Physio Cell Homeo & Membr

8/2/2019 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.


8/51Copyright 2010 Pearson Education, Inc.

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.



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.



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



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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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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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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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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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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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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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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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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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

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Physio Cell Homeo & Membr