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Physiology 209

H2O
  • 45% – 75%
  • Key solvent; where metabolic reactions take place
  • Variation by
    body composition
    • Skin70%
    • Muscle75%
    • Organs - Heart, liver, brain, kidney70-80%
    • Fat (adipose tissue)10%
  • Water & solid content are about the same in everyone, but the water percentage varies due to the varying fat mass
  • Variation with age and gender
    • Baby75%
    • Female : Male (body fat variation)50% : 60%
    • Seniors Female : Male45% : 50%
    • Body water content is greater in infants and males
  • Significant for water-soluble medications (final concentration in body)
  • In dynamic steady state – individual & environment, and amongst internal components
  • Water balance
    • Intake – fluids, foods, oxidative water from metabolism
      • (C6H12O6 + 6O2 → 6CO2 + 6H2O + energy)
    • Output – insensible (lungs, skin), kidneys (balancer), stool
      • Insensible – not noticeable, unavoidable
    • Obligatory vs facultative
      losses
      • Obligatory – 1.5L/day
        • Insensible: 1.0L
        • Urine + stool: 0.5L
      • Facultative – vary with intake
        • Urine – kidney is major homeostatic organ
    • Insensible perspiration
      • Pure water
      • Passive evaporation (affected by environment)
      • Entire skin surface
      • Continuous
    • Sweating
      • Electrolyte solution
      • Active secretion
      • Sweat glands
      • Activated by heavy work/high temp
  • Volume relatively constant – helps maintain solute concentration & blood volume/pressure
  • Water Balance
    • Negative water balance
      • Reduced intake
      • Excessive loss from gut
      • Excessive sweating
      • Excessive loss of expired air (dry air)
      • Excessive loss of urine
    • Water 'intoxication' (positive water balance)
      • Excessive intake
      • Renal system failure
  • Average male is regarded as 70kg
  • Body water compartments – 60% of body mass
  • Water is freely moving; compartments are not rigidly isolated chambers
Intracellular Fluid (ICF)
  • Body water compartments – 60% of body mass
  • Aggregate of fluid bound by internal surface of cell membranes
Extracellular Fluid (ECF)
  • 1/3 of body water compartments
  • Major subcompartments
    • Plasma
      – fluid medium in which blood cells are suspended
      • 25% of ECF, 5% of total body water compartments
    • Interstitial Fluid (ISF)
      • 75% of ECF, 15% of total body water compartments
      • True 'Milieu Intérieur'
      • Percolates between individual cells
  • Minor subcompartments
    • Lymph
      • Lymphatic system – network of blind - ended terminal tubules
        • Coalesce to form larger lymphatic vessels → converge to large lymphatic ducts which drain into large veins in chest
      • 1 – 2% of ECF
    • Transcellular fluid
      • Aggregate of small fluid volumes secreted by specific cells into a number of body cavities (lined by epithelial cells) & having specialized functions
      • <1 – 2% of ECF
      • Intraocular, cochlear, cerebrospinal, pleural & pericardial, peritoneal, synovial, fluid in ducts of glands, bladder, etc
      • Does not affect body fluid balance; very local; however, has important functions
  • Number recap
    : Total H2O 60%, ICF 40%, ECF 20%, ISF 15%, Plasma 5% (of total body weight)
  • For healthy individuals, total volume & relative distributions between compartments must remain constant (though they are in dynamic equilibrium)
  • Hematocrit (Ht)
    – percentage of blood volume occupied by Red Blood Cells (erythrocytes)
    • Height of erythrocyte column/height of whole blood column
    • Ht = Packed Cell Volume (PCV)
    • Normal value for males = 45%
Methods to Determine Compartment Volumes
  • Direct (ie centrifuge & measure)
  • Indirect – indicator dilution method
    • Know: total quantity of test substance, concentration of substance after dispersion
    • Add quantity Q of indicator to vein → allow time to equilibrate → remove known volume of blood & centrifuge for plasma → measure concentration (c) of substance in plasma → calculate V = Q/c
    • Indicator choice
      • Non-toxic, diffuse readily, distribute evenly through compartments to be measured, induce no changes in distribution of water, easy to measure
      • Antipyrine, D2O, T2O – for total body water measurements
