S Ghosh Physiology 1

LECTURE - 4

Continued from Lec- 3

9/30/2015

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When faced with unusually heavy demandsOrdinary homeostasis is not enough

because “ homeostat” is raised beyond its capacity,

perhaps to a higher level of function

Resetting :Essential function for Long Term Survival

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Anticipatory adaptationAnticipates & modulates in context of future needs &

Resource allocation

Reaction to immediate Physiological demands

Regulation of BP, pH, Temp

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PRIOR KNOWLEDGE

PREDICTION

EFFECTOR

CONTROLLEDVARIABLE

SENSOR

SETPOINT

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Example

Variations of blood pressure- Morning when you get out of bed- Blood pressure rises- Blood flow to brain maintained when

you stand up to maintain oxygen tension in brain

Unsatisfactory social interaction

- Neural signals: sustained: Essential Hypertension, Type II Diabetes

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Stability through change

Goal of regulation is not constancy

It

is fitness under natural selection

Prior information predicts demand

Adjust all parameters to meet that demand

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ALLOSTASIS

• INVOLVES WHOLE BRAIN AND BODY RATHER THAN SIMPLE LOCAL FEEDBACK

• FAR MORE COMPLEX FORM OF REGULATION THAN HOMEOSTASIS

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Acclimatization or acclimation• is the process of an organism adjusting to change in its environment

, allowing it to survive changes in temperature, water and food availability, other stresses and often relates to seasonal weather changes.

• acclimatization occurs in a short time, (days to weeks) and within one organism's lifetime (compare adaptation).

• this may be a discrete occurrence or may instead represent part of a periodic cycle, such as a mammal shedding heavy winter fur in favor of a lighter summer coat.

• acclimation is an important characteristic among many organisms because it allows them to evolve over time while changes are also simultaneously occurring in their environment.

• organisms adjust their morphological, behavioral, physical, and/or biochemical traits in response to these environmental changes that they are faced with.

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• HIGH ALTITUDE– naturally acclimatize to new environment by

developing an increase in the number of red blood cells to increase the oxygen carrying capacity of the blood, in order to compensate for lower levels of oxygen in the air

• HEAT- Desert– body make internal adjustments to compensate for

the change in environmental conditions. A heat acclimatized person will begin to sweat earlier and more intensely under heat, have a lower heart rate, and a lower skin temperature. The salt content of sweat also decreases as people

acclimatize – If people do not acclimatize, then the person is at

higher risk of heat related injuries (heat stroke, heat cramp).

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Adaptation

• the process whereby a population becomes better suited to its habitat.

• this process takes place over many generations,and is one of the basic phenomena of biology

• The ability to acclimatize is an adaptation

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Adaptation…..Achieves a new steady state

Preserves viability

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• is the increase in the volume of an organ or tissue due to the enlargement of its component cells.

Ventricular hypertrophy

the increase in size of the ventricles of the heart.

1.aerobic or anaerobic exercise - changes can be beneficial or healthy

2. high blood pressure or other disease states pathological changes

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Pregnancy →Growth and multiplication of milk-secreting glandular cells in the breast→ future breast feeding.

Hyperplasia of the breast –

A focal expansion of the number of cells in a breast

duct, associated with an increased risk of developing

breast cancer.

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• Hypertrophy and hyperplasia are two distinct process, they frequently occur together,

• Example:hormonally-induced proliferation and enlargement of the cells of the uterus during pregnancy.

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Some insult or injury

The transformation of one type of mature differentiated cell type into another

mature differentiated cell type,

as an adaptive response  

By such a change in differentiation (and hence patterns of gene expression)

the cells are more resistant to the effects of the insult.  It is usually a reversible phenomenon.

Details from Pathology

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Partial or complete wasting away of a part of the body.

Causes include poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself.

Physiological process of breakdown of tissues, involving apoptosis on a cellular level.

Pathological atrophy -- occurs as a result of disease or loss of trophic support due to other disease,

As part of normal development --- shrinking and involution of the thymus in early childhood and the tonsils in adolescence.

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Principal Adaptive Responses

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Apoptosis is one of the main types of programmed cell death which involves a

series of biochemical events leading to specific

cell morphology characteristics and

ultimately death of cells.

Genetically controlled mechanisms of cell death involved in the regulation of tissue homeostasis.

The 2 major pathways of apoptosis

•the extrinsic (Fas and other TNFR superfamily members and ligands) and

•the intrinsic (mitochondria-associated) pathways,

•both are found in the cytoplasm.

