Red Blood Cells _Erythrocytes_

Physiology 2nd SCT- 1st semester



Body fluid compartments-homeostasis

Homeostasis is the process through witch bodily equilibrium is maintained. The body is designed to

maintain a constant „internal milleu“ with regard to the body´s:



 Fluid compsition

 Temperature

 Blood pressure

 Blood glucose levels...ect.



The body as an open system:



The body exchanges material and energy with it´s surroundings, meanwhile the amount of body

fluids are kept constant. Fluid intake must be matched tp prevent body fluids from increasing or

decreasing. So the body must balance the net gain or net loss.

The human body is about 55-60% in adult males and 50-55% in adult females, due to higher

proportion of body fat.

Aprox 42 L in a 70 kg man.



Water sources:



 Drinks, food and metabolism of CO2 and H20 (oxidation of carbohydrates). Around 2300ml

per day, although it varies.



Water losses:



 Urine

 Fecal

 Insensible.

Evaporation from the respiratory tract and skin surface (not sweat which is sensible)

 Sweat loss.

At room temp it´s ~25% of heat loss, it decreases in cold and increases in heat & exercise.

 Pathological loss.

Bleeding, vomiting, diarrhea.



Electrolytes:

Any substance containing free ions that behaves as an electrically conductive medium. Because they

generally consist of ions in solution, electrolytes are also known as ionic solutions. They must be

consumed and eliminated in equal quantities.

In physiology, the primary ions of electrolytes are sodium (Na+), potassium (K+), calcium (Ca2+),

magnesium (Mg2+), chloride (Cl−), hydrogen phosphate (HPO42−), and hydrogen carbonate (HCO3−).

The electric charge symbols of plus (+) and minus (−) indicate that the substance in question is ionic

in nature and has an imbalanced distribution of electrons, which is the result of chemical

dissociation.



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Electrolyte sources:



 Na+ and K+ , usually by ingestion of food.

 Clinically theu enter the body parenterally, through i.v. solution.



Electrolyte losses:



 Renal excretion

 Stool loss

 Sweating

 Abnormal routes e.g. vomit and diarrhea







Metabolized substances:



Substances that are chemically altered must also be in balance BUT the amount consumed will not

have a simple one to one relationship to the eliminated amount. There must be a chemical

conservation btw substrates and end-products.



The distribution of various substances within the body in NOT homogeneous!!



Body fluid compartments



A region of the body with different chemical

compostion or unique behavior. Usually separated

from each other either by membranes or by whole cells

forming a epithelial (or endothelial) lining.



The total body fluid is distributed mainly btw 2

compartments; the intra- and extracellular fluid. The

extracellular fluid is divided to interstitial fluid and

plasma.



1. Intracellular fluid

Aprox 36% of body weight, so ~ 25L in a 70 kg

man.

The fluid of each cell contains it´s mixture of

different constituents but the concentration of these substances are similar from one cell to

another.

2. Extracellular fluid

Aprox 24% of body weight.

 Plasma: blood without red and white blood cells. It exchanges substances

continuously with the interstitial fluid through pores in the capillary

membranes, soluble to all solutes except proteins. So plasma and interstital

fluid have the same compsition except for protein.

3L in 70 kg man = about 4.5% of body weight

 Interstitial space: Space btw the cells that makes up the organs.

8L in 70 kg man = about 11,5% of body weight



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 Also there is EC fluid in bone, dense CT and transcellular water in secretions

such as digestive secretions, intraocular fluid, CSF, sweat and synovial fluid.

The remaining 6 L is in these minor compartments.





Blood contains both extracellular fluid (plasma) and intracellular fluid (fluid in RBC), BUT blood is

considered to be a separated fluid compartment because it´s contained in a chamber of it´s own.

Plasma volume : Blood volume x (1-hematocrit)

The plasma water is the initial wate access point for ingested nutrients, and the exit point for the

body´s waste. Access to ALL the cells of the body, except RBC, is by the interstitial space.



The ionic compsition:



Different btw body compartments BUT

the total osmotic concentartions of EC

and IC fluid is similar (despite the

differece in total ionic concentration).



Main EC cation: Na+

anion: Cl- and HCO3-



Main IC cation: K+

anion: phosphates (inorganic,

2-

HPO4 & H2PO4- AND organic, ATP ect.)

and proteins.



The EC fluid production in pathological conditions: differs btw





Transudatum Exusdatum

extravascular fluid with low protein content any fluid that filters from the circulatory system

into lesions or areas of inflammation

High BP Inflammation

Clean-water like fluid Turbid

No protein (-Rivalto reaction) Protein (+Rivalto reaction)

Low density High density





EXPRESSING FLUID COMPOSITION:



1. Molality: Concentration as moles solute per kg of solvent.

2. Molarity(M): Concentration expressed as moles solute per L of solution. M means

moles/liter! Physiological concentrations are low so they are often expressed in units of

millimolar (mM)=10-3M, micromolar (µM)=10-6M, nanomolar (nM)=10-9, or

picomolar(pM)=10-12M.

3. Electrochemical equivalence (Eq): The weight in grams of an ionic substance that replaces or

combines with one gram (mole) of monovalent H+ ions.

For monovalent ions like Na+ and Cl- one Eq is equal to one GMW.

For monovalent ions like Ca++ and Mg++ one Eq is equal to one-half GMW.



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Physiological concentrations are small and often measures in mEq/L= 10-3 Eq/L.

These units are useful in concidering how much of a substance is needed to maintain

electoneutrality.

4. Complications in determining plasma concentration: Not all ionic substances from freely-

diccociated, freely-dissolved species.

a. Many bind proteins

b. Plasma is 97% water. The 3% is protein and lipids. So ionic concentrations are

somewhat underestimated when expressed in terms of whole plasma.







Osmotic concepts



Osmosis is the net diffusion of water accross a

semipermeable membrane from a region of high water

concentration to one of lower concentration. The

semipermeable membrane separates 2 compartments,

solute particles cannot go through BUT water will cross untill

solute concentration on both sides is equal. The force

generated: osmotic pressure (q).



Particles which dissociate to form ions exert an osmaotic

force in proportion to the number of osmotic particles

formed. For example: 1 mol NaCl if dissolved completely

formes a 2 osmolar solution and CaCl2 formes a 3 osmolar solution and so on. At physiological

conditions milliosmolar concentrations units are most appropriate (1mOSM= 10-3 osmoles/L).



But biological membranes are not impermaeble to all solutes so solutes can exert effcive osmotic

forces btw body compartments.



Except plasma proteins (all solutes can cross capillaries except proteins, ↑protein

concentration in plasma) so the exert an important net osmotic force across the capillary barrier.

↑plasma protein=↑water moves to plasma from interstitial space.



Membrane pumps effectively keep Na+ from entering cells= ↑EC *Na++ so water moves out

of cells into EC space. The osmotic force generated by a decrease in EC [Na+] causes EC water to go

into cells.





The Donnan equilibrium



Proteins are large, osmotically active, negatively charged ions. They cannot move btw compartments

so the distribution of other ions is influenced in an attempt to maintain electoneutrality and osmotic

equilibrium on both sides of the membrane.



 Diffusable cation concentration is higher in the compartment with non-diffusable anionic

proteins and diffusable anion concentration is lower.







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 ↑total osmotic forces exerted by diffusable ions in the proteins free compartment ; there

are more diffusable ion particles in the protein-containing compartment.

 The end result of the Gibbs-Donnan effect is that more water moves into the protein

containing compartment than would be predicted on the basis of the protein concentrations.



Measurement of body fluid compartments



Based on the definition of concentration in a well mixed compartment:



Concentration = Amount injected / Volume distribution



Needed to correct for any substance excreted during the time it takes for the injected substance to

distribute itself in the compartment. Equation for volume distribution:



Vd = (Amount injected-Amount excreted) / Concentration after equilibrium



The measure the volume of a compatment one must have a substance that distributes itself only in

the compartment of interest. Volumes for compartments where no such substance exists can be

determined by substraction.



 Total body water: Deuterated water (D2O), titrated water(THO) and antipyrine are used.

 EC-fluid volume: Labeled inulin, succrose, mannitol and sulfate.

 Plasma volume: Radiolabeled albumin or Evans blue dye (binds to albumin)

 IC-fluid volume: By substraction [ICF=TBW-ECFV]

 Interstitial fluid volume: By substraction [ISFV=ECFV-PV]



Calculations



Osmolarity is the same in all compartments, calculate:



 Initial total body solute: (Plasma osmolarity) x (TBW)

 Initial EC solute: (plasma osmolarity) x (ECV)

 New total body solute: previous Amt. + Added Amt.

 New TBW: Old TBW + Added body water

 New total body osmolarity: New total body solute / New TBW

 New EC solute: Old EC solute + Added EC solute

 New ECV: New EC solute / New Total body osmolarity

 New ICV: New TBW – New ECV

 If desired, estimate New [Na+]p as: New body osmolarity / 2



 Calculations! Initial conditions: ICF= 25L, ECF=17L, [Na+]p=140mEq/L

o Ingestion of 420 mEq NaCl.

ICF=23,3 L, ECF= 18,7L, [Na+]p= 150mEq/L

o Inhibiting and absorbing 1,5 L H20

ICF=25,9L, ECF=17,6L ,[Na+]p=135mEq/L

o Infusing 1,5 L isotonic saline

ICF=25L , ECF=18,5 L, [Na+]p=140 mEq/L





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Clinical conditions



Hypernatremia :

↑*Na++ in blood = ↓IC fluid volume . Cell shrinkage with brains cells being of particular significance.

Necessary to rule out: hypoproteinemia and hypolipidemia.

Increases EC osmolarity (cell shrinkage), if water is freely accesible the hypernatremia may be

prevented. It´s often seen in coma patients or infants without access to free water. Conditions:



 Increased insensible water loss

 Exessive sweat loss.

 Central or nephrogenic diabetes isipidus (↓ADH secretion/response)



Hyponatremia:

↓*Na++ in blood = ↑IC fluid volume. Cell swelling. Necessary to rule out hyperproteinemia and

hyperlipidemia.

Decrease EC osmolarity (cell swelling). Conditions:



 Large water ingestion.

 Syndrome of inapropriate ADH secretion (SIADH). ↑↑ADH = water retention and

concentrated urine.



Severe hyperglycemia:

↑*Glucose+ in blood= Glucose act as an effective osmole and can induce hyponatremia and cell

shrinkage. Cell shrinking needs correcting, NOT the hyponatremia.



Increased ECF volume:

↑central venous pressure (bulging of jugular veins) in conjunction with edem is often a indicative if

increased ECFV. If osmolarity is normal the IC fluid is probably normal.



Decreased ECF volume:

The main danger is hypovolemia which ultimately decreases tissue perfusion. Clinical presentation:

dry mucus membranes, lack of urination, tenting of skin, slow capillary refill. The conditions tening to

cause isotonic decreases in ECFV have little direct effect on cell volume, NOTE that the fluid lost has

the same osmolarity as ECF. Volume loss stimulates thirst and ADH secretion. This results in water

retention and occationally, 2° hyponatremia. Causes:



 Vomiting, diarrhea, bleeding, burns (direct loss if interstitial fluid, also protein loss so plamsa

contracts)



Solutions used clinically for volume replacement



The osmotic concentration depends on the gram molecular weight of the solute and it´s

dissociability.



 Isotonic solutions: Same osmotic concentration as plasma





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 Hypertonic solutions: ↑osmitic concentration than plasma. Will decrese IC volume.

 Hypotonic solutions: ↓osmotic concentrations than plasma. Expands IC volume.



General categories if IV solutions:



 Dextrose solutions: Glucose is rapidly meatbolised to CO2 and H20. The volume is distibuted

IC and EC.

 Saline solutions:

o Hypotonic (eg. 0.2%)

o Isotonic (0.9%)

o Hypertonic (eg. 5%)

 Dextrose in saline. Has also various concentrations. Gives ↑volume and ↑calories.

 Plasma expanders: E.g. Dextran with long chain polysaccharide, these solutions are confined

to the vascular compartment and preferentially expand this portion of ECF.









Hemostasis

Platelets (thromocytes)



Flattened disk like fragments that are ~ 1µm x 4 µm.



Act as participants in the vascular clotting system. They are continuously being replaced, each

platelet circulates 9-12 days before being removed by splenic phagocyets.



They transport of chemicals important to the clotting process. By releasing enzymes and other

factors, they help initiate the clotting process.

