AE

Transport of Solutes & Water (CH 5)

General Principles

  • Chapter focus: Transport of solutes and water across cell membranes and epithelia; overview of passive transport, primary and secondary active transport, water balance, and epithelial transport.
  • Transport aims to maintain homeostasis by regulating intracellular and extracellular solute and water composition.
  • Net flux concept: flux = influx − efflux; transport systems can be passive (no energy) or active (energy expenditure).
  • Transport mechanisms can be broadly categorized as:
    • Passive transport: simple diffusion and facilitated diffusion through specific proteins.
    • Primary active transport: energy (ATP hydrolysis) directly fuels uphill transport.
    • Secondary active transport: energy stored in existing gradients (often Na+ or H+) drives uphill transport of another solute.
  • Body-water compartments and purpose of transport:
    • Water and solute movements are essential for cell volume regulation and tissue homeostasis.
    • Movement of solutions between compartments is needed to maintain homeostasis in blood, interstitial fluid, cells, and transcellular spaces.

Fluid Compartments and Osmolarity

  • Total body water (TBW) ≈ 42 L in a normal adult male.
  • Major compartments:
    • Intracellular fluid (ICF): ~25 L (2/3 of TBW).
    • Extracellular fluid (ECF): ~17 L (1/3 of TBW) consisting of:
    • Blood plasma (intravascular): ~3 L
    • Interstitial fluid: ~13 L
    • Transcellular fluid: ~1 L (specialized spaces: CSF, synovial, biliary, etc.)
  • Osmolality across compartments is nearly the same: ~290 mOsm (osmolar concentration per kg of water).
  • The compartments are in osmotic balance, but ion composition differs across membranes:
    • Plasma/ECF: higher Na+ and Cl−; high water content.
    • ICF: high K+ and organic phosphates; different proton balances.
  • Osmolarity vs. Osmolality (important distinctions):
    • Osmolarity: osmoles per liter of solution (Osm/L).
    • Osmolality: osmoles per kilogram of water (Osm/kg).
    • In practice, osmolality is easier to measure and interpret in biological fluids; osmolality ≈ osmolality in these compartments is ~290 mOsm.
  • Tonicity:
    • Tonicity is the effective osmolality of a solution as seen by a cell, considering only impermeant solutes.
    • Isotonic: same effective osmolality as the intracellular environment; no net water movement.
    • Hypertonic: higher effective osmolality than intracellular fluid; water leaves cells, cells shrink.
    • Hypotonic: lower effective osmolality than intracellular fluid; water enters cells, cells swell.
  • Major numeric references (from typical values in slides):
    • Total body water: 42 L; ICF ≈ 25 L; ECF ≈ 17 L (3 L plasma, 13 L interstitial, 1 L transcellular).
    • Osmolality across compartments: ~290 mOsm.
    • Extracellular Na+ ~145 mM; K+ ~4.5 mM; Cl− ~116 mM; Protein ~0 mM in plasma; Osmolality ~290 mOsm.
    • Intracellular Na+ ~15 mM; K+ ~120 mM; Cl− ~20 mM; Protein ~4 mM; Osmolality ~290 mOsm.

Ion Gradients, Electroneutrality, and Donnan Considerations

  • Electroneutrality and osmolality are maintained across compartments:
    • Bulk fluids are electrically neutral: total positive charges equal total negative charges.
    • Anions and cations balance; proteins contribute fixed negative charges inside cells.
  • Anion gap (diagnostic concept):
    • Anion Gap =
      ext{Anion gap} = [ ext{Na}^+]{ ext{plasma}} - ig([ ext{Cl}^-] + [ ext{HCO}3^-]ig)
    • Normal values ≈ 9–14 mEq/L; larger gaps suggest excess organic anions (e.g., ketones in Type 1 diabetes).
  • Donnan equilibrium (impact on cell volume):
    • Na+/K+ pump excludes NaCl from the intracellular space, helping maintain osmotic balance.
    • Donnan effect describes distribution of charged particles near a semi-permeable membrane, leading to unequal distribution of charges unless active transport maintains balance.
    • In final steady-state with Na+/K+-ATPase present, osmotic equilibrium is achieved, but water distribution adjusts to volume changes.
  • Net effects:
    • Osmotic equilibrium is achieved by active transport (Na+/K+-ATPase) maintaining ion gradients that oppose diffusion.
    • Water follows ions to maintain osmotic balance; disruption of pumps or channels alters cell volume.