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Biological clock:

the bodyguard of temporal homeostasis.the timing of the body’s biological functions

organism to function properly

CRUCIAL

www.glimmerveen.nl/le/biological_clock.html

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Doctors should listen to the rhythm of an illness

• We should better stay in bed in the morning for that is a dangerous time: most heart attacks happen in the morning shortly after getting up.

• Many diseases show a clear rhythm (rheumatism, migraine, asthma etc). Also the result of therapy can be very different depending on the cycle: when a woman with breast cancer is operated during the second half of her cycle, the chance to get it back is 25%, when the surgery is done during the first half it is 37%. But it is still rarely so that the planning of the treatment is made according to this knowledge.

• The effectiveness of drugs can depend on the time of day they are taken. Both the effect and the side effects can be very different depending on the moment of taking them. Slowly some insight in these rhythms is growing, but doctors find it often difficult to take in consideration.

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TIGHTJUNCTIONS

DESMOSOMES

GAPJUNCTIONS

• NEURAL

• NEURO ENDOCRINE

• ENDOCRINE

• AUTOCRINE

• PARACRINE9/30/2015 S Ghosh Physiology 26

Tightly stitched seams between cells.

Completely encircles each cell, preventing the movement of material between the cell.

Characteristic of cells lining the digestive tract, where materials are required to pass through cells, rather than intercellular spaces, to penetrate the bloodstream.

TIGHTJUNCTIONS

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GAPJUNCTIONS Narrow tunnels between cells

that consist of proteins called connexons.The proteins allow only

the passage of ions and small molecules. Communication between cells through

the exchange of materials or the transmission of electrical impulses.

NEURAL

NEUROENDOCRINE

ENDOCRINE

AUTOCRINE

PARACRINE

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Outside of cell

Inside of cell (cytoplasm)

Lipid Bilayer

Proteins

Transport Protein Phospholipids

Carbohydratechains

Structure of the Cell Membrane

Go to Section:

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Signal transduction – how a cell communicates

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Signal transduction – how a cell communicates and second messengers

• There are three basic types of secondary messenger molecules:

• Hydrophobic molecules: water-insoluble molecules, like diacylglycerol, and phosphatidylinositols, regulate membrane-associated effector proteins

• Hydrophilic molecules: water-soluble molecules, like cAMP, cGMP, IP3, and Ca2+, that are located within the cytosol

• Gases: nitric oxide (NO) and carbon monoxide (CO), which can diffuse both through cytosol and across cellular membranes.

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1 MOLECULE OF 1ST MESSENGER

10 RESPONSE6

Cyclic AMP

Cyclic GMP

Calcium ions

Inositol Triphosphate [IP3]

Diacylglycerol [DAG]

Sutherland awarded Nobel Prize for cAMP 9/30/2015 S Ghosh Physiology 33

CELLULAR HOMEOSTASIS

• Cell membrane is selectively permeable

• Allows for:– OSMOTIC EQUILLIBRIUM– CHEMICAL DISEQUILLIBRIUM– ELECTRICAL DISEQUILLIBRIUM

•End Result : ?

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• Behavior of charged particles near a semi-permeable membrane to sometimes fail to distribute evenly across the two sides of the membrane.

• The usual cause is the presence of a different charged substance that is unable to pass through the membrane and

• thus creates an uneven electrical charge.

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• For example, the large anionic proteins in blood plasma are not permeable to capillary walls.

• Because small cations are attracted, but are not bound to the proteins, small anions will cross capillary walls more readily than small cations

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Gibbs–Donnan effect

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• Also known as the Donnan effect, Donnan law, Donnan equilibrium, or Gibbs–Donnan equilibrium)

IT IS WELL RECOGNIZED THAT the plasma water Na+ and Cl-concentrations and interstitial fluid (ISF) Na+ and Cl- concentrationsare different despite the high permeability of Na+ and Cl- ions acrossthe capillary membrane, which separates these two fluid compartments

This difference in ionic concentrations between the plasma and the ISF is attributed to the much higher concentration of proteins in the

plasma compared with the ISF. Proteins are large-molecular-weight substancesand therefore do not cross the capillary membrane easily.

The low protein permeability across capillary membranes is responsible

for causing ionic concentration differences between the plasma and ISF

and is known as the Gibbs-Donnan effect or Gibbs-Donnan equilibrium

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Gibbs-Donnan equilibrium is established when the altered distribution

of cations and anions results in electrochemical equilibrium.

It is also well recognized that another consequence of the Gibbs-Donnan effect is that there are more osmotically active particlesin the plasma space than in the ISF at equilibrium .

Consequently, the plasma osmolality is slightly greater than the

osmolality of the ISF and intracellular fluid (ICF).

Indeed, the plasma osmolality is typically 1 mosmol/l H2O greater than that of the ISF and ICF .