Formation of a temorary patch (platelet plug) in the wall of the damaged blood vessel.



Hemostasis



Prevents blood loss through the walls of damaged blodd vessels, also establishes a framework for

further tissue repairs.



3 main phases:



1. Vascular phase

Lasts 30 min.

Endothelial cells at injury site undergo changes:

- Contract and expose their basement membrane

- Release chemical factors and local hormones (ADP, tissue factor and prostacyclin)

- Endithelial cell membranes become „sticky“



2. Platelet phase

Within 15 sec of the injury.

Platelets begin to attach to sticky endothelial cells, the basement membrane and exposed





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collagen fibres. Platelets attach to collagen in the tissue and a protein called von Willebrand

factor that leaks into traumatized tissue from plasma.

As platelets „stick“ they become „activated“. Activated platelets release:



- ADP → 1° stimulus for platelet aggregation (positive feedback)

-Thromboxane A2 → causes platelet aggregation and local vasoconstriction

-Serotonin → Causes local vaso constriction

-Ca++ ions

The aggregation of platelets eventually leads to a platelet plug: A temporary mass of

platelets that stops blood loss and forms a framework for the clot.

3. Coagulation phase

Begins 30 sec + after injury (unlike first 2 that begin almost immediatly)

A sequence of steps leading to the conversion of fibrinogen (a circulating plasma protein) to

insoluble protein fibrin.

A network of fibrin grows and covers the surface of the platelet plug. RBC´s and additional

platelets are trapped in this tangle forming a blood clot that seals the damaged vessel wall.







Coagulation



Requiers clotting factors:



 Ca++ ions

 11 different proteins, most synthesized by the liver.

Many are pro-enzymes (inactive) that activate in the in the clotting process.

The synthesis of some requiers VIT K.



- Extrinsic pathway



A certain activator factor will be produced by

the tissue, it activates the clotting factor

„tissue thormoplastin activator“.

Begins with the release of tissue factor or by

damaged endothelial cells or peripheral tissue.

The greater the dagmage the more tissue

factor released and faster clotting will occur.

Tissue factor combines with ca++ and another

procoagulant (factor VII) to form an enzyme

called tissue thromboplastin (Factor III).



- Intrinsic pathway



Exposure of platelets to collagen activating the whole system via „contact factor“.

Begins with the activation of proenzymes exposed to collagen fibres at the site of injury.

Eventually, several activated proenzymes, Ca++ and Platelet factor-3 (PF-3) interact to form a

complex called platelet prothomboplastin.





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- Common pathway



Begins when thromboplastin from either intrinsic or extrinsic pathway appear in the plasma.

Thromboplastin and activated Factor X form = Prothombin activator.

Prothrombin activator catalyzes the conversion of prothrombin into thrombin (involves 2 sparate

proteolytic cleavages by serine protease).

Thrombin catalyszes the conversion of the plasma protein fibrinogen to insoluble fibrin.









Interaction among the pathways:



Damage to the blood vessel enacts both the intrinsic and extrinsic pathways about 15 sec.



Ex. Pathway is short and fast and produces a small amount of thrombin very quickly. The speed

allows for a quick clot formation.



The Ex. Products are reinforced by a larger amount of thrombin made by the somewhat slower

intrinsic pathway.



Clot retraction:



Once the fibrin meshwork has appeared, RBC and platelets stick to it. Platelets than contract and

the clot undergoes clot retraction :



- Pulls torn vessel egdes together, reducing residual

bleeding at stabilizing the injury.

- Reduces the size of the injuerd area, making it

easier for fibriblasts, smooth muscle ceææs and

endothelial cells to complete repairs.





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Fibrinolysis



As repairs proceed, the clot gradually dissolved (fibrinolysis). The process begins with the activation

of the proenzyme plasminogen by 2 enzymes:



- Thrombin: activated in common pathway

- Tissue plasminogen activator: Released by damaged tissue

- Its main enzyme plasmin cuts the fibrin mesh at various places, leading to the production of

circulating fragments that are cleared by other proteases or by the kidney and liver.



Plasminogen is converted into plasmin which digests the fibrin strands and erodes the foundation of

the clot.



Manipulating Hemostasis: Antocoagulant drugs



 Heparin : Inactivates thrombin

 Caumadin : Block activation of Vitamin K

 Streptokinase : Converts plasminogen to plasmin

 Aspirin : Inhibits platelet aggregation

 Citarte : Chelate calcium



Hemophilia: several different hereditary disorders with similar signs / symptoms.

Hemophilia A

Lack of Factor VIII. Most common type (83%). X-linked.



Hemophilia B

Less common. Deficiency of Factor IX. X-linked.









Blood

Blood is a specialized bodily fluid that delivers necessary substances to the body's cells—such as

nutrients and oxygen—and transports waste products away from those same cells. Blood accounts

for 7% of the human body weight, with an average density of approximately 1060 kg/m³, very close

to pure water's density of 1000 kg/m3. The average adult has a blood volume of roughly 5 L,

composed of plasma and several kinds of cells.



Components:



1. Fomed elements: 37-54%

99,9% RBC

1 Hyperchromia





Anemias

Reduced number of RBC due to decreased erythropoesis (iron or B12 deficiency), increased

erythrolysis (heamolysis or hepatosplenomegalia) or bleeding (acute/chronic, menstruation or birth)



 Hyperchromic megaloblastic anemia (pernicious anemia)



Origin: Vit B12 (IF) or Folic acid (intake) deficiency.

Signs:

1. ↓RBC number → stimulated erythropoiesis→no RBC→LEFT SHIFT (towards immature

cells-reticulocytes)in peripheric blood→megaloblast in peropheric blood.

2. ↑Hb per RBC, hyperchromia

3. Hipacidity/ anacidity with stomcah cell atrophy



Symptoms: Neurological problems, sore tongue, weight loss, pale skin, often with lemon tint,

diarrhea.



Therapy: Vit B12 (i.m.), Folic acid (p.o.), Iron (p.o.)



 Hypochromic anemia



Iron deficiencey anemia, the most common form. Aprox. 20% of women, 50% of pregnant

women and 3% of men are iron defiecient.

Origin: Lack of iron due to bleeding (acute or chronic) or increased requirement for iron

(pregnant or lactating women, adolescents in rapid growth)

Signs:

1. ↓Hct & Hb

2. Small RBC

3. ↓serum *ferritin+ and *iron+

4. ↑Iron binding capacity (TIBC) in blood

5. Blood in stool



Symptoms: Unspceific



Therapy: Iron (p.o.). This anemia is more problematic since it´s hard to keep iron in solble

form. It´s possible to increase serum levels but not normalyse.





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 Hemorrhagic

Blood loss (RBC loss), can be acute or chronic.

 Sickle cell anemia

A single mutation in the gene for the β chain of globin resulting in abnormal hemoglobin. Β-

chains link together and become stiff rods under low O2 conditions. This pathological form

makes it impssible for RBC to pass through capillary walls or can block them. RBC become

sickle shaped and are more resistant to malaria. High frequency of gene is due ti positive

selection in centrain places of the world.

 Thalasemia

Hb chain is normal but decreased. Often seen in people of Mediterranean origin. One of the

globin genes is abcent or faulty.

 Hemolytic anemia

↑Hemolysis = Jaundice

 Aplastic

Cause unknown



Polycytemia



↑number of RBC, elevated Hct with normal blood volume. High blood viscocity, more work for the

heart. Blood may become 2-3 times more viscous and thus hard for heart to maintain CO.

Treatment is cytostatic therapy- inhibiting RBC production in red bone marrow.









Blood types









A blood type is a classification of blood based on the presence or absence of inherited antigenic

substances on the surface of RBCs. These antigens may be proteins, carbohydrates, glycoproteins, or

glycolipids, depending on the blood group system, and some of these antigens are also present on

the surface of other types of cells of various tissues

The ABO system is the most important blood group system in human blood transfusion. The

associated anti-A antibodies and anti-B antibodies are usually "Immunoglobulin M". ABO IgM



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antibodies are produced in the first years of life by sensitization to environmental substances such as

food, bacteria and viruses.





Phenotype Genotype

A AA or AO

B BB or BO

AB AB

O O





The Rhesus system is the second most significant blood group system in human blood transfusion.

The most significant Rhesus antigen is the RhD antigen because it is the most immunogenic of the

five main rhesus antigens.



Erythroblastosis Fetalis



A type of hemolytic anemia.

It is an alloimmune condition that develops in a fetus, when the IgG antibodies that have been

produced by the mother and have passed through the placenta include ones which attack the red

blood cells in the fetal circulation. The red cells are broken down and the fetus can develop

reticulocytosis and anaemia.



The mother sensitizes againts the 1st childs Rh antigen (being that it´s oposite to hers) after labor, or

after the placenta has broken, mixing the blood types. The problem starts at the 2nd pregnancy

when the mothers anti-Rh antibodies will cross the placenta (small molecules) and attack the fetal

RBCs. Resluts in amenia and hypoxia of the fetus. With each pregnancy the reaction is stronger

leaving a the child in danger for brain damage and death if blood transfusion is not performed.









White blood cells (leukocytes)

Cells of the immune system defending the body against both infectious disease and foreign materials

(toxins and pathogens). All WBC types are produced and derived from a multipotent cell in the bone

marrow known as a hematopoietic stem cell. Leukocytes are found throughout the body, including

the blood and lymphatic system.Different disorders can cause characteristic changes in circulating

population of WBC. Leukopenia=↓WBC.



A typical µL of blood contains 6000-9000 WBC, just a fraction of the total ans much less than

circulating RBC. Most of the WBCs at a given moment are in the CT or organs of the lyphatic tissue.



Types of WBC are clssified on

the appearance of granules in

light microscope.









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Granulocytes



 Neutrophils

50-70% of circulating WBC. Cytoplasm has pale neutral colored granules that contain

bactericidal compounds. They are polymorphonuclear. 12µm in diameter. First to arrive at

injury site, their activity and death in large numbers forms pus. Attack and digest bacteria

that have been surface marked for destruction. Survive in blood stream for ~ 10 hrs.

 Eosinophils

2-4% of circulating WBC. Reddish granules and a bilobular nucleus. Move into tissue after

several hours and survive from minutes to days. Phagocytose Ab-coated bacteria, protozoa

and cell debris. By exocytosis of toxic compunds onto target surface. Predominant in

parasitic infectiona and allergic reaction, then they increase in number.

 Basophils

Less than 1%. Small, only 8µm in diameter. Granules appear dark blue. Migrate to injury site

and discharge the content of the granules:

Histamine a vasodilator. ↑permeability of capillaries.

Heparin an anticoagulant.

This incraeses inflammation and attrackts other WBCs.





Agranulocytes



 Lymphocytes

20-30% of circulating WBC. Large spherical basophilic nucleus and little cytoplasm.

Continuously migrate from the blood stream through peipheral tissue and back into the

blood stream, they are B, T and NK cells.

 Monocytes

2-8% of circulating WBC. Almost twice the size of RBC. Large kidney shaped nucleus.

Individual monocytes use the circulation as a highway, they stay there for ~24hrs before

entering the tissue. In tissue they become: Macrophages.



Never Let Monkey Eat Banana

60 + 30 +6 +3 +3









Jaundice



A RBC lives btw 90-120 days. It dies in the spleen, due to rupture of rigid cell membrane, which

doesnt regenerate due to lack of cytoplasmic organelles. After hemolysis the Hb will be excreted by

the kidneys.







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The catabolism of heme yields bile pigments (from hemolysis, from RBC prcurosr in red bone marrow

and heme proteins of liver and other tissues). There is no evidence for the direct synthesis of biliruv-

bin from heme precursors.



Bilirubin is a pigmented organic anion waste product closely related to porphyrins and other

tetrapyrroles, it´s insoluble in water.



Hemoglobin→ verdoglobin→ biliverdine→ bilirubin→ urobilinogen→ urobiline→ stercobilinugen→

stercobiline.



Formation



250-350 mg bilirubin forms daily. 70-80% is derived from the breakdown of RBCs. 20-30% comes

from heme proteins primarily from bone marrow.

The heme mioety is degreded to iron and biliverdin by heme oxygenase. Bilirubin reductase converts

biliverdin to bilirubin this occurs primarily in cells of the reticuloendothelial (mononuclear phagocyte)

system.



Plasma transport



Because of internal hydrogen bonding, bilirubin is not water soluble. Unconjugated (indirect)

bilirubin is transported in plasma via Albumins and CANNOT pass through glomerular membrane-

does NOT appear in urine due to it´s large size. The binding may get weaker in certain conditions.