      • Radioactively labeled Inulin, sucrose, mannitol – for ECF (does not pass cell membrane)
      • Evans’ blue (T1824) or I131 – Albumin – for plasma (does not pass capillary wall)
Ionic Compositions
  • ICF – high in K+ & Mg++, low in Na+ & Cl-
  • ECF – high in Na+ and Cl-, low in K+
  • 0.9% NaCl – dilute sea water – matches proper concentration
  • Artificial physiological solutions – substitute for plasma/ISF (examples, don’t need to memorize)
    • Physiological saline – 9g NaCl + H2O to make 1L
    • Ringer’s solution – 8.6g NaCl, 0.3g KCl, 0.3g CaCl2, + H2O to make 1L
    • Locke-Ringer solution – 9g NaCl, 0.4g KCl, 0.2g CaCl2, 0.2g MgCl2, 0.5g NaHCO3, 0.5g dextrose (simple sugar, energy), + H2O to make 1L
Units of Concentration
  • Amount (mass) of solute1g% = 1g solute in 1dL of water
  • Number of solute molecules1mol = gram molecular weight/1L of H2O
  • Molality (m) – number of moles of solute dissolved in 1Kg solvent
  • Molarity (M) – amount of solute in specific amount of solution
  • Number of reactive unitsEq = molarity of ion * valency (ie Na+ 1Eq/mol, Ca2+ 2Eq/mol
  • Viability of cells depends on relative constancy of internal environment (milieu intérieur) & requires exchanges with internal & external environment
  • Plasma | Capillary wall | ISF | Cell membrane | ICF
  • Important transports: lungs, skin, kidneys, GI tract
Cell Membrane
  • Functions – support distinct compositions of ICF & ISF; be selectively permeable
  • Highly permeable to H2O, lipid-soluble substances, dissolved gases (O2, CO2), small uncharged molecules
  • Less permeable to larger molecules, charged particles
  • Impermeable to very large molecules
  • Properties due to bimolecular phospholipid layers w/ molecules exhibiting lateral mobility
    • Phospholipid, hydrophilic heads, hydrophobic tails
    • Amphipathic – both hydrophilic & hydrophobic parts
  • Cholesterol inserted in phospholipid layer adds stability & rigidity
  • Proteins
    • Integral – closely associated with phospholipids, mostly cross the membrane (transmembrane)
    • Peripheral – loosely associated, mostly on cytoplasmic side
  • Glycocalyx
    – carbohydrates & glycoproteins on outer side of membrane; gives distinct identity
  • Fluid mosaic model
  • Functions of plasma membrane proteins
    • Selective transport channel
    • Enzyme
    • Cell surface receptor
    • Cell surface identity marker
    • Cell adhesion
    • Attachment to cytoskeleton
Transmembrane Transport Pathways
  • Via phospholipid bilayer
  • Via interaction with protein cluster (channel/carrier)
  • Factors – lipid solubility, particle size, electrical charge, available & number of carriers/ion channels
  • Passive – energy independentActive – energy dependent
Diffusion
  • Resulting from random thermal molecular motion
  • Net flux = high → low concentration
  • If permeable, can go through membrane
  • J = PA(C0 – Ci)
    • J – net flux across membrane
    • P – permeability/diffusion coefficient of membrane
    • A – surface area of membrane
    • C0 – Ci – concentration gradient of diffusing molecule
    • Diffusion time increases in proportion to the square of the distance
  • Dissolve through lipid components for non-polar molecules and through channels for ions
Ion Channels
  • Consist of single protein or clusters of proteins
  • Show selectivity based on diameter & distribution of charges
  • Movement affected by electrochemical (electrical & concentration) gradient
  • Ligand-gated, voltage-gated, mechanically-gated
  • Channels: Na+, K+, Ca+, Cl-
  • Number of ions flowing through channels generating ionic current depends on
    • Channel conductance
    • How often channel opens
    • How long channel stays open
Carrier-Mediated Transport
  • Specificity – usually transports one type of molecule only
  • Saturation – rate of transport reaches maximum when all binding sites on all transporters are occupied; limit – transport maximum (Tm) exists
  • Competition – structurally similar substances compete for same binding site on carrier
  • Facilitated diffusion
    – carrier enables solute to penetrate more readily – passive
    • Solute binds to carrier → changes carrier configuration → solute is delivered to other side of membrane → carrier resumes original configuration
    • Ie for glucose, insulin increases number of transporters
  • Active transport
    • Requires chemical energy (usually ATP)
    • Susceptible to metabolic inhibitors
