Physio Cell Homeo & Membr
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Transcript of Physio Cell Homeo & Membr
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For class PowerPoints, go to
www.trinityphysiology.org
Tentative schedule
F, 09/24 20m QUIZ /discussion EXAM, F 10/08
Physiology I09/13/10 10/08/10
Margaret Anderson
http://www.trinityphysiology.org/http://www.trinityphysiology.org/ -
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Physiology I
Cell 1: Homeostasis and membranefunction
Learning objectives:
Define/describe, explain physiologicalsignificance, and give examples:
Homeostasis and roles of feedback mechsDistribution of solutes and water in ECF & ICF
Cell (plasma) membrane & capillaryendothelium
Diffusion coefficient (Stokes-Einstein eqn)
Permeability, partition coefficient
Diffusion (Ficks Law)
Carrier-mediated transport
Osmosis, osmolarity
Osmotic pressure (vant Hoffs Law)
Tonicity and effective osmotic pressure
Oncotic pressure
Physiology is the study of the normalfunctions of a living organism and itsvarious components.
To achieve optimal health,the components mustfunction together.
Selected questions in Cases and Problems 1 & 2, Costanzo 3e.
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Claude Bernard (1865) If we break up a living organism by isolating its differentparts, it is only for the sake of ease in analysis and by no means to conceive themseparately. Indeed, when we wish to ascribe to a physiological quality its value andtrue significance, we must always refer it to the whole and draw our final conclusions
only in relation to its effects on the whole.
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DIGESTIVE SYSTEM
URINARY SYSTEM
CELLS
CIRCSYSTEM
RESPIRATORYSYSTEM
Organ systems < organs < tissues < cells
Multicellular organisms require an infrastructure of tissues, organs, and organsystems to ensure survival and functions of individual cells.
Claude Bernard: Constancy of the internal environment isthe condition for free life.
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HOMEOSTASIS
Homeo similar (not same) stasiscondition (not static)
Adaptive mechanisms respond toconditions or stimuli to producea relatively constant internal
environment
Conditions are sensed and thencontrolled
Each system works in concert withothers.
Homeostasis involves feedback /feedforward mechanisms
Walter B. Cannon, the Father ofAmerican Physiology, coined theword homeostasis in 1929.
Negative feedbackPositive feedback
Feedforward mechanisms
Photo
:Cannon,
W.B.
The
WayofanInvestiga
tor.1968.
Some physiologists argue for using the term
homeodynamics instead of homeostasis.
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Desired levelof something
Adapted from Rhoades and Bell, 3rd ed., Fig 1.2
Opposes change: maintains relative status quo
Negative feedback control system
1. Regulated
variable is sensed2. Sensor feeds backinfo about its level tothe controller
3. Controller compares
sensed level with desiredlevel (set point).
4. If a difference, controller sends an errorsignal to the effector to tell it to bring variablecloser to set point: to oppose the change
Error signal
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Examples of negative
feedback:
Heat/cool a roomYou eat a candy bar
Silbernagl & Despopoulos. 2009.
Fig D 1, p. 7.
Negative feedbackloops stabilizeconditions around a
constant value.
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Positive feedback:Reinforces change
Silverthorn5e
,Fig.
6-27b
escalates a response snowball effect.
: Moves condition away from its initial value
Positive feedback loops arerelatively rare in physiology.
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Reinforces change
Positive feedback:Example: parturition
Silverthorn 5e, Fig. 6-28
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Adapted from Rhoades and Bell, 3rd ed., Fig 1.2
Feedforward control
Feedforward controller generates commands without directlysensing regulated variable, although it may sense a disturbance.
Example: smelling orseeing food can stimulatesalivation and gastricsecretion of HCl.
Feedforward systemsoften act in concert withfeedback systems.