A + B = AB AB: indirect bilirubin

B: direct bilirubin



Liver uptake



The indirect bilirubin travels to the liver where hepatocytes will take up the bilirubin. The uptake is

via active transport and is rapid, but does´nt include uptake of serum albumin.



Conjugation



Free bilirubin concentrated in the liver is conjugated with Glucoronic Acid to form Bilirubin

Diglucoronide, or conjugated bilirubin. Catalysed by Glucoronyl transferase. Yields a reletively small

watersoluble molecule.



Bile excretion



Conjugated bilirubin is secreted into the bile canaliculus with other

bile constituents. It reaches the GI-track where it is deconjugated and

reduced to Strereobilinogens (gives color of stool) and UBG by

bacteria. A substantial amount are absorbed back by the portal vein

and reabsorbed by Na+ couples 2° active transport to the liver where

it is turned back to bilirubin and excreted back to GI-tract, this is the

ENTEROHEPATIC CIRCULATION OF BILE.



Or it can reach the kidney via the systemic circulation (from the

lowest part of the GI tract, past the portal vein), where it will be



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filtered and disappears with urine (and gives it´s color). The kidneys can excretes bilirubin

diglucoronide but NOT unconjugated bilirubin.



2 forms of hemoglobin:



Unconjugated (indirect) bilirubin Conjugated (direct) bilirubin

Albumin bound Conjugated to UDP, not albumin bound

Lipid soluble Water soluble

Cannot filtrate through glomeruli Filtrates through glomeruli

Cannot give positive reaction in diazol probe Gives a positive reaction in diazol probe





There are 3 forms of Jaundice:



Generally is a yellowish discoloration of the skin, sclerae (whites of the eyes) and mucous

membranes caused by hyperbilirubinemia (increased levels of bilirubin in the blood). This

hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluids.

Treatment is UV-light which break down the double bonds of bilirubin or blood transfusion e.g. in

fetal jaundice, where fetal bilirubin (2α2γ) is replaced by adult bilirubin (2α2β). Fetal hemoglobin has

less, 2,3 bisPglycerate.

Normal serum bilirubin :10-20 µmol/L



1. Pre-Hepatic (hemolytic)

To many RBC are broken down, increased bilirubin. Each bilirubin needs to be bound to

albumin in plasma: ↑indirect bilirubin in plasma (CANNOT ENTER URINE). There will be

increased uptake by hepatocytes and thus increased production of conjugated bilirubin and

UBG. Darker stools and urine. E.g. neonatal jaundice.

2. Hepatic (heaptocellular)

There are 2 populations of hepatocytes: healthy and those affacted by a disease. The healthy

cells do their job- so UBG is in the urine and strereobilinogen in the feces. BUT the sick

hepatocytes will release their conjugated bilirubin into the blood stream, via weak liver

sinusoids. The conjugated bilirubin will appear in both plasma and urine. A small amount of

UBG may be in urine. Is due to hepatitis, virus or alchoholism.

3. Post- Hepatic (obstructive)

Obstruction on the bile duct (common and/or above the cystic) and conjugated bilirubin

cannot enter GI-tract. NO UBG is produced resulting in light colored urine and feces. Even

bile itself cannot enter GI, and it´s very importnant to absorbtion and digeation of lipids,

resulting in high amount of fat in feces. The patient may develp hemorrhage since VitK is not

absorbed.

Conjugated bilirubin and bile are continuously produced and pressure will increase. It may

rupture the bile duct membrane releasing conjugated bilirubin into blood stream (NEVER

happens normally). It will be excreted via urine, making urine very dark.









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Basic hemodynamics









Aorta: Has the highest pressure, and a fluctuation pressure due to systole and diastole.



Arterioles: Provide the largest proportion to the TPR, there is huge resistance. Fluctuation diaspears

and pulastile pressure exists.



Capillaries: Further decresed pressure



Big veins: The pressure decreases even further.



The pressure must continuously decrease from aorta to big veins, this is the driving force of

circulation.



The velocity profile:



Plot:









The flow rate depends on the total cross section size of the vessels.



↑ total cross section = ↓ velocity



Capillaries [smallest velocity] > Veins > Aorta [biggest velocity]





21

At the end of the big veins the actual cross section is still larger than the aorta since there are 2 large

veins and only 1 aorta. The least velocity of flow is the the capillaries where exchange takes place.

This gives time for perfusion.



The total resistance of vessels in a series is the sum af the individual ones: R=R1+R2+R3...

In the vascular system the total resistance is greater than any of the individual ones. This is valid for

a series: Aorta→Arteries→Capillaries→Veins



BUT if the resistor is connected paralell, to calculate the total resistance: 1/R=1/R1+1/R2+1/R3... This

makes sure that the total resistance is always smaller than individual ones and blood vessels of the

sam type are connected paralell.



Laminar flow



Layers inside the blood vessel with different velocities,

but same direction. The closer to the wall the slower,

with the highest velocity in the middle. NO SOUND.



Turbulent flow



Flow in different directions, much less effective and

produces VORTEXES.



Reynolds number, Rn. Gives probability of getting turbulent flow. ↑Rn = ↑prob. of turbulent flow.

Detrmined by:



 Directly proportional to the velocity

 Directly proportional to the diameter

 Directly proportional to the density of the fluid

 Invertly proportional to the viscosity of the fluid









MAP

The pressure difference btw the proximal and distal end in a vessel is the driving force of blood flow.

The pressure differecne equals the resistance of the tube times intesity of flow.



The mean arterial pressure is a term used in medicine to describe a notional average blood pressure

in an individual. It is defined as the average arterial pressure during a single cardiac cycle. Its not

equal to the avergate of systolic and diastolic because the arterial pressure remains nearer to the

diatolic pressure during most of the cardiac cycle.







The pressure in the aorta is continuously changing btw 2 extremes btw systole and diastole, thats

why an average point is needed.







22

1/3(SP-DP) is the pulse pressure; the change in blood pressure seen during the contraction of the

heart.





TPR

Total peripheral resistance is the sum of the resistance of all peripheral vasculature in the systemic

circulation. This should not be confused with Pulmonary Vascular Resistance, which is the resistance

in the pulmonary vasculature.









 Directly proportional to length of tube :L

 Directly proportional to viscocity: n

 Directly proportional to a constant : 8/pi

 Inversly proportional to the 4th power of the radius, The radius is the only parameter that

can be regulated. The most important vessel type in TPR are the arterioles, provide 60% of

TPR.



Thus in vasoconstriction ↓radius and ↑resistance & ↑MAP, because TPRxCO=MAP



Law of LaPlace



T=rxPt Tension of wall equals to radius times transmural pressure



The transmural pressure difference btw intravascular pressure and extravascular pressure. This

applies to capillaries; despite that capillaries have relatively large pressue and very this wall they do

not burst, the transmural pressure is high but radius is SO small- so effective tension will be low

enough for the single cell layer to withstand the tension.







Compliance/elastic vessels

Big arteries with elastic distensable walls. Volume can easily be increased.

Pressure of the aorta as a function of the volume decrease:









↑Volume =↑Pressure in the aorta. The compliance decreses with age and it gradually become more

difficult to distend the aorta and it results in greater pressure increase with volume increase.



During ejection of blood, only 1/3 will drain towards the peripheral blood, 2/3 will remain in the

aorta. The pressure increaes in ejection but at the end of systole the aortic wall will recoil. The recoil

gives a continuous perfusion of blood. The remaining blood in aorta after ejection will then flow

towards peripheral blood. Befor complete emptying of the aorta the next ejection will occur.





23

Determination of pulse pressure:

pulse pressure=systolic pressure – diastolic pressure



 Stroke volume

 Velocity of ejection

 Inversly proportional to compliance





The pressure increses due to ejection, reaches max

value at the peak of the ejection and then decreases.

„incisura“ a sudden increase in pressure again, due to

closure of aortic valves, as they close blood wants to

reenter the heart, but cant. In peripheral blood vessels the incisura is not so sharp.May appear as a

„dichroic notch“.



The aortic pulse wave is shorter than in peropheal vessels BUT the velocity of the pressure wave has

nothing to do with velocity of blood itself. The ONLY thing that determines the velocity of the

pressure wave is the COMPLIANCE OF THE AORTA.



Parameters of the pulse pressure wave:



 Rythmicity (rythmin/arrythmic)

 Frequency (HR)

 Compressibilty (hard/soft)

 Amplitude (difference btw sys and dia pressures, high/low)

 Rate of rise (how fast is the upstroke, fast/slow)

 Equality (all pressure waves are identical)



3 important diseases that change the pressure wave:



 Aortic stenosis

Systolic murrmurr due to pathological ventricular emptying, btw S1 and S2. Amplitude and

rate of rise are affected: Slower and Lower waves.

 Aortic insufficiency

Diastolic murrmurr btw S2 and S1, due to pathological ventricular filling. Bigger preload due

to 2 sources of blood; left atria and aorta. Results in larger diameter of left ventricule and

hypertrophy. Contractile force and rate of rise will increase, fast upstroke with high

amplitude. Can be so strong as to move the head of the patient.

 Artherosclerosis

Rigid aortic wall due to ca++ desosit. Less compliance and thus ↑ pressure. Normal diastoloic

pressure BUT higher systolic pressure. Fast and low waves.



Important things:



- Systolic pressure:

↑Stroke volume= ↑ SP

↓Compliance=↑ SP

↑Rate of ejection= ↑ SP



24

- Diastolic pressure:

↑TPR = ↑DP

↓compliance= ↑DP (not as muc as SP)

- Pulse pressure:

↑Stroke volume = ↑ SP = DP→ == ↑PP

↑TPR = ↑DP = SP → == ↑PP

↓Compliance = ↑DP = ↑↑ SP == ↑PP



Resistance vessels

Arterioles that accout for 60% of TPR. An arteriole is a small diameter blood vessel that extends and

branches out from an artery and leads to capillaries. [1]



Arterioles have thin, slim and skinny muscular walls (usually only one to two layers of smooth

muscle).



Capillaries are the smallest of a body's blood vessels, measuring 5-10 μm in diameter, which connect

arterioles and venules. They exchange matabolites btw plasma and interstitial space, via:



 Passive diffusion (O2 and CO2)

 Endo-exotranscytosis

 Fused vesicle channel

 Clefts (btw adjacent endothelial cells, not in all tissue)

 Bulk flow (filtration of water through the endothelial cells)







Starling forces









1. Hydrostatic pressure if the capillary Pc

Expels water out FROM plasma (filtration)

2. Hydrostatic pressure of the interstitial space Pi

Backwark movement of water TO plasma (reabsorbtion)

3. Oncontic pressure of the plasma πc

Most important are the albumins. Support movement of water TO plasma.(reabsorbtion)







25

4. Oncotic pressure of the interstitial space πi

Molecules FROM plasma (filtration)



The Starling equation is an equation that illustrates

the role of hydrostatic and oncotic forces (the so-

called Starling forces) in the movement of fluid across

capillary membranes.







If the effective pressure is zero there will be no filtration or absorbtion.

Peff= positive= Net Filtration

Peff=negative=Net Absorbtion

Peff=0= NO net fluid movement



The net oncotic pressure is more or less the

same along the whole length. The net

hydrostatic pressure of interstitial space

decreases from arterial to venous end. The

difference btw the 2 will decrease along the

length of the capillary.



ΔP is greater than Δπ = Net filtration



ΔP is lower than Δπ= Net absorbtion







Arterial end filttrates and venous end absorbes, the remains will go to lymph ~10%.







Edema



An abnormal accumulation of fluid beneath the skin, or in one or more cavities of the body. ↑water

in interstitial fluid of the connective tissue. Is because filtration exceeds absorbtion OR the lymphatic

passage is obscured.



1. ↑hydrostatic pressure at arterial end = ↑filtration.

Most usual reason is hypertension.

2. ↑hydrostatic pressur at venous end = ↓absorbtion because of obstructed veins. May lead to

ventricular failure and either systemic (RV) or pulmonary (LV) edema.

3. ↓oncontic pressure of plasma=↑filtration. Plasma albumins are responsable for 80% of total

oncotic pressure, may be caused by hypoproteinemia (liver disease, kidney disease or

starvation)

4. Lymphatic obstruction, fluid in interstitial space cannot leave. Wucheria bancrofti and

Elefantiasis OR amputation.

5. ↑Capillary permeability=↑filtration. E.g. due to bee sting, with histamin secretion which

causes vasodilation and ↑ permeability.





