliculus

• Cl⁻ that entered via the basolateral exchanger travels through the cytoplasm
• Exits through apical Cl⁻ channels (uniporters) into the canaliculus lumen
• Cl⁻ must be present for the H⁺/K⁺-ATPase to function efficiently (K⁺ cycling requires a KCl efflux pathway)

Step 5 - K⁺ Recycling (Na⁺-K⁺-ATPase + K⁺ Leak)

• Basolateral Na⁺-K⁺-ATPase pumps K⁺ into the cell and Na⁺ out → maintains intracellular K⁺
• K⁺ leaks from cytoplasm into the canaliculus through apical K⁺ channels
• This luminal K⁺ is then recycled back into the cell by H⁺/K⁺-ATPase (exchanged for H⁺)
• Na⁺ in the canaliculus lumen is reabsorbed back into the cell (creating very low luminal Na⁺ ~3 mEq/L)

Step 6 - Water Entry (Osmosis)

• The accumulation of H⁺, Cl⁻ in the canaliculus raises osmolarity
• H₂O follows by osmosis from the cell into the canaliculus

Final Composition of Gastric HCl Secretion

Stimulants and Inhibitors

Pulmonary Circulation

Overview

1. Anatomy of Pulmonary Vessels

• Pulmonary arteries travel with airways (peribronchovascular sheaths)
• Pulmonary veins follow Miller's dictum: as far from airways as possible; drain the periphery and interlobular septa
• Capillaries form a dense sheet around alveoli - 50-70 m² of gas exchange surface
• Pulmonary arterial walls are thin with little smooth muscle compared to systemic arteries

2. Hemodynamic Characteristics (Normal Values)

3. Pulmonary Blood Flow Equation

Q = ΔP / R

Flow = (PA pressure - Left atrial pressure) / Pulmonary vascular resistance

≈ (15 - 8) / PVR ≈ 7 / PVR

4. Regulation of Pulmonary Blood Flow

Hypoxic Pulmonary Vasoconstriction (HPV) - The Major Regulator

• Trigger: PAO₂ falls below 70 mmHg → pulmonary arteriolar vasoconstriction
• PAO₂ between 70-100 mmHg: minimal effect on tone
• Mechanism:
  • Hypoxia inhibits O₂-sensitive K⁺ channels in vascular smooth muscle → membrane depolarization
  • Depolarization opens voltage-gated Ca²⁺ channels → Ca²⁺ influx → contraction
  • Also: ↑ endothelin, ↑ reactive oxygen species, ↓ nitric oxide release
• Function: diverts blood from poorly ventilated alveoli to well-ventilated alveoli, optimizing V/Q matching
• Clinical problem: In widespread lung disease (e.g., multilobar pneumonia), hypoxia is diffuse → generalized HPV → pulmonary hypertension

Other Vasoactive Factors

5. Regional Distribution of Blood Flow - West's Zones

6. Pulmonary Circulation During Exercise

• CO increases 5-fold during maximal exercise
• The pulmonary circuit accommodates this via:
  1. Recruitment - previously closed capillaries open (especially in upper zones)
  2. Distension - existing vessels dilate
• This keeps mPAP from rising proportionally - the mPAP-CO relationship is curvilinear (not linear), preserving low RV afterload
• Normal α (distensibility coefficient) = 1-2% per mmHg; pathological stiffening (↓ α) causes mPAP to rise steeply with exercise

7. Pulmonary Venous System

• 3-4 bronchial veins converge per lung → 2 main pulmonary veins per lung → 4 total draining into the posterior left atrium
• Pulmonary veins are 60% thinner than arteries; less smooth muscle; more extracellular matrix
• Large pulmonary veins lack an internal elastic lamina
• Venous sclerosis and muscularization contribute to pulmonary hypertension in left heart failure

8. Pulmonary Lymphatics

• Deep plexus: peribronchovascular connective tissue; follows airways to respiratory bronchioles; also follows pulmonary artery/vein branches
• Superficial plexus: visceral pleura
• Lymph drains centripetally toward the hilum, propelled by respiratory movements and cardiac pulsations → extrapulmonary nodes around primary bronchi and trachea
• No lymphatics in alveolar walls

9. Effect of Aging

• Gradual ↓ in conduit artery extensibility
• ↑ muscularization of medium/small vessels (collagen deposition, elastin deterioration)
• Mild intimal fibrotic remodeling → slight rise in mPAP and PVR by the 7th decade
• Main pulmonary artery dilates slightly with age