Anticipates change
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DIGESTIVE SYSTEM
URINARY SYSTEM
CELLS
CIRCSYSTEM
RESPIRATORYSYSTEM
Homeostasis of the internal environment:Intracellular fluid (ICF)Extracellular fluid (ECF)
ICF and ECF reach a state of [dynamic] osmotic equilibrium,
but they are in chemical and electrical disequilibrium
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What is the weight of interstitial fluidin this person?What is the volume of interstitialfluid in this person?
Healthy humans maintain remarkablyconstant conditions in their blood andtissue fluids
(2 subcompartments)
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Body fluid compart ment s(70 kg person)
no protein:ultrafiltrate of plasma
Contains proteinse.g. albumin,clotting proteins
Contained within cells Bathes cellsLiquid part of
blood inside
vessels
See Costanzo 3e and 4e Figure 1-1.
TOTAL BODY WATER (~ 45 L)
ECF (15 L)
I NTRACELLULAR FLUI D(~ 30 L)
I NTERSTI TI ALFLUI D (~ 12 L)
PLASMA(~ 3 L)
capillariescell membrane
Explain: Total blood volume is ~ 5 L. Plasma is ~ 3 L.
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interstitial fluid
Endothelial cells make up the capillary
wall (endothelium) & separate blood
plasma from interstitial fluid.
We need to consider the mechanisms bywhich substances move (or not) acrossthe cell membrane and the endothelium.
Silverthorn 5E, fig. 3-25a
Screen51show
sc.s.
ofcapillary Cell membrane: simple
diffusion and carrier-mediatedtransport.Endothelium : bulk flowdependent on oncotic
pressure and blood pressure.
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FACTS :1. The major cation in the ICF is K2. The major cation in the ECF is Na3. The major anions in the ICF are large
proteins that carry a net negative charge4. The major anion in the ECF is Cl
5. Cells have a shell of negative charges inside
and positive charges outside6. Except for the shell, the ICF and ECF are
electroneutral
++
+++
+++
++++
++ + +
The intracellular environment is inchemical and electrical disequilibriumwith the interstitial fluid.
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Intracellular (C), interstitial (I) and plasma (P) compartments are in chemical disequilibrium
FYI: The most abundantnonionic small molecule solutesin the ECF are glucose and urea.
ECF
ICFSilverthorn, 5E, Fig 5-3b.
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5-10nm
cholesterol
The cell membrane consists of a phospholipid bilayer
with associated proteins and carbohydrates
Structural components
of the cell membranedetermine themovement of materialsinto and out of the cell.
Phospholipid molecules areamphipathic: polar(hydrophilic) heads and
nonpolar (hydrophobic)fatty acid tails.
Silverthorn 5e Fig. 3-6 Silverthorn 5e Fig. 2-8
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Materials pass through the membrane by simplediffusion or by carrier-mediated transport
The cell membrane is selectively permeable,
which means that some substances can pass
through it and others not. Animal Physiology 2e, Fig 2.1
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Examples: Diffusion and carrier-mediated transport across membranes
Wang, y., S.A. Shaikh, and E. Tajkhorshid. 2010. Exploring transmembranediffusion pathways with molecular dynamics. Physiology 25: 142-154.
Diffusion downhill along concgradient through lipid bilayer or
through AQP channel
Leucine transporter (LeuT)
depends on Na gradient tomove leucine uphill, from lowconcentration to highconcentration. The Nagradient is set up initially byexpenditure of ATP.
Maltose ABC transporterdepends on direct use ofATP as source of cellularenergy
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Movement
along
concentration
gradient(downhill)
Membrane transport molecules
CarriersChannels(simple diffusion)
Passivetransporters
(facilitateddiffusion noATP used)
Primary activetransporters (useATP directly)
Secondary activetransporters (coupleto ion gradients setup by primary activetransport)
Movement againstconcentrationgradient (uphill)
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Simple diffusion results from kinetic energy of molecular motion.