26

NOTE that normally there is filtration at arterial end and absorbtion at venous end EXCEPT:



 There is only absorbtion in the lungs (very low hydrostatic pressure)

 There is only filtration in the kidney (very large hydrostatic pressure)





Capacitance vessels

Veins carry low-oxygen blood from the tissues back to the heart; the exceptions being the pulmonary

and umbilical veins which both carry oxygenated blood. They store up to 60% of the blood. They are

in the low pressure area of the circulatory system.



Factors that effect the venous blood pressure:



 Amount of blood in circulatory system

 SNS activity (can cause venoconstriction = ↑VR=↑CO)

 Compliance. Usually very high.

 Respiration. Inspiration=↑VR due to high pressure gradient

Expiration=↓VR with decreasing pressure gradient







Muscle pump of the veins & peripheral valves should always be mentioned together. They have no

function on their own.









Deep vein thrombosis is the formation of a blood clot ("thrombus") in a deep vein. The problem

occurs when the clot becomes detached from the venous wall. It travels towards heart and then

lungs, where it can obstruct blood flow due to small diameter blood vessels. A small enbolism may be

unnoticed BUT large „riding“ embolism blocks 2 large vessels abd may cause death.



Pressure waves in big arteries- 3 types





1st grade changes in pressure: have the greates frequency and greatest amplitude. ↑ in systole,↓in

diatole.



2nd grade changes in pressure: Due to respiration, Inspiration = ↑VR=↑EDV=↑SV. So in inspiration

the systole is a bit higher and lower in expiration, note that respiration is MUCH less frequent than

HR.



3rd grade changes in pressure: Traube-Hering waves, Smooth muscle cells in arteriole walls show

slow waves due to a continuous depolarization of the smooth muscle cells. As they contract the

radius of the vessel decreases and TPR will increase slightly. Note that it is a very slow process and

causes low changes in amplitude.



27

Muscle tone

The continuous and passive partial contraction of the muscles. 3 types:



1. Resting myogenic tone

Intrinsic ability of smooth muscle of blood vessels to maintain continuous contracting. Doen

NOT depend on innervation or hormones.



2. Resting vasocontriction tone

The synpathetic innervation of the great majority of our blood vessels. There will be a

continuous discharge rate. It results in continuous stimulation of the appropriate smooth

muscle cells, maintaining a contraction on top of the reting myogenic tone.



3. Reflex vasocontriction

In a pressor response, ↑SNS activity, results in more contraction of smooth muscles.









Regulation of circulation

The neural regulation:



1. Somatomotor:

Allow for voluntary movements- skeletal muscles. Only one

motor neuron needed from spine to target muscle.

Neurotransmitter: ACH

Receptor: N-cholinergic Receptor









2. Parasympathetic:

A division of the Autonomic nervous sysytem. 2 neurons are

needed, one long preganglionic- the ganglion lies on or in the target organ- and one shorter

postganglionic neuron. Its target cells are Smooth muscle, Cardiac muscle and glands.



1st synapse: ACH + N-cholinergic Receptor



2nd synapse: ACH + M-cholinergic Receptor







3. Sympathetic: 3 types

a. COMMON

2 neurons; one short pregenglionic –

ganglion far from innervated organ – long

postganglionic neuron. Effector organs are





28

Smooth muscle, Cardiac muscle and Glands.



1st synapse: ACH + N-cholinergic receptor

2nd synapse: NOR + adrenergic receptor



b. RARE

Sympathetic cholinergic fibres, innervate sweat glands, arrector pili m, some arterioles of

skeletal muscle (vasodilation). Like parasympathtic EXCEPT that the ganglia are

postitioned far from target organ AND the are activated in sympathetic activation.

2 neurons:



1st synapse: ACH + N-colinergic Receptor

2nd synapse: ACH + M- cholinergic Receptor



c. A single preganglionic neuron.

The synapse: ACH + N-colinergic Receptor

The target cells a chromaffine cells of adrenal medulla which are modified sympathetic

neurons producing hormones (NOR-EPI & EPI).









Receptors:



The adrenergic receptors are a class of G protein-coupled receptors that are targets of the

catecholamines. Adrenergic receptors specifically bind their endogenous ligands, the catecholamines

adrenaline and noradrenaline, and are activated by these.





β1

Coupled to Gs protein → ↑cAMP → positive tropic effects (↑HR)



Agonists: ISOPROTERENOL & ADRENALINE (physiological)



Antagonist: PROPRANOLOL & PINDOLOL





β2

Coupled to Gs protein →↑cAMP→



- Smooth muscle in airwaves, skeleatl muscle arterioles, coronaries and bladder = RELAX!

Bronchodilation and Vasodilation.



Agonist: ISOPROTERENOL, ADRENALINE AND SALBUTAMOL (asthma medication)



Antagonist: POPRANOLOL (non-selective β-blocker, ↓HR and bronchoconstiction)









29

α1

Coupled to Gp protein→↑ IP3 → ↑*Ca+++i



- Smooth muscle in most arterioles

- Smooth muscle CONTRACTION.

- Systemic vasoconstriction → ↑TPR → ↑MAP

- Mediate resting contrictor tone



Agonists: NOREPI AND PHENYLEPHRINE (in nosespray, vasocontricts)



Antagonists: PHENOXYBENZAMINE AND PRAZOSIN (α1 blocker=↓MAP)









Muscarinic

Muscarinic acetylcholine receptors belong to a class of metabotropic receptors which use G proteins

as their signalling mechanism.



Agonist: ACH and muscarine



Antagonist: Atropine!



There are 5 subtypes

M1: Brain – IG3 pathway

M2: Heart - ↓cAMP - ↓HR to normal sinus rythm after SNS activation

M3: Brain and smooth muscle – IG3 pathway





Nicotinic

Ionotropic (i.e. ligand-gated) receptors, nAChRs are directly linked to an ion channel and do not make

use of a second messenger like metabotropic receptors do. Nicotinic acetylcholine receptors are

present in many tissues in the body, and are the best-studied of the ionotropic receptors. The

neuronal receptors are found in the central nervous system and the peripheral nervous system. The

neuromuscular receptors are found in the neuromuscular junctions of somatic (voluntary) muscles;

stimulation of these receptors causes muscular contraction.







There are 2 major kinds of control mechanism:





Local control mechanism (Autoregulation)

Only is a limited number of arterioles in a certain body area affected, so there is no significant

cahnge in TPR, and MAP is NOT be greatly affected.



There will be an effect of perfusion of a particular organ, the local contol mechanism will control local

prefusion without cahngin MAP. This is via local HUMORAL vasodilators and vasocontictors by

modifying the basal myogenic tone *Vasodilation = ↓Tone = ↑Flow and vice versa+. These are

„mostly“ locally acting factors.



30

2 important mechanisms:



1. Bayliss effect

When pressure is increased in blood vessels the flow will not increase BUT the vessel wall will

be streched, and thus the smooth mucsle cells. When smooth muscle cells are streched

strech-activated non-specific cation channels open. ↑Ca++ ions enter the smooth muscle

cells → Contraction (vasoconstriction).

Q=P/R

R: resistance

P: flow

The ratio of R and P will change but Q will remain unchanged, thus flow will remain the same.

Bayliss works only in the „autoregulatory range“ ~ btw 60-140 (not concrete)



The mechanism: ↑MAP = ↑Stretch of wall= ↑Stretch activated channels = Depolarization

and ↑*Ca+++i = Vasoconstriction =↑R BUT Q WILL REMAIN THE SAME!!!



2. Local meatbolites.

Explaines the increased perfusion in tissue with increses activity.



Vasodilator metabolites (produced in all working  Hypoxya*

tissue= use dependent production)  Hypercapnia*

 Acidosis*

 Adenosine

*different in pulm.

Vasodilator vasoactive substances  EPI (β2-r)

 Histamine * (with intact endithelium)

 Nitric Oxide (NO)

 Kinins

 Prostaglandins

 ACH (with intact endothelium)

 Serotonin* (with intact endothelium)

*different in pulm.

Vasoconstrictor vasoactive substances  NOREPI (α1-r)

 Histamine (without endothelium)

 Endothelins

 AT-II (RAS)

 ADH/VP

 ACH (without endothelium)

 Serotonin (without endothlium)









Systemic control mechanism

A large number of arterioles are affected. So there will be a large change in TPR and thus also MAP.

The aim is to adjust MAP through great change in TPR.



2 important mechanism:





31

1. Nervous control / SNS!

Most blood vessels are innervated by SNS, they maintain the resting vasocontrictor tone.

Vasocontriction in through increses activity of the SNS. Vasodilation is possible through

decrease in SN-activity, passively.

NOTE! The parasympathtic nervous system has very little to do with blood vessels, and is

NOT an important regulator of TPR. Except at local control where only a part of an organ is

affected: Active vasodilator mechanism. Active because the nerve fibres are activated to

cause vasodilation, this is NOT in systemic control of TPR.

The locally acting active vasodilator meachanisms are:

a. Parasympathetic vasodilator fibres.

The ONLY situation where PNS has anything to do with blood vessels. Result in

vasodilation at (TPR is not affected) :

-Meninges

-Penis

b. Sympathetic cholinergic fibres

Vasodilation of certain skeletal muscle arterioles, a concious activation, preparing

muscler for increased activity.

c. Axon relex

Pain receptors in skin send information to CNS. At the same time it has collateral

branches to local blood vessels of skin. Substance P is secreted,causing the release of

nitric oxide from the endothelium.



2. Humoral control

„Mostly“ systemically acting factors: Epinephrine and Norepinephrine. They are synthesized

in adrenal medulla (modified sympathetic ganglion).

 Almost 100% of circulating Epinephrine (75-85% of total released) is produced in

Adrenal medulla due to the presence on PNMT (Phenylethanolamine N-

methyltransferase) that converts Norepi to Epi.

 Almost 100% of Norepinephrine is produced in sympathetic postganglionic fibres

that release NOREPI onto synapses, that what is not reabsorbed or destroyed

diffuses into circulation. Produced to a smaller extent in Adrenal medulla.



EPI→Preferentially β-R

WHEN THEY ACT AS HUMORAL AGENTS!!!!

NOREPI→Preferentially α-R



1. Application of low concentration of epinephrine.

The β receptor is most sensitive to Epinephrine.









32

- HEART (β1): positive chrontropic (↑HR) and inotropic effect (↑contractile force) which

results in ↑SV, more blood ejected. With more blood going to aorta the systolic pressure

increases.

- ARTERIES (β2): most importantly coronary arteries. There will be vasodilation, relaxation of

smooth muscle; ↓TPR resulting in decresed dialstolic pressure , easier for blood to leave the

aorta (less resistance). More blood will go to tissues.

Pulse pressure (difference btw SP and DP) will increase BUT MAP will remain as it was.

This is a kick start for circulation, with more blood going to circulation and more blood giong

to tissues.



2. Application of low concentration of norepinephrine.

The α receptor is most sensitive to norepinephrine, most importantly α1.









- ARTERIES & VEINS (α1):

Vasoconstriction: ↑TPR →↑DP, because it´s more difficult for blood to leave the aorta due

to high resistance. More blood will be in aorta and less blodd will go to tissues.

Vasocontriction & Venoconstriction: Systolic pressure will increse due to Frans-Starling law,

in ↑TPR the SV ↓ but is restored by frank-starling law. →↑CO → ↑SP.

BUT Diastolic pressure increases more than systolic pressure = pulse pressure will drop with

less start to circulation.

Since ↑TPR and ↑CO = ↑↑↑ MAP.

BUT this rise in MAP will initiate the depressor reflex evoking the classcail depressor

responce = ↓↓ HR = ↓↓ CO = ↓↓ Blood to circulation

So the net effect of norepinephrine doen NOT stimulate heart rate.









Reflex control of the cardiovascular system; central regulation of MAP.

Two important centers of regulation located in the Medulla oblongata.



The pressor center in the ventro-rostro-lateral nuclei



The depressor center in the postero-caudo-lateral nuclei and functionally

including the CIA (Cardiac inhibitory area).



Pressor center

The pressor center neurons have spontaneous activity and can produce spontaneous action

portentials. Their activity is adjusted by inputs from:





33

 Chemoreceptors (CCR & PCR)

 Low-pressure baroreceptors of the right atrium and vena cavas

 Pain receptors of the skin

 Receptors of the cerebral vessels





INPUT Location Activation Signal transmission Significance

Central Medulla ↑pCO2/↓pH of Intrinsic activity

chemoreceptor oblongata –in blood and CSF. of pressor center

pressor center. (not by ↓pO2!!)