In addition to the modulating effect of Gibbs-Donnan equilibrium on the

[Na+]pw and plasma osmolality, alterations in the osmolality of the ISF

and ICF will also lead to changes in the [Na+]pw and plasma

osmolality due to intercompartmental H2O shift since the body

fluid compartments are in osmotic equilibrium.

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(e.g., cytoskeletal rearrangement)

wide array of signaling events

(e.g., altered expression of osmolyte transporters

and heat shock proteins)9/30/2015 S Ghosh Physiology 42

Membrane Transporters

• Channel proteins– Water filled pores

• Gated : voltage or ligand• Open

• Carrier proteins – – Uniport– Symport– Antiport

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BIOCHEMISTRY

Na+/K+-ATPase

• Helps maintain resting potential, • Helps avail transport, and • Helps regulate cellular volume.• It also functions as signal transducer/integrator

to regulate MAPK pathway, ROS, as well as intracellular calcium.

• For most animal cells, the Na+/K+-ATPase is responsible for 1/3 of the cell's energy expenditure. For neurons, the Na+/K+-ATPase is responsible for 2/3 of the cell's energy expenditure.

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Cell to swell up and lyse.

The Na+-K+ pump is a mechanism to prevent this.

The pump transports

3 Na+ ions out of the cell and

in exchange takes 2 K+ ions into the cell.

Pr- Pr-

Pr-Pr-

+ ++

+

+

+

H2O

H2OH2O

H2O

OSMOSIS

3 Na+

2K+

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Membrane is far less permeable to Na+ ions than K+ ions. Sodium ions have a tendency to stay there. The opposing osmotic tendency that results operates to drive the water molecules out of the cells. Furthermore, when the cell begins to swell, this automatically activates the Na+-K+ pump, which moves still more ions to the exterior.

Na+ ions K+ ions

ADPATP

K+ 9/30/2015 S Ghosh Physiology 46

Electrical status of the cells……• Resting Membrane Potential• Cell interior is negative as compared to cell

exterior• It is mostly due to K+

– 40 times more permeable to K+ than to Na+– RMP~ -70 mV

• Changes in ion permeability changes the membrane potential– Mostly one of the four ions – Na+, Ca+2 Cl- & K+,

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Excitable tissues

• Muscles & Nerves• Can generate electrical signals and also

propagate them through long distances• Like all other cells

– Negative RMP• Uneven distribution of ions• Membrane permeability of the ions different

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Nernst Equation• Membrane Potential that would result if the

membrane were permeable to only one ion– Described by Nernst equation– E ion =( 61/z)log [ion]out / [ion]in

• Ideally it should have been -90 mV – if K+ alone would have been the ion responsible

• But real value is -70mV – other ions must be contributing– Membranes are slightly permeable to Na+

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• Goldman-Hodgkin-Katz equation• Na+, K+, Cl- are the three ions that

influence membrane potential in resting cells

• More of this when you do Biopotential lectures

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Questions to be brought up in the Tutorials

On Friday [2/10] & Monday [5/10]

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DIRECTED SELF LEARNINGmeant for the students to study since these are topics

learnt in earlier days

Effects of Osmosis on Life

• Osmosis- diffusion of water through a selectively permeable membrane

• Water is so small and there is so much of it the cell can’t control it’s movement through the cell membrane.

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Hypotonic Solution

Hypotonic: The solution has a lower concentration of solutes and a higher concentration of water than inside the cell. (Low solute; High water)

Result: Water moves from the solution to inside the cell): Cell Swells and bursts open (cytolysis)!

• Osmosis Animations for

isotonic, hypertonic, and hypotonic

solutions

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Hypertonic Solution

Hypertonic: The solution has a higher concentration of solutes and a lower concentration of water than inside the cell. (High solute; Low water)

Result: Water moves from inside the cell into the solution: Cell shrinks (Plasmolysis)!

• Osmosis Animations for

isotonic, hypertonic, and hypotonic

solutions

shrinks

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Isotonic SolutionIsotonic: The concentration of solutes in the solution is equal to the concentration of solutes inside the cell.

Result: Water moves equally in both directions and the cell remains same size! (Dynamic Equilibrium)

• Osmosis Animations for

isotonic, hypertonic, and hypotonic

solutions

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What type of solution are these cells in?

A CB

Hypertonic Isotonic Hypotonic9/30/2015 S Ghosh Physiology 56

• Cells release ions through activation of K channels and/or anion channels, KCl-cotransport, or parallel activationof K+/H+ exchange and Cl-/HCO3- exchange.

• They release osmolytes during cell swelling.