    • Can transport against concentration gradient
    • Primary active transport
      • Chemical energy transferred directly from ATP
      • Phosphorylation of transporter changes conformation & affinity of binding site
      • Ie sodium potassium pump – 3Na+ out, 2K+ in
  • Active – energy dependent – carrier-mediated active transport (primary & secondary), pino/phagocytosis
  • Sodium potassium pump
    • Phosphorylation of pump → change in conformation → affinity for Na+ decreases
  • Other active transporter proteins – Ca-ATPase, H-ATPase, H/K ATPase
  • Secondary Active Transport
    – relies on electrochemical gradient to bring along another solute
    • Ie glucose transported with Na+
    • Cotransport – both solutes move in the same direction
      • Na+/glucose, Na+/amino acids
    • Countertransport – solutes move in different directions
      • Na+/Ca+, Na+/H+, Cl-/HCO3-
  • Endocytosis
    – cell membrane invaginates, forming channel, pinching off to form vesicle
    • Pinocytosis (Fluid endocytosis) – ingestion of dissolved materials, liquid contents slowly transferred to the cytosol – not selective
    • Phagocytosis – ingestion of solid particles, particles pinched into phagocytic vacuole (phagosome) – fuses with lysosomes and then degraded
    • Receptor-mediated
      • Clathrin-dependent receptor-mediated endocytosis
      • Potocytosis
  • Exocytosis – diffusion of vesicle, releasing content in ECF
Osmosis – diffusion of water
  • Water diffuses freely across most cell membranes
  • Aquaporins – groups of proteins facilitating osmosis – forms water permeable channels
  • Osmosis – net movement of H2O across semipermeable membrane
  • Osmotic pressure – pressure required to oppose the movement of water across a semipermeable membrane
  • Osmolarity – total solute concentration of solute – 1 osmol = 1 mol of solute
    • 1 mol glucose = 1 osmol1 mol NaCl = 2 osmol
  • Osm = osmol/liter
  • Ie saline drip – 0.9% saline = 0.15 NaCl = 300mOsm = same mOsm of body
    6.7 atm = 5100 mmHg
  • Isosmotic
    – solutions with same number of osmotically active particles
  • Hypoosmotic – solutions with lower number of osmotically active particles
  • Hyperosmotic – solutions with higher number of osmotically active particles
  • Only nonpenetrating particles can exert osmotic pressure
    • Extracellular Na+ is nonpenetrating as it is pumped out after moving in
  • Isotonic – cell retains size
  • Hypotonic – cell swells
  • Hypertonic – cell shrinks
Capillaries
  • Single layer of flattened endothelial cells & supporting basement membrane
  • Diffusion through water filled channels & across cell membranes
  • Pinocytosis/exocytosis – endocytosis & vesicle formation on luminal side → exocytosis & vesicle release on interstitial side
  • Bulk flow – flow of molecules due to pressure difference (ultra filtration)
  • Filtration – bulk flow across porous membrane (acts like sieve) withholding some particles
Blood
  • Transport – nutritive, respiratory, excretory, hormone transport, temperature regulation
  • Acid-base balance – normal pH range 7.30-7.45
  • Protective
  • Contains both ECF (plasma) & ICF (inside blood cells)
  • May be studied in vivo & in vitro
  • Accounts for ~7% of body mass = ~5L
  • Normovolemia
    – normal blood volume
  • Hypovolemia – lower blood volume
  • Hypervolemia – higher blood volume
  • Centrifuged blood – 55% plasma (yellow), ~0% buffy layer (WBCs, platelets), 45% RBCs
  • Hematocrit
Plasma
  • Similar to ISF
  • > 90% water
  • -0.9g/dl NaCl Na+, K+, (Ca++, Mg++)Cl-, HCO3-, (PO4--
  • Glucose, amino acids, lipids, O2, CO2
Plasma Proteins (Colloids)
  • (unlike ISF) Proteins (colloids) = 7g% - albumins, globulins, fibrinogen
    • Separating plasma proteins
      • Differential precipitation by salts
      • Sedimentation in ultracentrifuge
      • Electrophoretic mobility
      • Immunological characteristics
  • Electrophoresis – fraction method based on movement of charged particles along voltage gradient
    • Influenced by number, distribution of charges, & MW of each protein
    • Stained and scanned – area under graph peaks shows amount
    • In renal disease – albumin (big left peak) gets significantly smaller
    • In bacterial infection – γ globulins increases due to presence of antibodies
  • Majority produced in liver
    • Albumin, fibrinogen, α1, α2, β globulins
  • γ globulins produced in lymphoid tissue