Peripheral Aortic & carotid ↓pO2 of blood, CN IX & X

chemoreceptors bodies and severe to pressor center

↑pCO2/↑pH

Low pressure Wall of right Stretch; ↑VR CN X (sensory part)

baroreceptors atrium and vena

cavas

Pain receptors of Nociceptors in Pain Somatosenory

skin various layers of nerves

the skin

Receptors of Baroreceptors in Stretch; change in Viscerosensory

brain vessels the walls of brain ICP. nerves

vessels





They will stimulate the activity of the pressor center. The axons of the pressor center go downwards

and stimulate preganglionic neurons of the sympathetic nervous system. The postganglionic neurons

innervate the most important organ of the cardiovascular system (heart, arterioles and veins). These

are the effector organs of the cardiovascular reflex mechanism.



Depressor center

Limits the pressor center, by way of inhibition. The neurons of the depressor center have NO

spontaneous activity. Its inputs are:



 High pressure baroreceptors of the carotid sinus and aortic arch

 Low pressure baroreceptors of the pulmonary arteries

 Mechanoreceptors of the abdominal wall



INPUT Location Signal transmission Activation

High pressure Carotid sinus CN IX & X Stretch-↑MAP

baroreceptors Aortic arch Not the same as PCR Phasic nature: not

[Most important] In the arterial walls contant fireing

Activation range: btw

50-200 mmHg

Low pressure Wall of pulmonary Viscerosensory nerves Stretch - ↑Pulm.

baroreceptors arteries arterial pressure

Mechanoreceptors Abdominal wall Somatosensory nerves STRONG mechanical

stimuli









34

The nerve fibres conducting the action potential from the baroreceptors to depressor center are

BUFFER NERVES. There are 4 buffer nerves in the body: left/right vagus & left/right glossopharyngeal.

If they were to be cut there would be no spontaneous activity of depressor center, and MAP would

rise to 220mmHg.



Decending pathways travel in the spinal cord, inhibiting neurotransmission of pressor fibres, at

preganglionic neurons.



The Depressor center blocks the pressor center activity:



1. Within the medulla oblongata, directly at pressor center.

2. Within the SNS preganglionic neurons, in the thoracolumbar part of spine.

3. At the heart, the CIA works through the vagus (not sensory) mediating parasympathetic

activity to SA-NODE= Negative tropic effect.



The „Classic“ Pressor & Depressor responses.

Pressor response Depressor response

HEART β1-adrR. Direct: via vagus (PNS):

↑SV & ↑HR = ↑CO = ↑MAP ↓HR=↓CO=↓MAP

Indirect: through resting

vasoconstricor tone; inhibition

of pressor center

↓HR & ↓SV=↓CO=↓MAP

ARTERIES α1-adrR mostly Indirect:

Vasoconstriction=↑TPR=↑MAP Vasodilation = ↓TPR =↓MAP

BUT β2 cause vasodialtion in

arteries of working muscle and

coronaries

VEINS α1-adrR Indirect:

Venoconstriction: ↓Storage of Venodilation: ↑Storgae of

blood in veins= ↑VR = blood in veins = ↓VR = ↓SV=

↑Starling = ↑SV = ↑CO= ↓CO = ↓MAP

↑MAP

ADRENAL MEDULLA ↑Epinephrine release ↓Epinephrine release





There is equilibrium btw the 2, since the pressor center cannot decrease MAP and depressor center

cannot increase MAP.







The pressor reflexes – there are 4

1. Chemoreceptor reflex

2. Bainbridge reflex

3. Loven reflex

4. Cushing reflex







1. Chemoreceptor reflex



35

- PCR:

Activated by hypoxia or severe hypercapnia/acidosis (e.g. in physical exercise) sensed by

receptors in carotid and aortic bodies. Increased activity of pressor center (through CN IX, X).

↑SNS activity resulting in the „classical“ pressor response.

- CCR:

Senses the chemical composition of the blood and CSF, sensitive to hypercapnia and acidosis.

Sensation and response is within the medulla oblongata. Results in incresed SNS avtivity and

the „classical“ pressor response.



Both PCR and CCR increase MAP. They have a working range, mostly under 70-80 mmHg MAP. The

most important is to activate respiration during physical exercise. Special features are the double

target of ↑pCO2 and single target of ↓pO2.



2. Bainbridge reflex

The reflex involves a innervated heart, with intact nerve fibres. The reflex activated is the

VASO-VAGAL REFLEX, which means that both effernt and afferent pathways are found in

vagus. The aim is to match the amount of blood entering the ventricle and the amount of

blood ejected = VR and CO.



The reflex is initiated ↑VR – stretch of the atrium sensed by the low pressure baroreceptors.

They start the vaso-vagal reflex:

Baroreceptors → CN X → Pressor center → inhibited CN X (at CIA ) & activated SNS at SA-

node

The effects are at the Heart, especially the SA-NODE and HR will increase big time resulting in

increased CO (SVxHR=CO) and increased MAP (TPRxCO=MAP).

The reflex works as a frequency buffer fluctuating around a set point:

↑VR = Bainbride reflex =↑HR = Decreased diastolic time = ↓VR = De-activated bainbridge =

↓ HR = Increased diastolic time = ↑VR......



The reflex depends on the initial HR and is NOT to be confused with Frank-Starling

Machanism which is noly for de-ineervated heart!

Bainbridge Reflex is involved in Respiratory Sinus Arrhythmia. During inhalation intrathoracic

pressure decreases. It triggers increased venous return which is registered by baroreceptors,

which via Bainbridge Reflex constantly activates sympathetic nervous system within each

inhalation of each respiratory cycle.







3. Loven reflex

Intiated by a painful stimulus to the skin, which will initiate general vasoconstriction and

increase MAP. It´s sensed by the nociceptors of the skin. There are 2 responses:

i. Pressor reflex: systemic vasoconstriction and ↑ MAP = fight or flight

ii. Local axon reflex: Local vasodilation and ↑local flow = tissue repair







4. Cushing reflex comes later.



36

Depressor reflexes- there are 3

1. Baroreceptor reflex

2. Pulmonary baroreceptor reflex

3. Goltz reflex







1. Baroreceptor reflex

High pressure baroreceptors in aortic arch and carotic sinus. Sense ↑MAP and stimulate the

depressor center through CN IX, X. Response:

- CIA: ↑PNS activity on SA-NODE via vagus nerve (direct)

- Inhibition of SNS fibres via inhibition of pressor center

This results in the „classical“ depressor response, resulting in ↓MAP.

Significance:

- Most important reflex to regulate MAP

- The MAP buffer reflex of circulation, it provides a negative feedback loop in which an

elevated blood pressure reflexively causes blood pressure to decrease; similarly, decreased

blood pressure depresses the baroreflex, causing blood pressure to rise.



Experiment 1: Occlusion a carotid artery below carotid sinus, there will be less flow to carotid

sinus and LESS depressor reflex= ↑MAP



Experiment 2: Occlusion of both carotic arteries above the carotid sinus. There will be increased

pressure at the carotid sinus increasing the activity of the depressor center = ↓MAP







2. Pulmonary baroreceptor reflex

Baaroreceptors in pulmonary artries, low pressure 25/8 mmHg. The sense ↑MAP-PULM. It

will inhibit SNS fibres (not affecting CIA at all) causing dilation of arteries and veins , more

blood will be ratained in venous circulation: ↓MAP = ↓MAP-PULM.

Significance:

- Protective factor against high MAP-PULM that causes EDEMA.

- Camplementary role to the funtcion of the high pressure baroreceptor reflex. Little brother.







3. Goltz reflex

A storng mechanichal stimuli to the abdomen is sensed by machanoreceptors in abdominal

wall, that activate splanchnic nerves. They give ascending pathways to the spinal cord and

collateral braches to the depressor center. CIA will be activated, vagus is stimulates causing

increased PNS activity on SA-NODE = ↓HR, Sinus arrest, ↓MAP.









37

Endothelium

Functions of the endothelium:



 Matrix / Barrier

 Metabolic

 Immunomodulatory

 Mitogenic (production of growth factors for vasculature growth)

 Hemostatic

 Regulation of vascular tone



Hemostatic role:



 ANTI-coagulant in intact endothelium

o Non-Wetteble surface

o Prostacylins

o Thromobomodulin

o Antithrombin

o Plasminogen Activator

o Heparin

 PRO-coagulant in damaged endothelium

o Wetteble surface

o Von Willebrand factor

o Thromboxane A2

o Factors V, IX, X

o Thromboplastin

o Plasminogen activator inhibitor



Regulation of vascular tone:



- Mechanoreceptors : sense blood flow, sheer stress forces, they are always present as long as

there is blood flow.

- Ligand receptors: All stimuli



They signal endothelium. Endothelium releases products that cause:



- Vasoconstriction (ACE, Thromboxane A2, Leukotriens, Endothelins)

- Vasodilation (Prostacylins, Nitric oxide!!!)



Nitric oxide (NO)



Nitric oxide or nitrogen monoxide is a chemical compound known as the 'endothelium-derived

relaxing factor', or 'EDRF'. This gas is an important signaling molecule in the body of mammals,

including humans, and is an extremely important intermediate in the chemical industry. It is also a

toxic air pollutant produced by cigarette smoke automobile engines and power plants.









38

NO is an important messenger molecule involved in many physiological and pathological processes

within the mammalian body both beneficial and detrimental. Appropriate levels of NO production

are important in protecting an organ such as the liver from ischemic damage. However sustained

levels of NO production result in direct tissue toxicity and contribute to the vascular collapse

associated with septic shock.



Ach binds to M-achR, Serotonin to 5-HT or

mechanoreceptors react to sheer stress, ON ENDOTHELIAL

CELLS. NO is biosynthesised endogenously from L-arginine

and oxygen by various nitric oxide synthase (NOS) enzymes

and by reduction of inorganic nitrate. The endothelium

(inner lining) of blood vessels use nitric oxide to signal the

surrounding smooth muscle to relax by ↑cGMP, thus

resulting in vasodilation and increasing blood flow. Nitric

oxide is highly reactive (having a lifetime of a few seconds), yet diffuses freely across membranes.

These attributes make nitric oxide ideal for a transient signal molecule between adjacent cells and

within cells. Bayliss effect works against it; to keep flow constant.

Viagra: inhibits the enzyme that degrades the cGMP, that way sustaining vasodilation.



Ach, Serotonin or NORepinephrine binding directly on the smooth mucle cell (with damaged

endothelium) causes vasoconstricion. Bypass endothelium lining of the vessel.





Regional circulation

1. Pulmonary circulation



The blood pressure is much lower, 25/8.

The pulmonary arteries are short and wide (↓R *resistanse+) and the CO (Q) is the same as in the

systemic circulation. As a consequense (Q=P/R) the MAP-pulm is much lower.



AND acording to the Hagen-Pouisille law, the resistanse of a tube is directly proportional to a

constant, divided by pi. The resistance is also directly proportional to the length, viscocity and

inversly proportional of the RADIUS in the power of 4.



Amount of blood is the same, length of circulation is shorter. Radius is larger = ↓Resistance



The consequence:

Low hydrostatic pressure (PC-pulm) while other starling forces are the same. Net filtration pressure is

less than 0! Reabsorbtion dominates over filtarion. No water molecules leave the capillaries, no

water goes into the alveoli, this keeps the lungs are dry as possible. Prevents pulmonary edema,

where alveoli get filled up with water and no proper gas exchange is present. Lifethreatning.



Pulmonary edema:

a. Toxic edema due to increased capillary permeability

b. Edema due to pulmonary arterial hypertension (fibrosis) → ↑Pc-pulm

c. Edema due to pulmonary venous hypertension (LV failure, mitral stenosis) → ↑Pc-pulm

→↑NFP →Filtration dominates over resorbtion.



Nervous control:



39

Direct effect of SNS is negligible! BUT theter is indirect systemic SNS activation

(e.g. in the pressor reflex). →↑CO→↑Pulmonary Flow.



Humoral control:

Hypoxia -

Hypercapnia –

Acidosis - VASOCONTRICTION → Ventilation perfusion matching

Histamine -

Serotonine -

(cause vasodilation systemically)



Ventilation perfusion matching: guarantees that good blood will be matched with good air; normal

ventilation. Hypoventilation with vasoconstriction will occur in the case of ↓pO2 and ↑pCO2.