Rules:1. Diffusion does not use energy from an outside source. It is
referred to as passive transport.2. Molecules move from [high] to [low], downhill, along a
concentration gradient3. Net movement occurs until the concentrations come to
equilibrium4. Diffusion can take place in an open system or across a partition5. Diffusion is rapid over short distances but slow over long
distances6. Diffusion rate increases with increased temperature7. Diffusion rate increases with a greater concentration gradient8. Diffusion rate is inversely proportional to molecular size
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Time required for diffusion increases exponentially with
the distance traveled (t ~ x2). E.g., a molecule that travelsone m in 0.5 ms will travel 100 m in 5 s:1m ~ (12) x (0.5 x 10-3 s) = 0.5 x 10-3 s100 m ~ (1002) x (0.5 x 10-3 s) = (10 x 103) x (0.5 x 10-3 s)
= 10 x 0.5 s = 5 sMolecular
agitation
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Copyright 2010 Pearson Education, Inc.
Some materials pass through the bilayer by simple diffusion
Costanzo, p. 7 J = PA (CA CB) P = KD/x
(CA CB)
A
A (CA CB)
partitioncoefficient (K)
diffusioncoefficient (D)
x
P
x
J
Silve
rthorn5e,
Fig.
5-6.
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Copyright 2010 Pearson Education, Inc.Costanzo, p. 7 J = PA (CA CB) P = KD/x
(CA CB)
A
A (CA CB)
partition coefficient:K = conc in oil/conc in water
diffusion coefficient (D):Stokes-Einstein eqn
x
P
x
Silve
rthorn5e,
Fig.
5-6.
D = K T6 r
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Table 1-1 (Costanzo
Cases, 3e)
Molecular radii and oil-water partition
coefficients of four solutes
Solute Molecular radius, Oil-water partition
coefficient, K
A 20 1.0
B 20 2.0
C 40 1.0
D 40 0.5
Of these four solutes, which has the highest permeabilityin a lipid bilayer? Which has the lowest permeability?
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Calculate the net rate of diffusion of Solute A acrossthe lipid bilayer.Which equation will you use?In which direction will net diffusion occur?
See Case 1, question 6, Costanzo Cases and Problems, 3e.
Lipid bilayer, surface area = 1 cm2 , permeability = 5 x 10-5 cm/sec
Solute A: 20 mM/ml Solute A: 10 mM/ml
M t i l th h th b b i l
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Copyright 2010 Pearson Education, Inc.
Materials pass through the membrane by simplediffusion or by carrier-mediated transport
1. Simple diffusion through phospholipidbilayer or channel (passive transport)
2. Carrier-mediated transport
a. facilitated diffusion (passive transport)
b. primary active transport
c. secondary active transport
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Copyright 2010 Pearson Education, Inc.
Facilitated diffusion is an example ofcarrier-mediated transport
Like simple diffusion:No outside source of
energy is usedDirection of transport is
from [high] to [low]Net transport stops when
concentrations of the
molecule are equal on bothsides of the membrane
Like other carrier-mediatedtransport systems,facilitated diffusion exhibits:
Stereospecificity
Saturation
Competition
The carrier protein does not form an
open passage between the ICF and ECF
Silverthorn 5e, Fig 5-11
Facilitated diffusion carrier proteins areoften called passive transporters.
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Copyright 2010 Pearson Education, Inc.
All transport molecules* exhibit stereospecificity
*Transport molecules involved in facilitated diffusion,primary active transport and secondary active transportallexhibit stereospecificity, saturation, and competition.
For example, the carrier forD-glucose (GLUT) will bindand transport D-glucose butnot the nonphysiologicalstereoisomer L glucose.
The binding site
recognizes, binds andtransports only aspecific molecule (orsubset of molecules)
Silverthorn 5e, Fig 5-11
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Copyright 2010 Pearson Education, Inc.
All transport molecules exhibit competition
The GLUT transporter binds and transports both glucose andgalactose, which compete for the glucose binding site. In the
presence of galactose, the transporter moves fewer glucosemolecules per unit time across the membrane because itcarries galactose some of the time.