Passive Transport

  • Definition: movement down electrochemical or chemical gradients without direct energy input.
  • Electrically neutral solutes diffuse passively via Fick’s law: Jx = Px ig([X]{ ext{o}} - [X]{ ext{i}}ig)
    • Jx: flux of solute X, Px: permeability.
    • Factors affecting diffusion: concentration gradient, size, surface area, diffusion distance, water solubility.
  • Electrically charged solutes (ions) diffuse down electrochemical gradients; not just concentration gradients.
  • Driving forces and equilibrium:
    • The equilibrium condition across a membrane is given by the electrochemical potential difference; if it is zero, there is no net flux.
    • Nernst equation describes the equilibrium potential for an ion across a membrane:
      Ex = rac{RT}{zF} ext{ln}igg( rac{[X]{ ext{o}}}{[X]_{ ext{i}}}igg)
    • At body temperature, for monovalent ions, this is often approximated as
      Ex \approx -60 \, ext{mV} \,\log{10}\bigg( rac{[X]{ ext{i}}}{[X]{ ext{o}}}\bigg)
    • Example (K+): if \[K^+]{ ext{o}} = 0.1 \times [K^+]{ ext{i}}, EK ≈ -60 \,\text{mV}.
  • Facilitated diffusion (passive transport via proteins):
    • Pores (always open, non-selective) and channels (alternating open/closed, highly selective, rapid flux).
    • Carriers (transporters) operate via conformational changes and are saturable; never open on both sides at once.
  • Facilitated diffusion components:
    • Pores: non-selective pathways (e.g., water channels).
    • Channels: selective, gated by voltage, ligands, or second messengers.
    • Carriers: include transporters like GLUT for glucose; saturable with flux that follows Michaelis-Menten kinetics.
  • Resting gradients and driving forces:
    • Large inward driving force for Na+ and Ca2+; outward driving force for K+.
  • Carrier-mediated transport characteristics:
    • Always alternating sides; net flux is saturable; typical maximum flux (Jmax) occurs when all carriers are occupied.
    • Km defines the substrate concentration at half-maximal flux.
  • GLUT family example (glucose transporters):
    • Structure features: extracellular space, cytosol, amphipathic helices forming conduit, substrate-binding side chains.
    • Transporters move glucose via facilitated diffusion across membranes.

Primary Active Transport

  • Definition: energy from ATP hydrolysis directly drives uphill transport.
  • Na+/K+-ATPase (the Na/K pump):
    • Maintains Na+ and K+ gradients across the plasma membrane.
    • Cycle: 3 Na+ ions pumped out, 2 K+ ions pumped in per ATP hydrolyzed.
    • Two major conformations: E1 (inside-facing, high Na+ affinity), E2 (outside-facing, high K+ affinity).
    • Overall effect: Na+ efflux, K+ influx, contributing to osmotic and electrical gradients.
  • Other P-type ATPases and relevant examples:
    • Plasma membrane Ca2+-ATPase (PMCA): Ca2+ efflux.
    • H+/K+-ATPase (HKA): H+ efflux (secretory tissues like gastric glands, kidney, intestines).
  • H+-ATPases and related energy machinery:
    • Mitochondrial F-type ATPase (ATP synthase) runs backward under certain conditions to use the proton motive force to synthesize ATP.
    • V-type ATPases maintain a high H+ concentration (low pH) in vesicles, lysosomes, etc., enabling vesicular transport.
  • ABC transporters (including CFTR):
    • Some family members hydrolyze ATP while functioning as transporters or regulators; CFTR is a Cl− channel regulated by ATP and mutations in CFTR are linked to cystic fibrosis.
  • Summary of primary active transport features:
    • Direct ATP hydrolysis fuels ion pumping and solute movement against gradients.
    • Maintains essential ion gradients (Na+, K+, Ca2+, H+).
    • Interacts with other transport and homeostatic mechanisms to regulate cell and tissue function.