2. Coronary circulation



There is a very strick correlation btw the cardiac cycle and the coronary circulation.



Ohm´s law: R=u/I R: resistance, u: potential difference, I: current



This applies to a hydrodynamic situation aswell: intensity of perfusion of the coronary system equals

the driving force, which is the pressure gradients divided by the resistance of a vessel. This pressure

gradient in the coronary circulation is the pressure difference btw the aorta and the coronary system.



The flow is phasic (discontinous)



 Phasic driving force (MAP fluctuates)

 Compression – Decompression

 Subendocardial vs. Subepicardial.



1st stage of cardiac cycle: isovolumetric contraction (aortic valve is closed),

resistance of the coronary arteries is large due to contraction of the ventricular wall – vessels are

compressed.

This is just prior to ejection, lowest pressure in aorta = very low pressure gradient. Thus; with low

pressure gradient and high resistance there is low perfusion of blood through the coronary

circulation. It´s worst period.

There may be retrograde perfusion, blood flows towards aorta due to much compression, but only in

the left ventricle.



2nd stage of cardiac cycle: Isotonic contraction (valves open blood flow out). In ejection there is high

pressure in aorta, increases the driving force. Here there is still considerable compression and high

resistance (ventricular myocytes are contracted) BUT the driving force has increased.



3rd stage: Diastole. Relaxation of the ventricular wall. Blood vessels are no longer compressed,

decreasing resistance greatly AND high pressure in aorta (especially in the beginning of diastole)

making the driving force high. High driving force + low resistance + no compression = ↑↑perfusion.

The best period for coronary perfusion. At rest diastole is 2x longer that systole. IMPORTANT!!

With ↑HR the diastole shortens, decreasing coronary perfusion and ventricular filling. Heart attack



40

may occur if HR goes above 220. But since CO= SVxHR, in heavy physical burden muscles require

more perfusion and thus CO is increased, which results in ↑HR. The heart performs greater work,

metabolic demand increases, greater perfusion demanded BUT diastole is shorter here. To

compensate: The caranary vessels have an extremely large resting myogenic tone(like the brain). In

this case the heart preforms greater work but there is not enough blood supply to meet the

demands. Hypoxia acts upon the resting myogenic tone causing powerful vasodilation. It makes

sure that there will be an increased perfusion in the coronary system in the shortened diastole. 4x

greater perfusion can be achieved.



The resting vasoconstriction is negligible.

There is NO continuous discharge of SNS on coronary blood vessels (SNS affects indirectly via ↑work

resulting in ↑FLOW due to local metabolites).

The coronary blood vessels will NOT participate in the depressor resonce.

The resting vasoconstriction tone is also negligible.



= in a pressor response there will not be vasoconstriction!



The smooth muscle cells of the coronary system have β2 receptors, their stimulation by SNS results

in vasodilation!



The most important adjustment of the coronary system is USE DEPENDENT HUMORAL

AUTOREGULATION by the persence/absence of local metabolites (use dependent) – due to the very

large resting myogenic tone. The most powerful vasodilators are HYPOXIA AND ADENOSINE

(byproduct of ATP). Adenosine binds to receptors in the coronary vessel walls and is later washed

away by blood. But the Bayliss effect works againt it (myogenic control).



Humoral control : Dominates in ↑MAP



Myogenic control (Bayliss): Dominates in ↓MAP



Arteriovenous oxygen difference is very large in the cardiac muscle. The cardiac muscle is very

effective in using and utilizing the oxygen. The heart is aerobic and needs oxygen.



3. Cerbral circulation



In the brain there is a very high resting myogenic tone (++++). This means that

smooth muscle cells in the walls of the blood vessels are continously contracted.

The magninitude is controlled by local metabolites :hypoxia, hypercapnia, acidosis (rather in CSF),

↑temperature, adenosine, ↑*K++. Prodiuced in the working tissue. They result in a decreased

myogenic tone → Local vasodilators. The single most powerful vasodialtor in the brain is

HYPERCAPNIA. Cause increased perfusion in the cerebral circulation.



There is no resting vasocontrictor tone (no continous SNS-no pressor effect) thus there will be no

depressor effect since there is no SNS activity to repress. The reflex vasoconstriction is also negligble

in the brain. So the humoral contol always dominates over the myogenic bayliss reciprocal effect.



The brain has a special compartment. The cranium containing blood, brain and CSF.



Monroe-Kellie´s law:



41

Vbrain+Vblood+VCSF = Constant.



The volume inside the cranium cannot be changed, there is no way to expand the skull. If the volume

of something is increasing the volume other things are decreasing. E.g. in the case of tumor healthy

brain tissue dies and disapears to make room. Also intracranial pressure will increase and perfusion

will be badly affected. Because the perfusion is determined by the transmural pressure, the pressure

difference btw the 2 sides of the vessel.

TMP = MAP – ICP

The transmural pressure is the driving force of the brain circulation. So, decreased transmural

pressure e.g. due to a brain tumor the ICP will increase; the pressure difference will be smaller. With

decreased TMP the radius of the blood vessel will decrease; contriction of the cerebral blood vessels;

↑↑ resistance! Which means impaired perfusion. Results in hypoxia and dieing neurons. The

mechanism that will try and keep the TMP constant is the Cushings reflex.



The Cushings Reflex



The aim is to maintain or restore the transmural pressure.



 Baroreceptors in the walls of the brain vessels sense ↓TMP due to ↑ICP

 Direct action due to extreme ↓MAP, ischemia or blood loss.



They send stimuli to the pressor center in the medulla oblongata. The pressor center sends stimuli

alnog the spinal cord to systemic arteries (not coronary or cerebral), heart and veins.

The result is a positive tropic effect, vaso and venoconstriction (↑TPR). And since MAP = COxTPR

there will be ↑↑↑MAP. This increases the pressure inside brain vessels and by increasing the

intravascular pressure you increase the extravascular pressure.

↑MAP = ↑ICP = ↑TMP



The high MAP causes hypertension. Baroreceptors in carotid sinus and aortic arch will sense it and

activate the depressor center. There are 3 possible outputs:



 Inhibiting the pressor center directly BUT it cant since the pressor center is continously

stimulated.

 Inhibition of synaptic transmission btw the pressor center and the preganglionic synpathtic

neurons BUT it cant due to the continous stimulation of the pressor center. Cannot override.

 Increased vagal activity will decrease the heart rate.



This is a strange situation: ↑↑↑ MAP and ↓HR. Sign of raised ICP and brain tumor.



The ICP will eventually press the brain out through the foramen magnum, this will compress the

medulla where cardiovascular, vasomotor and respiratory centers are. This is called „coning“. The

treatment for this high ICP is diuretics to decrease blood volume.



4. Skeletal muscle



Moderate resting myogenic tone and resting vasocontrictor tone.









42

Humoral control: Mainly by humoral vasodilators

-Exercise →Use dependent production → vasodilation→↑FLOW

-Epinephrine→β2 receptors→ vasodilation →↑FLOW



Nervous control:

-Sympathetic cholinergic (M-achR) → Vasodilation

-Sympathetic adrenergic (β2) →Vasodilation

-Sympathetic adrenergic (α1) →Vasoconstriction



WORK will determine the actual diameter of a skeletal muscle artery.



Working muscle

↑ Sympathetic cholinergic

↑Production of metabolites -------------------------> PRESSOR CENTER

Increases EPI secretion and sympathetic activity

↑Epinephrine to β2 <----------------------------------- systemically.



= Vasodilation = ↑FLOW

Non-working organs:

↑Sympathetic adrenergic to α1

-not coronary aa. and brain aa.



=Vasoconstriction = ↓FLOW

This is called redistribution.



5. Skin



There is an extensive capillary network and AV anatomosis. Large amounts of blood stored. It has a

role in thermoregulation; countercurrent flow.



There is NO resting myogenic tone but HIGH resting vasoconstriction; pressor & depressor reflex. The

receptor is α1 adrenergic in A & V. But in sweat glands there are M-AchR for sympathetic cholinergic

effect.



Temperature:

Cold: ↑SNS → Vasoconstriction→↓Q to store heat

Heat: Bradykinin mechanism: Sympathetic cholinergic nerve fibres stimulate sweat glands. They

produce sweat and Bradykinin-forming enzyme, as a result Bradykinin is formed which is one of the

strongest vasodilators. →↑G to lose heat.



Exercise:

First: ↑SNS vasoconsriction (redistribution of blood to workin muscle)

Then: Vasodilation due to bradykinin mechanism to lose heat.



Both vasodilation and vasoconstriction are mediated by the SNS depending on temperature and

timing of exercise.



6. Kidney









43

2 arterioles, 2 capillary networks, 1 vein. There is resting myogenic tone (not as significant as in the

brain). There is no resting vasoconstrictor tone: no depressor effect BUT there is a strong reflex

vasocontrictor tone: vasoconstriction in pressor reflex, in redistribution.



Regulation of flow is to maintain a constant flow and is

Myogenic autoregulation: predominantly done by the Bayliss effect (VERY IMPORTNAT IN THE

KIDNEY).

Nervous: ↑SNS (pressor relflex) → Vasoconstriction → Redistribution

Humoral: both vasocontricion and vasodilation agents.



The Bayliss effect importance: Plot the renal plasma flow as a function of MAP.









Renal plasma flow is the amount of plasma which protrudes the kidneys through 1 minute. This gives

the intensisty of blood perfusion. Since the bayliss effect only works under a regulatory zone of the

kidney, at first at low pressure, if you increase the MAP you increase the renal plasma flow. BUT the

bayliss effect switches on (at ~60 mmHg) and as you increase the MAP you increase the resistance of

the blood vessel aswell. It will keep the level of renal plasma flow at a constant level. When you

reach a certain MAP (~140 mmHg) the Bayliss cant compensate anymore. This shows that the

production of primary ultrafiltartion is dependent on the MAP.



7. Splanchnic area



In general nervous control dominates over humoral control. A certain resting myogenic tone is

present, not very significant, BUT a large reflex vasoconstriction. Storng vasoconstriction in a pressor

response; redistribution in physical activity.





Shock

Circulatory shock, commonly known as just shock, is a serious, life-threatening medical condition

where insufficient blood flow reaches the body tissues. As the blood carries oxygen and nutrients

around the body, reduced flow hinders the delivery of these components to the tissues, and can stop

the tissues from functioning properly. The process of blood entering the tissues is called perfusion, so

when perfusion is not occurring properly this is called a hypoperfusional state. The causes can be:



 Hypovolemic: This is the most common type of shock and based on insufficient circulating

volume. Its primary cause is loss of fluid from the circulation from either an internal or

external source. Hemorrhage, dehydration, trauma (contusion)





44

 Cardiogenic: This type of shock is caused by the failure of the heart to pump effectively. This

can be due to damage to the heart muscle, most often from a large myocardial infarction.

↓CO (heart attack), ↓VR (heart tamponade)

 Vasodilative: or Distributive shock - As in hypovolaemic shock there is an insufficient

intravascular volume of blood. This form of "relative" hypovolaemia is the result of dilation of

blood vessels which diminishes systemic vascular resistance. Neurogenic, anaphyactic shock,

septic shock.



Stages:



I. Non-progressive – Compensated.

characterised by the body employing

physiological mechanisms, including

neural, hormonal and bio-chemical

mechanisms in an attempt to reverse

the condition.

II. Progressive – Decompensated. The

shock will proceed to the progressive

stage and the compensatory

mechanisms begin to fail.

III. Irreversable. The vital organs have failed and the shock can no longer be reversed. Brain

damage and cell death have occurred. Death will occur imminently.



Hemorrhagic – symptoms:



 ↓MAP, due to decrease in circulatory volume.

 ↑HR, weak, thready pulse due to decreased blood flow combined with tachycardia.

 ↓Body temperature (↓MR), due to decreased perfusion and evaporation of sweat.

 Pale, cold, wet skin

 ↑Respiratory efforts, due to sympathetic nervous system stimulation and acidosis.

 Muscle weakness

 Depressed mental function. Anxiety, restlessness, altered mental state due to decreased

cerebral perfusion and subsequent hypoxia , often with pupils dilated.



Stage I: The degree of symptoms/mechanism depends on the amount of blood loss. The key

response of the body is the negative feedback systems: Generally ↑SNS to maintain MAP!



 Baroreceptor Depressor reflex ↓*

 Chemoreceptor Pressor reflex ↑*

 Cushings reflex ↑*

 RAS ↑**

 ADH/Vasopressin ↑**

 ANF ↓**



*sec **min/hr



Stage II: Positive feedback.