10. Pulmonary Hypertension (Definition)

• Defined as mean PAP ≥ 25 mmHg at rest
• Pulmonary arterial hypertension (PAH): elevated PVR + normal PCWP (<15 mmHg)
• Common causes: idiopathic PAH, left heart disease, chronic lung disease (HPV-driven), pulmonary emboli, connective tissue disease

Transport of Oxygen in Blood

Overview

1. Dissolved O₂

• Calculated using Henry's Law: Dissolved O₂ = 0.003 × PO₂
• At normal PaO₂ of 100 mmHg: dissolved O₂ = 0.3 mL O₂/100 mL blood
• This is grossly insufficient - if dissolved O₂ alone delivered O₂ at a cardiac output of 5 L/min:
  • O₂ delivery = 5 L/min × 0.3 mL/100 mL = 15 mL O₂/min
  • O₂ demand at rest = 250 mL O₂/min ← grossly inadequate
• Hence hemoglobin is essential

2. Hemoglobin - Structure

• Globular protein with 4 subunits
• Each subunit has a heme moiety (iron-binding porphyrin) + polypeptide chain (α or β)
• Adult hemoglobin A = α₂β₂
• Each subunit binds one O₂ molecule → maximum 4 O₂ per hemoglobin
• Iron must be in ferrous (Fe²⁺) state to bind O₂

3. O₂-Binding Capacity and O₂ Content

1 g Hb binds 1.34 mL O₂ Normal Hb = 15 g/100 mL → O₂ binding capacity = 20.1 mL O₂/100 mL

O₂ content = (O₂-binding capacity × % saturation) + dissolved O₂

= (20.1 × 0.98) + 0.3 = 19.7 + 0.3 = ~20 mL O₂/100 mL blood

DO₂ = Cardiac output × O₂ content = 5 L/min × 20 mL/100 mL = 1000 mL O₂/min (at rest)

4. The O₂-Hemoglobin Dissociation Curve

• First O₂ binding to Hb increases affinity for the second → second increases for third → affinity for the fourth is highest
• Flat upper part (60-100 mmHg): loading zone - O₂ stays tightly bound; tolerates altitude well
• Steep middle part (20-60 mmHg): unloading zone - small ↓ PO₂ releases large amounts of O₂

5. Loading and Unloading of O₂

• Lungs (loading): PaO₂ = 100 mmHg → saturation ~98% → O₂ tightly bound (high affinity, flat portion of curve)
• Tissues (unloading): PVO₂ = 40 mmHg → saturation ~75% → affinity decreases, O₂ released
• O₂ extracted at rest = 98% - 75% = ~23% per pass through tissues
• During exercise: tissue PO₂ falls to ~20 mmHg → saturation drops to ~35% → ~63% extracted per pass

6. Shifts of the Dissociation Curve (P₅₀ Changes)

Rightward Shift (↓ Hb-O₂ affinity, ↑ P₅₀) - facilitates O₂ unloading

The Bohr Effect: ↑ PCO₂ / ↓ pH → right shift → more O₂ unloaded to active tissues. This is the dominant physiological mechanism matching O₂ delivery to metabolic demand.

Leftward Shift (↑ Hb-O₂ affinity, ↓ P₅₀) - facilitates O₂ loading (but impairs unloading)

7. Effect of Carbon Monoxide

• Occupies heme sites → reduces O₂-binding capacity
• Causes left shift of remaining curve → O₂ binds more tightly to remaining sites → impaired tissue unloading
• Combined effect: catastrophic O₂ delivery failure

8. Hemoglobin Variants Affecting O₂ Transport

9. PO₂ Values Along the O₂ Transport Pathway

Atmosphere       → 159 mmHg
Alveolar air     → 104 mmHg   (diluted by water vapor + CO₂)
Pulmonary capillary (arterial end) → 40 mmHg
Pulmonary capillary (venous end)   → 104 mmHg (equilibration in 0.25 sec)
Systemic artery  → 95 mmHg    (venous admixture/shunt lowers from 104)
Interstitial fluid → 40 mmHg
Intracellular     → 23 mmHg   (mitochondria ~1-5 mmHg)
Mixed venous blood → 40 mmHg

10. Pulse Oximetry

• Oxyhemoglobin and deoxyhemoglobin have different light absorbances at 660 nm and 940 nm
• Measures arterial pulsatile signal (subtracts venous/capillary background)
• Does not directly measure PaO₂ - but P₅₀ allows estimation from the curve
• Limitation: Cannot distinguish oxyhemoglobin from carboxyhemoglobin (both read as "saturated") → CO poisoning will falsely read SpO₂ ~100%