Secondary Active Transport

  • Definition: energy is derived from existing gradients, typically Na+ or H+ gradients established by primary active transport.
  • Na+-dependent cotransporters (symporters):
    • Use the Na+ gradient to drive uphill transport of substrates such as glucose, amino acids, phosphate, and some ions.
    • Examples include Na+-glucose cotransporters in epithelia.
  • Exchangers (antiporters):
    • Na+-Ca2+ exchanger (NCX): uses Na+ gradient to move Ca2+ out of the cell.
    • Na+-H+ exchanger (NHE): exchanges Na+ for H+ to regulate intracellular pH.
    • Cl−/HCO3− exchangers (AE family, DRA): swap Cl− and HCO3− to help regulate pH and anion balance.
    • Na+-driven Cl−-HCO3− exchangers (NDCBE) and other organic anion transporters (OAT) participate in solute movement.
  • Key concept: Secondary active transport depends on the energy stored in the Na+ or H+ gradient generated by primary active transport.

Water Transport & Regulation of Cell Volume

  • Osmosis is the net movement of water across a semipermeable membrane toward the side with higher solute concentration.
  • Water movement is always passive and occurs through:
    • Lipid bilayer diffusion (limited for water).
    • Facilitated diffusion via aquaporins (AQPs).
  • Osmolality and osmosis drive cell volume changes:
    • Water moves in response to osmotic gradients; cell volume changes accordingly.
    • Osmolality ~290 mOsm across compartments ensures a baseline balance.
  • Water and volume regulation processes:
    • Regulatory Volume Increase (RVI): in hyperosmotic conditions (high extracellular osmolarity), cells accumulate ions and impermeant solutes to draw water back in.
    • Regulatory Volume Decrease (RVD): in hypo-osmotic conditions, cells lose ions/solutes to reduce water influx.
    • Long-term hyperosmolality (hours to days) involves accumulation of relatively impermeant solutes (e.g., sorbitol, inositol, betaine, taurine).
    • Urea can cross membranes and influence osmolality; in isotonic or quasi-isotonic changes, water distribution changes as urea equilibrates.
  • Practical examples and figures:
    • Isotonic saline (0.9% NaCl) increases extracellular volume without changing intracellular volume because its effective osmolality is ~290 mOsm.
    • Solute-free water ingestion or hypertonic glucose solutions initially creates an osmotic gradient that redistributes water between compartments until osmolality equilibrates.
  • Donan equilibrium and its implications for cell volume:
    • Na+/K+ pump helps maintain osmotic balance and prevents uncontrolled water movement.
    • Donnan effects can lead to intracellular negative potential and water movement unless compensated by active transport.

Epithelial Transport

  • Epithelial cells show polarized transport with distinct apical and basolateral membranes and tight junctions.
  • Na+ absorption model (the USSING model):
    • Na+ enters across the apical membrane via channels or transporters.
    • Na+ is pumped out across the basolateral membrane by Na+/K+-ATPase.
    • K+ pumped into the cell by the Na+/K+-ATPase is recycled to the lumen via channels on the apical membrane.
    • The lumen becomes negative relative to the interstitium, promoting passive Cl− movement paracellularly.
  • Na+ absorption details:
    • Apical entry: Na+ channels or cotransporters allow Na+ to enter the epithelial cell from the lumen.
    • Basolateral exit: Na+/K+-ATPase pumps Na+ into the interstitial space.
    • K+ influx via the pump is balanced by leak channels to maintain homeostasis.
    • Cl− follows passively via paracellular pathways due to the lumen’s negative potential.
  • K+ secretion:
    • K+ channels on the apical membrane secrete K+ into the lumen as part of electrolyte balance.
  • Glucose absorption and Na+-coupled transport:
    • Na+ and Cl− move from lumen to interstitial space by basolateral active transport; glucose enters the epithelial cell from the lumen via Na+/glucose cotransporter (secondary active transport).
    • Glucose exits the cell across the basolateral membrane via a Na+-independent carrier (facilitated diffusion).
  • Cl− secretion in epithelia:
    • Uptake via Na+/K+/Cl− cotransport drives Cl− into cells; Cl− exits into lumen through CFTR channels; lumen becomes negatively charged, promoting Na+ secretion via paracellular pathways.
  • Water transport follows ions:
    • Water moves through cells and tight junctions into interstitial space; the luminal and interstitial spaces become nearly isosmotic after transport.
  • Lateral intercellular spaces and basal interstitial spaces:
    • The solute solution entering basal spaces is slightly hyperosmotic, drawing water into these spaces; the resulting interstitial solution is nearly isosmotic.
  • Regulation of epithelial transport:
    • Regulation mechanisms include:
    • Synthesis or degradation of transporters.
    • Recruitment of transporters to the membrane (translocation of transporter-containing vesicles).
    • Post-translational modifications (e.g., phosphorylation).
    • Changes in paracellular permeability.
    • Changes in luminal solute concentrations.
  • Practical model and implications:
    • Epithelial transport underlies absorption and secretion processes in gut and kidney tubules, and is essential for maintaining systemic electrolyte and fluid balance.