45

 Tissue damage , heart, kidney, CNS, lysosomes, acidosis, ↓ATP

 Blood. ↑thormobosis, endothelial collapse.

 THERAPY NEEDED!



Stage III: Exessive tissue damage, therapy is no help.



Therapy:



Regardless of the cause, the restoration of the circulating volume is priority. As soon as the airway is

maintained and oxygen administered the next step is to commence replacement of fluids via the

intravenous route. It is to be noted that NO plain water should be given to the patient at any point,

as the patient's low electrolyte levels would easily cause water intoxication, leading to premature

death. An isotonic or solution high in electrolytes should be administered if intravenous delivery of

recommended fluids is unavailable.

Head-Down postition.

Inotropic agents in cardiogenic shock. Which enhance the heart's pumping capabilities, are used to

improve the contractility and correct the hypotension.

Oxygen Therapy

Corticosteroids (↑SV, stabilize lysosome membrane) reduce inflammatory responce.

Anti-histmins

Pain relief

??SNS drugs??









Respiration

The goal of respiration is to provide oxygen and remove carbon dioxide from tissues. There are 4

major functions:



1. Pulmonary ventilation; inflow and outflow of air.

2. Gas exchange. Diffusion of O2 and CO2 btw alveoli and blood.

3. Transport of O2 and CO2 in the blood and body fluids.

4. Peripheral gas exchange.



Note that ventilation and gas transport require energy to power a mechanical pump (the heart) and

the muscles of respitation, mainly the diaphragm. In heavy breathing, energy is also required to

power additional respiatory muscles such as the intercostal muscles. The energy requirement for

ventiliation and gas transport is in contrast to the passive diffusion taking place in the gas exchange

steps.



The function of the airway is to clean, warm and moisten the air.



To understand breathing we must understand various pressure changes.



We have 3 different pressures:







46

1. The atmospheric pressure (0 in pysio)

2. Intrapulmonary pressure, pressure measured inside the alveoli. If there is no air movement,

they will be tha same. Thus at rest the intrapulmonary pressure is 0. To cause flow of air into

the alveoli during inspirationm the pressure must fall to a value slightly below atm. or 0. And

in expiration the oposite happens, the alveolar pressure rises above 0.

3. Intrapleural pressure, it is always lower (negative) than the atmospheric, -4mmHg.



Pressure differences:

The transmural pressures will decide if the compartments tend to be bigger or smaller.



1. Transpulmonary pressure: difference btw intrapulmonary pressure (0 at rest) and

intrapleural pressure (-4). It is a measure of the elastic forces in the lungs thant tend to

collapse - recoil pressure. The transpulmonary pressure works againts it trying to streach the

lung. So at rest the lung will not move.

2. Transthoracic pressure: btw the intrapleural and atmospheric. Its in equilibrium at FRC

(functional residual capacity)+1. Than the chest alone will have no tendency to move. The

volume within the thorax decides its tendency.

a. Maximum expiration: thorax has a tendency to be bigger.

b. Maximum inspiration: thorax has a tendency to be smaller.

3. Chest & lung : btw intrapulmonary pressure and atmospheric pressure. Is in equilibrium at

FRC or at the end of passive expiration:



Plot the pressure volume diagram:









Inspiration:

At the beginning the intrapulmonary pressure is 0 and intrapleural pressure is -4. Then the

diaphragma (80% of work) and external IC muscles contract. Increasing the interthoracic space. The

intrapleural pressure will become more neg (~-6) creating an even bigger transpulmonary pressure

difference, that expands the lungs. As the lungs expand their volume

increases, acording to Boyles law „Forcing the volume V of the fixed

quantity of gas to increase, keeping the gas at the initially measured

temperature, the pressure p must decrease proportionally. Conversely,

reducing the volume of the gas increases the pressure“. Intrapulmonary

pressure decreases below 0 creating a pressure gradient via the

airways – air moves into the lungs.

At the end of inspiration the intrapulmonary pressure will go back to 0 again and their is no

movement of air. The intrapleural pressure remains -6, this is important because as we expand the

lungs there will be an even greater recoil.







47

Expiration:

A totally passive process (under normal conditions). Transpulmonary pressure is no longer

maintained and the elastic coil of the lung causes a decreased volume of the lung – increased

pressure inside and air will move out. At the end of expiration the pressure returns to 0 again, and

intrepleural pressure to -4. In forced expiration, using the internal IC muscles, the intrapleural

pressure will return to -4 quicker and may for a short time be more positive.



Compliance of the lungs:



How easy it is to inflate the lungs, depends on resistance. We have 2 elements, the lungs and thorax

their compliance can be measured separately.



There are 2 forces of the lung recoil: of the elastic forces of the lung tissue itself (collagen and elastic

fibres) and the elastic force caused by the surface tension of the fluid that lines the inside walls of the

alveoli. Tissue elastic forces tend to collapse the air-filled lung represent ~1/3 of the total lung

elasticity, but the fluid-air surface tension in alveoli is ~2/3. Increases when surfactant is not present.

Since water molecules tend to decrease the surface which they act upon (decreasing the radius of

the alveolus, forcing air out), thus surface tension is the force provided by water molecules that try to

decrease the radius of the alveoli, due to strong attraction to one another. If it wasnt there there

would be very large surface tension and tendency to collapse.



Law of Laplace: Pressure = 2x surface tension

Radius of alveolus





Surfactant is a phospholipid produced by pneumocytes type II (10% of alveolar surface), it greatly

decreases the surface tension of water. They are wetting agents that lower the surface tension of a

liquid, allowing easier spreading, and lower the interfacial tension between two liquids, dissolving

uncontinously in the fluid lining of the alveoli.



Respiratory distress syndrome: Surfactant is not produced properly. Seen in premature babies,

which dont have working pneumocytes type II. The lungs will collapse exhausting the inspiratoy

muscles. Treatment is to insert a tube into the airway (artificial breathing) or treat the mother with

cortisol (steroid hormone) wich increases the maturation of the pneumocytes type II.



Atelectasis: is a collapse of lung tissue affecting part or all of one lung.[1] It is a condition where the

alveoli are deflated, as distinct from pulmonary consolidation. Infant respiratory distress syndrome is

another distinct type of atelectasis.



Surfactant will stabilize the alveoli of various sizes! Alveoli with different radii. Laplace law states that

the surface tension equals the readius times the TMP. In order to keep small alveoli open we need a

larger pressure difference (TMP btw alveoli). BUT then all the alveoli would eventually fuse to form

one large radius. So we have the same pressure in all. To keep them open surfactant produces a thick

layer on the small alveoli, decreasing their surface tension greatly, that way we stabilize alveoli of

different sizes.









48

Emphysema: a diorder with too big lung compliance. Elastic fibres are damaged and are NOT

replaced by collagen fibres. Decreaes the elastic recoil. Inflating is easy but expiration requires much

muscle work.



Pulmonary volumes:



-Total lung capacity: 5-7 L, increases first 20

years of life. Less in older ppl due to less

lung elasticity. VC+RV



-Tidal volume: Volume of air inspired or

expired in normal breathing. Aprox 0.5 L in

adult males.



-Inspiratory reserve volume (IRV): extra

volume of air that can be inspired over and

above the tidal volume with full force,

aprox 2,5 – 3 L.



-Expiratory reserve volume(ERV): the maximum extra volume that can be expired by forceful

expiration, after the normal tidal expiraion, aprox 1,1 L.



-Functional residual capacity (FRC): ERV + RV, aprox 2,5 L.



-Residual volume: volume of air remaining in the lungs after the most forceful expiration, aprox 1,2-

1,5 L.



-Vital capacity: Maximum inspiration after maximum expiration, aprox 4.0 L.



The airways:



Increase in total crossection as they descend. They have smooth muscle

surrouning the bronchi and bronchioles. The smooth muscle fibres are innervated

by the autonomic nervous system, it can make the total crosssection larger or

smaller. Changing the resistance of the airways.



Factors that will effect the radius of the airways:



1. Mechanical effect: Transmural pressure, the continous force that tries to stretch the lungs,

doing so it streched the elastic fibres aswell keeping the airways open. This is called lateral-

traction, which is a sort of pullin effect.

2. Nervous factor: The autonomic nervous system:

- SNS: Causes BRONCHODILATION (↓resistance and ↑crosssection). They act via Epinephrine

on β2.

- PNS: Cause BRONCHOCONSTRICTION (↑resistance and ↓crosssection). Via Ach on M-achR.

Atropin is a specific inhibitor of bronchoconstriction.

3. Humoral factor:

- Achetylcholine: acts on M-achR and cause bronchocontriction.

- Epinephrine: acts on β2 causing bronchodilation.



49

- Histamine: very powerful bronchocontrictor, released from mast cells (asthma and

anaphylactic shock), also stimulates mucous production, that can ostruct small airways.

- CO2: Hypercapnia is the single most powerful bronchodilator. Useful is „ventilation-perfusion

matching“.



Measurement of airway capacity is with a Tiffeneau test or Spirometry (meaning the measuring of

breath) is the most common of the Pulmonary Function Tests (PFTs), measuring lung function,

specifically the measurement of the amount (volume) and/or speed (flow) of air that can be inhaled

and exhaled. Spirometry is an important tool used for generating pneumotachographs which are

helpful in assessing conditions such as asthma, pulmonary fibrosis, cystic fibrosis, and COPD.

- FVC (Forced Vital Capacity). This is the total amount of air that can forcibly be blown out after full

inspiration, measured in liters.

-FEV1 (Forced Expiratory Volume). This is the amount of air that you can forcibly blow out in one

second, measured in liters. Along with FVC it is considered one of the primary indicators of lung

function. Should be around 80%, in healthy people. Decreases in bronchial asthma, 20-30%, highly

resistant airways.



The muscles of respiration:



Predoninantly the diaphragma.

IC muscles and accessory muscles.

Neuromuscular junction: Somatomotor fibres come from pons or

medulla. Ach is the neurotransmitter acting on N-achR. They cause the

opening of cationic channels that depolarize the membrane and starting

an action portential propagation. Inhibitors are curare and artificial

curare derivatives used in surgical anathesia, with breathing machines.



Work of breathing:



1. Resistive work

2. Compliance work



They make up the total work of breathing: W=Wr+Wc



The compliance is proportional to the tidal volume. If you increase the tidal volume, it will stretch the

fibres in the alveoli more; more compliance work.

Resistive work ; friction as air particles hit the walls of the airways. Thats why you need work to move

the air through the airways. The resisitive work is proportional to rate of breathing. ↑rate

=↑columns of air must be moved faster =↑friction.



How the total work of breathing will change the frequency.

Minute volume of respiration: MVR=TVxRF (tidal volume x respiratory fequency).



It is the volume of air which can be inhaled (inhaled minute volume) or exhaled (exhaled minute

volume) from a person's lungs in one minute. The higher the minute volume the more carbon dioxide

(CO2) the person is releasing, the converse is the lower the minute volume the lower the amount of

carbon dioxide the person is releasing. The aim of the body is to maintain a constant MVR, by proper

gas exchange.



50

Work of breathing as a function of respiratory frequency.

As we increase the frequency we increase the resistive work. If we maintain the

sam MVR and increase the frequency the tidal volume must decrease. So- if you

plot the compliance as a function of frequencym you will see that if you increase

the tidal volume you decrease the compliance work. The total work of breathing

is the sum of these 2 graphs and gives the most effective breathing – smallest

amount of work. Hering-Breuer reflex works to maintain this optimal frequency.





Dead space:



1. Anatomical dead space: Total volume of the conductive elements of airways. About 150 ml.

2. Physiological dead space: Anatomical dead space + non-perfused alveoli.







Gas transport in the blood:



In the pulmonary circulation arteries have venous blood and veins have

oxygenated arterial blood.



Alveolar gas exchange



What keeps O2 and CO2 moving trough the alveolar membrane is the partial

pressure. In the plasma we have greater partial pressure of CO2, that is why it leaves the blood going

to the alveolar space. And in the alveolar space the partial pressure of O2 is higher, forcing into the

plasma. This is by diffusion.

The rate of mobility of CO2 is greater BUT it´s partial pressure is less to compensate. So during the

sam amount of time, roughly tha same amount of O2 and CO2 will move through the alveolar

membrane and endothelium. Because, eventhough the driving force is different their permeability is

differents aswell.