Silverthorn 5e, Figs 5-11 and 5-17
Glucose in presenceof 1 mM galactose
Glucose only
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Copyright 2010 Pearson Education, Inc.
When all carrier molecules of a given type are bound withsubstrate molecules, the population is saturated.
All transport molecules exhibit saturation
The rate of transport is proportional tothe [substrate]until all carrier moleculesare transporting substrate.
The rate of transport stays the same (at its maximum)once all carrier molecules are occupied.
Silverthorn 5e, Figs 5-11 and 5-19
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The Na-K ATPase pump : an example ofprimary active transport.This carrier-mediated transport requires the direct input of energy from ATP. The
carrier molecule moves Na and K ions uphill, against their concentration gradients.
E1 E2
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Na-K ATPase pump
Examples of other primary active transport systems:Cell (plasma) membrane Ca ATPase (PMCA) pumps Ca ions out of cell most cellsSarcoplasmic and endoplasmic reticulum Ca ATPase (SERCA) pumps Ca out of cytoplasm
into the sarcoplasmic reticulum (or endoplasmic reticulum) muscle and some other cells.H-K ATPase pumps H from the ICF to the lumen of stomach (parietal cells in the gastric
mucosa)
Costanzo, 3e and 4e, Figure 1-6
Secondary active transport l h f l h
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Secondary active transport couples the movement of solutes across themembrane. This carrier-mediated transport depends on the indirect utilization ofATP for energy.
Co-transport (symport) Counter-transport (antiport)
Na and glucose move in the same direction(into the cell): symport. This SGLT transportermoves glucose from [low] outside to [high]inside against its concentration gradient.
Na and Ca move in opposite directions (Na into
the cell and Ca out): antiport. Ca is movedfrom [low] inside to [high] outside against itsconcentration gradient.
In both examples the potential energy stored inthe Na concentration gradient is used to drivethe carrier. ATP was used indirectly to maintain
the Na concentration gradient.
Facilitateddiffusion
Constanzo 3e and 4e, Figs 1-7 and 1-8.
Review and anticipation
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Review and anticipation
Fig 1-8
1
2
3
4
5
Question:
Which of thesetransport mechanisms[1], [2], [3] would beinhibited by a cardiacglycoside such as
ouabain?
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Osmosis and tonicity
In osmosis, water flows across asemipermeable membrane from asolution with low [solute] to asolution with high [solute]. We will
now address solute concentrationsand the movement of water.
Clinicians estimate a persons fluid loss in dehydration, forexample, by equating weight loss to water loss. Water loss/gainwill affect solute concentrations.
Animal Physiology 2e Fig 26-1
About 2/3 of the bodys water iscontained in cells. The rest isdistributed between the interstitial
fluid and blood plasma.
l i
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Osmolarity is expressed as the concentration of osmotically active particles (ions orintact molecules) in a liter of solution (Osm/L)
Osmolarity = g x COsmolarity (Osm/L) = g (# particles/mol in Osm/mol) x C (concentration in mol/L)
e.g. Glucose (does not dissociate in soln):
(6x1023 particles of gluc / 6x1023 molecules of gluc) = 1 OsM/mol glucfor 1 mol/L glucose: Osmolarity = 1 OsM/mol x 1 mol/L = 1 OsM/L
e.g. NaCl (assume complete dissociation into Na and Cl)[(6x1023 Na part) + (6x1023 Cl part)] / 6x 1023 NaCl molec) = 2 OsM/mol NaCl
for 1 mol/L NaCl: Osmolarity = 2 OsM/mol x 1 mol/L = 2 OsM/L
Osmolarity
Osmolarity also expressed asOsmolarity = n x C where n is the number of dissociable particles per molecule
1 Osmole = 6x1023 osmotically effective entities
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Comparing osmotic concentrations
What is the molar concentration of Soln A? Soln B?What is the approximate molar concentration of Soln C?