Supplemental Notes and Concepts

  • Ion concentrations in compartments (illustrative):
    • Extracellular (plasma): Na ≈ 145 mM; K ≈ 4.5 mM; Cl ≈ 116 mM; Protein ≈ 0 mM; Osmolality ≈ 290 mOsm.
    • Plasma water vs interstitial fluid vs intracellular fluid: all maintain osmolality ≈ 290 mOsm; concentrations of Na, K, Cl differ by compartment, driving diffusion and transport processes.
    • Intracellular: Na ≈ 15 mM; K ≈ 120 mM; Cl ≈ 20 mM; Protein ≈ 4 mM; Osmolality ≈ 290 mOsm.
  • Water and ion homeostasis are maintained by coordinated action of channels, transporters, and pumps in multiple tissue beds (blood, interstitium, gut, kidney tubules, etc.).
  • Transport system interactions:
    • Primary and secondary transporters work together to regulate ion concentrations and cell volume (e.g., Na+/K+-ATPase maintains Na+ gradient used by Na+-dependent cotransporters for nutrients like glucose).
  • Practical implications:
    • Understanding these transport processes helps explain clinical aspects like fluid therapy (isotonic vs hypotonic/hypertonic solutions), electrolyte disturbances, and pathophysiology of edema or dehydration.

Key Formulas and Constants

  • Passive diffusion (solute X):
    Jx = Px([X]{ ext{o}} - [X]{ ext{i}})
  • Nernst equation for equilibrium potential:
    Ex = rac{RT}{zF} \, ext{ln}igg( rac{[X]{ ext{o}}}{[X]{ ext{i}}}igg) \approx -60 \, ext{mV} \, ext{log}{10}igg( rac{[X]{ ext{i}}}{[X]{ ext{o}}}igg) ext{ at 37°C}
  • Na+/K+-ATPase stoichiometry:
    • 3 Na+ out, 2 K+ in per ATP hydrolyzed (Na+ efflux, K+ influx).
  • Anion gap:
    ext{Anion gap} = [ ext{Na}^+]{ ext{plasma}} - ig([ ext{Cl}^- ] + [ ext{HCO}3^- ]ig)
  • Donnan equilibrium considerations and osmotic balance depend on impermeant intracellular anions (proteins) and membrane permeability.

Connections to Foundational Principles

  • The material ties to core physiology concepts:
    • Homeostasis: precise control of fluid compartments, solute concentrations, and cell volume.
    • Electrochemical gradients underpin electrical excitability and secondary active transport.
    • Principles of diffusion, osmosis, and electroneutrality explain steady-state distributions and responses to perturbations.
    • Epithelial transport illustrates how organs specialize in absorption and secretion to regulate systemic milieu.

Practical Implications and Scenarios

  • Isotonic saline administration increases extracellular volume without changing intracellular volume due to matching osmolality.
  • Excess water intake or hypotonic solutions can cause cells to swell; regulatory mechanisms (RVD) attempt to restore volume.
  • Hyperosmotic conditions trigger regulatory volume increase by accumulating impermeant solutes; hypoosmotic conditions trigger regulatory volume decrease.
  • Outlines for clinical relevance:
    • Fluids management in dehydration, edema, or electrolyte disorders relies on understanding ionic gradients, osmolality, and the direction of water movement.
    • Epithelial transport mechanisms are relevant to intestinal absorption and renal tubule function, as well as diseases like cystic fibrosis (CFTR) and disorders of Na+ absorption.