Gas transport:



Oxygen - O2





- Physically dissovled [small amounts 1%]

determined by partial pressure (hypoxia & hypercapnia is the physicallys dissolved)

- Chemically combined to Hb [large amounts 99%]

determined by: concentration of Hb and saturation of Hb.



Each Hemoglobin has 4 heme groups, each heme can bind 1 O2 molecule. So 1 Hb can bind 4 O2,

with NONCOVALENT binding. Covalent binding formes methHb, which is pathological.



Oxygen-Hemoglobin saturation curve=

Maximal value is, theoretically, 100% and 100 mmHg pO2 in the

alveolar space is enough to saturate Hb.

The curve is sigmoid shaped. Due to the Positive cooperativity of Hb.



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Binding of the first 02 molecule is the hardest, that causes a conformational change in the Hb,

facilitating the binding og the next and so on. So the binding of the 4th is the easiest.



Oxygen-Myglobin saturation curve=

It´s an oxygen binding molecule in skeletal msucle, role is to store

oxygen, in order to provide it during physical activity. 1 O2 can bind to

1 myoglobin, shows simple saturation with NO positive cooperativity. It

has a left shift compared to Hb, meaning it has greater O2 affinity and

in lack of O2 myoglobin can take over.



Hb releases the oxygen into the working tissue. Factor that effect it are:



- Partial pressure : btw plasma and interstitial space of working tissue, which has lower pO2.

- ↓ pH. Decreased pH (acidity) = decreased Hb affinity to O2, shifts the saturation curve to the

right, it can still reach 100%. With less affinity O2 will be released in to the working acidic

tissue.

- ↑ Temperature. Shifts the saturation curve to the right, same as pH.

- ↑pCO2, hypercapnia. Shifts the curve to the right.

- 2,3 bis-phospho-glycerate. Binds to the β subunit of Hb, makes a conformational change

and decreases oxygen affinity. ↑2,3-BPG = ↓O2 affinity. Shifts the curve to the right.

BUT!!! Fetal Hb has no β subunit, 2α & 2δ. So 2,3-BPG cannot decrease oxygen affinity in

fetal Hb. So fetal Hb has higher O2 affinity than adult. There will be a left shift in the curve,

because since the mothers Hb cannot bind O2 as well with high 2,3-BPG it is released to the

fetus.

2,3-BPG also plays a role in high altitudes, anemia, hypoxia (↑) and stored blood (↓).



Carbonmonoxide poisoning:

CO bound to Hb formes carboxyhemoglobin. Binds on the heme group competeing with O2 for

binding but with x200 more affinity, it is a very effective blocker, patient will suffocate. To treat it you

need to get the patient to fresh air (first aid) or apply pure high pressure oxygen, it is the only

situation in medical practice where pure oxygen is allowed.



Carbondioxide-CO2



- Chemically dissoved in plasma as HCO3- (70%) [438 ml CO2/l in arterial blood]

- Physically dissovled (10%) [26 ml]

About 20x higher than O2. The only form that is transported in plasma alone.

- Bound to Hb (20%) [26 ml]



Hb-CO2: This is carbaminohemoglobin and is normal. CO2 binds to the globin part of Hb, to N-

terminus. Transported in plasma with RBC.



HCO3- production: Requiers RBC. So the importance of the RBC is not only to transport O2 but

also 90% of CO2 are transported via RBC!!!



In working tissue CO2 is produced, it enters the RBC. There is reacts with water, this need an

enzyme called cabonic acid anhydrid (CAA) which is why the process only takes place within RBC.

The end product is H2CO3 (hydrocarbonate) which will then dissociate from H+ forming HCO3-.



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Bicarbonate is transported out of the RBC with a

BAND III transport protein in a HCO3-/Cl-

exchanger, by facilitated diffusion.

The H+ is neutrlized by a buffer, which is Hb. Hb

binds to the H+ (binding is stonger e-if Hb is

reduced) and causes a conformational change

making Hb have less affinity to bind O2 (right

ward shift of ↓pH). Also the CO2 (physically

dissolved) will bind to the globin part of Hb, causin a conformational change, also making Hb´s

affinity for O2 less (right ward shift of hypercapnia).

Hb is bound to a positively chanrged K+, as it binds H+ it releases K+. This causes an increase in

intracellular osmolarity – water enters RBS, and it will swell slightly.

The hematocrit value for venous blood is higher than arterial blood due to this swelling.

This whole process is the „Chloride shift“ or „Hamburger shift“.



Bore-effect: how ↑pCO2 results in less Hb O2 affinity.



Haldain-effect: ↑pO2 results in less Hb CO2 affinity.



N2

Is only physically dissolved and the amount is linearly proportional to partial pressure in air.





Regulation of respiration

2 importanat regions in the brain have respiatory centers: PONS & MEDULLA OBLONGATA.



Pons centers (fine tuning of respiration):



1. Pneumotaxic

2. Apneustic



Medullary centers:



1. Inspiration center (dorsal respiratoy group)

2. Expiration center (ventral respiratory group)







There is a certain interaction btw these centers, there are inputs and outputs.



The inspiratoy RAMP signal: Freq. of

action

Frequency of action potential againts time. Shows the slowly potential

rising discharge rate in time which abrubtly decreases. The

gradual increase of activity in the inspiratoy center stimulates the

motorneurons that innervate the muscles of inspiration (mainly

daiphragm). Meaning that the inspiration is a gradual process, not a Time

sudden muscle contraction.



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The inspiratory center has similar function as the pressor center. It has spontaneous intrinsic

pacemaker activity and generates respiratory rythm. It is responsible for appropriating responses

to sensory information from chemoreceptors and mechanoreceptors in humans. Control length

and amplitude of inspiration.



CCR: central chemoreceptors stimulate inspiratory motorneurons. They are found in the

brainstem. They are stimulated by hypercapnia (mostly) and low pH. Hypoxia does NOT

stimulate the CCR, in case of hypoxia the neurons will be paralysed since the require O2 to

function.

PCR: are in carotid body and aortic body (locations are called glomuses), particularly sensitive

btw 60 – 30 mmHG, stimulated by hypotension. They send info viia CN IX, X. They are sensitive to

hypoxia (mostly), hypercapnia and lox pH.



Under normal conditions pO2 does not control breathing since O2 saturation rearly decreases

and pCO2 changes earlier. But low pO2 multiplies the ↓pCO2 effect. And ↑pH facilitates the

↓pCO2 effect.



Apart from stimulating the inspiratory center both CCR and PCR stimulate the Apneustic center

in the Pons. The apneustic center stimulates the

inspiratory center with several positive inputs. The

result is inspiration via decsending pathways (n.

Tractus Solitarius) that originate in the inspratory

center and terminate on motor neurons, most

importantly the phrenic nerve (C3-C5, mainly C4).

There will be a converge of the various stimulatory

inputs increasing the activity of the muscle,

gradually!!



The inspiratory center outputs will stimulate the

activity of the expiratory center & pneumotaxic

center.



- The pneumotaxic center inhibits the inspiratory AND apneustic centers via n. parabrachialis. It

shortens the inspiratory ramp signal by decreasing length and increasing frequency of

inspiration.

- The expiratory center will inhibit the inspiratory center via n. ambiguus. This center is inactive

in resting respiration but can tribute to increased ventilation. Overdirve mechanism for

inspiration and expiration, little known about mechanism.



By inhibiting these 2 centers there will be no activity in the decsending pathways to the

inspiratory muscles → relaxation → expiration.



The decreased activity of the inspiratory center pCO2 will slowly increase, this activates CCR and

PCR which starts the next phase of inspiration.



There is one more input to these centers: inhibitory inputs. Fibres originating from stretch in the

walls of the BRONCHIOLI receptors will inhibit the inspiratory and apneustic centers. They travel





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via the vagus nerve. In inspiration the bronchioli will be stretched, that will inhibit the inspiratory

center and apneustic center. This will also help in terminating inspiration.



Nervous cuts at various levels:



VAGUS INTACT VAGUS CUT

I. Above No change in Inhibition from stretch receptors is not

pneumotaxic breathing pattern, noavailable, more difficult to terminate

center centers affected. inspiration. Tidal volume increases and, to

maintain the minute volume of respiration,

the frequency decreases. MVR=↑TVx↓BR

II. Btw pneumotaxic Center needed for 2 mechanisms for terminating inspirations are

and apneutic termination of gone, weak inhibition from expiration center

inspiration has been is left. Long deep inspiration and short sudden

removed. ↑TV &↓BR expiration. APNEUSTIC BREATHING.





III. Btw Pons and Precise control of Irregular breathing, TV and BR change from

Medulla respiration is lost time to time. Average TV will be greater and

(pons). Irregular average BR will be lower. GASPING

breathing TV & BR BREATHING.

change. ATAXIC

BREATHING. Ataxia

means improper

muscle control.







IV. Btw inspiratory Descending pathways No breathing.

and expiratory from inspiratory

centers center will not reach

the motorneurons.

No breathing.





C4 is very important! Damage in the spinal cord btw medulla and C4, decending pathway btw

them is lost – the patient will die, if phrenic nerve will not receive stimulus from motorneurons.

Below C4 the connection will be intact and patient will survive.



Hering-Breuer Reflex:



Like every other reflex it has receptors,

afferent pathway, efferent pathway and

effector of the reflex.

Receptors are stretch sensitive in the

BRONCHIOLI. Activated by stretch in

inspiration. Inforation is sent via vagus to the

inspiratory center. Resulting in inhibition of

the phrenic nerve, affacting the diaphragma.

The inhibition means lack of motorneuron



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stimulation. The aim of the reflex is to set the tidal volume and breathing frequency to a

maximum effective breathing – with smallest effort. It is an efficiency-modulator.



Kussmaul breathing: high amplitude high frequnecy breathing due to acidosis. Acidosis will

stimulate the CCR and PCR which will cause increased activity of the inspiratory centers. Most

importnat cause is uncontrolled diabetes mellitus.



Cheyne-Stokes breathing: Periodic breathing; cretain stage of

activity followed by apnoe, or lack of breathing movement. A period of respiration is followed by

a long period of no respiration. 2 explination:



1. Hypersensitivity of CCR, this is pathological. A certain level of pCO2 will overexcite the CCR

which will overstimulate ther inspiratory center. This results in hyperventilation. The too

much O2 is inhaled, pCO2 greatly decreases (hypocapnia & hyperoxia) and none of the

chemoreceptors are activated. Resulting in no respiratory activity, untill pCO2 reaches the

activation threshold of CCR, this oocurs in patients

with brain hemorrhage.

2. Hyperventilation, voluntary.







Note that intoxications by alcholhol, morphine and heroine are powerful inhibitors of the

inspiratory center, resulting in hypoventilation and hypoxia. DO NOT GIVE OXYGEN. Because the

hypoxia stimulates the PCR and may be the only reason the patient is breathing at all.



Form of hypoxia:



1. Hypoxic hypoxia

Improper diffusion of O2 into blood, not enough O2 reaches the plasma. Reasons:

a. High altitudes.

b. Weakness of respiratory muscles.

c. Thickening of the alveolar wall. O2 cannot diffuse easily.



Treated with oxygen therapy.



2. Anemic hypoxia

There is enough O2 but not enough Hb. ↓RBC = ↓O2



3. Stagnation hypoxia

Impaired perfusion of a particular tissue or organ, local restriction in the flow of otherwise

well-oxygenated blood. Treatment involves impovement of the tissue perfusion

(vasodilators, massage...)



4. Histotoxic hypoxia

Enzymes responsable for utilisation of O2 are inhibited. Blocked respiratory enzymes, e.g.

due to cyanide poisoning. Instant death.









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Caisson disease:



Decompression sickness (DCS), the diver’s disease, the bends, caisson disease is the name given to a

variety of symptoms suffered by a person exposed to a decrease (nearly always after a big increase)

in the pressure around the body. The body must adapt to the pressure following a rapid ascent. It is a

type of diving hazard and dysbarism (changes in ambient pressure). In order to maintain respiration

oxygen must be provided by high pressure from a tank. By increasing the alveoli you increase partial

pressure of nitrogen aswell, and more nitrogen will be dissolved in the plasma and by that is will be

easily disposed in the adipose tissue. If the pressure comes to a sudden drop the adipose tissue

cannot dissolve as much nitrogen as before and it tries to enter the plasma in an amount so bubbles

will be formed. They will obstruct the walls of small blood vessels mainly in the brain and big joints,

impairing blood perfusion in the brain, may cause death. To prevent it pressure must return to

normal slowly, so nitrogen can be exhaled.









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