SOLUTION A = SOLUTION B = SOLUTION C =
1 OsM/L Glucose 2 OsM/L Glucose 1 OsM/L NaCl
Isosmotic: two solutions have the same osmotic concentrations(e.g. A and C)
Hyperosmotic: a solution with a higher osmotic concentrationthan the one to which it is compared (e.g. B is hyperosm to A & C)Hyposmotic: a solution with a lower osmotic concentration thanthe one to which it is compared (e.g. A & C are hyposm to B)
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Osmolarity Osmolality
Generated by Number of moleculesdissolved in 1 L of solvent Number of molecules dissolvedin 1 kg of solvent
Temperature Affects volume of solvent Does not affect mass of solvent
Units Osm/L or mOsm/L Osm/kg or mOsm/kg
Osmolarity and osmolality
Osmolality is the preferred term for physiological systems.
Physiological solutions are dilute (usually expressed in mOsm/L ormOsm/kg), and the solvent is water.
PROBLEM:
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PROBLEM:
Osmotic concentration (osmolar, Osm/L; milliosmolar, mOsm/L) isthe sum of the molar concentrations of all undissociated molecules,anions, and cations. Give the osmolarity of the following:
100 mM/L NaCl = ________ mOsm/L
100 mM/L K2SO4 = ________ mOsm/L
100 mM/L CaCl2 = ________ mOsm/L
100 mM/L glucose = ________ mOsm/L
100 mM/L glucose + 100 mM/L NaCl =_______ mOsm/L
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*One equivalent each from Na+ and Cl-.
NaCl does not dissociate completely in solution. Theactual osmoles/mol is 1.88. However, for simplicity, a
value of 2 is often used.Ca++ contributes two equivalents, as do each of the
2 Cl- ions.
Substance
Atomic/Molecular
Weight Equivalents/mol Osmoles/mol
Na+ 23.0 1 1
K+ 39.1 1 1
Cl-
35.4 1 1HCO3
- 61.0 1 1
Ca++ 40.1 2 1
Phosphate (Pi) 95.0 3 1
NH4+ 18.0 1 1
NaCl 58.4 2* 2
CaCl2 111 4 3
Glucose 180 1
Urea 60 1
Concentrations ofions may beexpressed in equivalents perliter. An equivalent (eq) is themolarity of an ion times thenumber of charges it carries.
Berne & Levy 6e, Table 1-4 Silverthorn 5e, Fig 2-14
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Problem: Atomic /molecular mass
Which of these solutesdissociate(s) whendissolved in water, andinto what?
Each of these molecules is made intoa 100 millimolar soln. Give the mEq/L
concentration of each component
NaCl: Na
+
___ mEq/L Cl
-
___ mEq/LCaCl2: Ca2+ ___ mEq/L Cl- ___ mEq/L
K2SO4 K+ ___ mEq/L SO4
2- ___ mEq/L
NaCl
CaCl2 K2SO4 Urea, (NH)2CO
Glucose, C6H
12O
6
Osmosis occurs when water moves across a membrane from a dilute
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The concentration difference produces anosmotic pressure difference, which is thedriving force for osmosis.
Osmosis occurs when water moves across a membrane from a dilutesoln of solute to a more concentrated soln, until the concs are equal.
Costanzo 3e and 4e, Fig 1-9
Gauge measures pressurein atm or mm Hg
Osmotic pressure exerted by a soluteis the driving force for osmosis.
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Copyright 2010 Pearson Education, Inc.
A
B
= nCRT
where
n = number of dissociable particles per moleculeC = total solute concentrationR = gas constant (0.082 atm L/mol oK)T = temperature in degrees Kelvin
Osmotic pressure is calculated by vant Hoffs Law
Consider a solution ofurea:1 mmol/L @ 37oCWhat is its osmotic pressure ()expressed in atmospheres?
Expressed in mm Hg?Assume semipermeablemembrane permeable only towater.
Silverthorn Fig 5-26 (3)
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Copyright 2010 Pearson Education, Inc.