Cells accumulate ionsthrough activation of Na, K, 2Cl cotransport, Na/H exchange in parallel to Cl/HCO3 exchange, or Na channels. Na taken up is extruded by the

Na/K- ATPase in exchange for K.Accumulation of organic osmolytes- generate sorbitol and glycerophosphorylcholineand monomeric amino acids by altered metabolism and take up myoinositol (inositol), betaine, taurine and amino acids by Na coupled transport

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• After acute swelling, cell volume is regulated by the process of regulatory volume decrease (RVD), which involves the activation of KCl cotransport and of channels mediating K(+), Cl(-), and taurine efflux.

• Conversely, after acute shrinkage, cell volume is regulated by the process of regulatory volume increase (RVI), which is mediated primarily by Na(+)/H(+) exchange, Na(+)-K(+)-2Cl(-) cotransport, and Na(+) channels.

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Osmolarity• is the measure of solute

concentration, defined as the number of osmoles of solute per liter of solution (osmol/L).

• The osmolarity of a solution is usually expressed as Osm (pronounced "osmolar"),

• Osmolarity measures the number of osmoles of solute particles per unit volume of solution.

Osmol1 osmole = 1 mole of

osmotically active particles

the amount of osmotically active particles that when dissolved in 22.4 L of solvent at 0 degrees celsius exerts an osmotic pressure of 1 atmosphere.

a solution of 1 mol/L NaCl corresponds to an osmolarity of 2 osmol/L. NaCl salt particle dissociates fully in water

to become two separate particles: an Na+ ion and a Cl- ion.

Therefore, each mole of NaCl becomes two osmoles in solution.

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Osmolality

• is a measure of the osmoles of solute per kilogram of solvent (osmol/kg). such as sodium, chloride, potassium, urea, glucose, and other ions in blood.

Osmolarity

• is the measure of solute concentration, defined as the number of osmoles of solute per liter of solution (osmol/L).

HUMAN RANGE275-299 milli-osmoles per kilogram

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Clinical relevance• Cell membranes in general are freely permeable to

water, • the osmolality of the extracellular fluid (ECF) is

approximately equal to that of the intracellular fluid (ICF). • Therefore, plasma osmolality is a guide to

intracellular osmolality.

• This is important, as it shows that changes in ECF osmolality have a great affect on ICF osmolality - changes that can cause problems with normal cell functioning and volume.

• If the ECF was to become too hypotonic, water would readily fill surrounding cells, increasing their volume and potentially lysing them (cytolysis).9/30/2015 S Ghosh Physiology 61

Osmolality of blood increases Osmolality of blood decreases

More concentrated

Less

Con centrated

increased suppressed

More concentrated blood plasma

Less concentrated urine9/30/2015 S Ghosh Physiology 62

Plasma Osmolality = (2 x (Na + K)) + (BUN / 2.8) +

(glucose / 18)

Plasma Osmolality: (280 — 285 mOsm/Kg)·      As cell membranes in general

are freely permeable to water, the osmolality of the

ECF is approximately equal to that of the ICF·      Therefore, plasma osmolality is a guide to

intracellular osmolality

Na- Sodium, K – Potassium, BUN- Blood Urea Nitrogen

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TONICITY vs OSMOLALITY

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Effect of tonicity on cell integrity

Tonicity is a measure of the osmotic pressure of two solutions separated by a semipermeable membrane.

It is commonly used when describing the response of cells immersed in an external solution.

Like osmotic pressure, tonicityis influenced only by solutes that cannot cross the membrane,

as only these exert an osmotic pressure. Solutes able to freely cross the membrane do not affect tonicity

because they will always be in equal concentrations on both sides of the membrane. 9/30/2015 S Ghosh Physiology 66

• Osmolarity and tonicity are related, but different, concepts.

• The terms ending in -osmotic (isoosmotic, hyperosmotic, hypoosmotic) are not synonymous with the terms ending in -tonic (isotonic, hypertonic, hypotonic).

• The terms are related – they both compare the solute concentrations of

two solutions separated by a membrane. • The terms are different because

– osmolarity takes into account the total concentration of penetrating solutes and non-penetrating solutes, whereas tonicity takes into account the total concentration of only non-penetrating solutes.

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• Penetrating solutes –can diffuse through the cell membrane,

causing momentary changes in cell volume as the solutes "pull" water molecules with them.

• Non-penetrating solutes –cannot cross the cell membrane, and

therefore osmosis of water must occur for the solutions to reach equilibrium.

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Solution can be both hyperosmotic and isotonic

• The intracellular fluid and extracellular can be hyperosmotic, but isotonic –

if the total concentration of solutes in one compartment is different than the other, but one of the ions can cross the membrane, drawing water with it and thus causing no net change in solution volume.

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