A
B
= nCRT
where
n = number of dissociable particles per moleculeC = total solute concentrationR = gas constant (0.082 atm L/mol oK)T = temperature in degrees Kelvin
Osmotic pressure is calculated by vant Hoffs Law
Consider a solution ofurea:1 mmol/L @ 37oCWhat is its osmotic pressure () expressed in atmospheres?Expressed in mm Hg? Assume semipermeable membrane
permeable only to water.
n = 1 C = 0.001 M/L = 1 mM/L37oC = 310o KR = 0.082 L-atm * mol-1 * K-1
RT = 25.45 L-atm/mol = 2.54 x 10-2 atm = 19.3 mm Hg
Tonicity of the solution is described relative to the cells response
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_____tonic
_____tonic
_____tonic
TONI CI TY is definedbiologically in terms ofthe response of a living
cell immersed in a solution
y p
Soln: hypertonic isotonic hypotonic very hypotonic
Lang,F.an
dS.Waldegger.
AmerSci85:4
56463.1997.Tonicity and osmolarity (osmolality) are both taken into account to determine
the appropriate intravenous solution to administer to a patient.
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= 1 = 0 to 1 = 0
Cell membranes are variably permeable to substances
The reflection coefficient (, sigma) is a measure of theability of a molecule to pass through the membrane
Vant Hoffs eqn modified by Staverman: = (nCRT)
Impermeable partially permeable completely permeable
Constanzo 3e & 4e, Fig 1-10
e.g. serum albumin e.g. urea
C id t l ti 300 l/L d 300 l/L
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= 1 = 0 - 1 = 0
Consider two solutions: 300 mmol/L sucrose and 300 mmol/L ureaWhat is the osmotic concentration (osmolality) of each?
Are they isosmotic? Are they isotonic?
The cytoplasm of red blood cells is ~ 300 mOsm/kg H2O
RBCs in sucrosesoln maintainnormal volume
RBCs in urea soln swell and burst
= (nCRT)
Explain
results
RBC membrane is permeable to urea. Urea has a reflection coefficient (, sigma) of0. Therefore urea does not exert any effective osmotic pressure. Water followsurea into cell along osmotic gradient. Cell swells and bursts.RBC membrane is impermeable to sucrose ( = 1). Sucrose is an effective osmole
because it balances osmotic pressure of the intracellular solutes.
H2N C NH2
Oll
If a molecule exerts osmotic pressure across a
membrane, it must not cross the membrane.
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Table 1-2
(Costanzo
Cases 3e)
Comparison of six solutions
Solution Solute Concentration g = n
1 Urea 1 mM/L 1.0 0
2 NaCl 1 mM/L 1.85 0.5
3 NaCl 2 mM/L 1.85 0.5
4 KCl 1 mM/L 1.85 0.4
5 Sucrose 1 mM/L 1.0 0.86 Albumin 1 mM/L 1.0 1.0
g = n, osmotic coefficient; , reflection coefficient
Practice: p. 7, Costanzo Cases 3e#4. Calculate the osmolarity and effective osmotic pressure of each solutionat 37oC, RT = 25.45 L-atm/M, or 0.0245 L-atm/mM. Then answer #5-#7.
Oncotic pressure is osmotic pressure produced by large
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Copyright 2010 Pearson Education, Inc.
p p p y g
molecules (especially proteins)
contains protein molecules
contains no protein molecules
Oncotic pressure is produced bylarge proteins in the plasma(=colloid osmotic pressure). Plasmaoncotic pressure combines with thehydrostatic effects of blood pressureto influence the movement of fluidsacross capillary walls. Silverthorn, 5e. Fig. 5-3.
C ill d h li l ll
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***
Capillary endothelial cell
water-filled pore
lipid-soluble substancese.g. CO2, O2
plasma
proteins
+ +
vesicular transportof some proteins
BP
hydrostatic PIF ~ 0
***cap ~ -25
***
***
***
******
lumen
Water anddissolvedsubstances
cap ~ 25 mm Hg
BP>25 net filtration out of cap
BP