VASCULAR SYSTEM - THE HEMODYNAMICS -

Lecture 2

Dr. Ana-Maria Zagrean

Microcirculation • Main function:

-transport of nutrients…

-removal of cellular excreta…

• Arteriols (highly muscular, their diameters can change manyfold)

• Metarteriols/terminal arteriol (do not have a continuous muscular coat, but

smooth muscle fibers encircle the vessel at intermittent points)

• Precapillary sphincters (smooth mm cell, local control of blood flow)

• Capillaries

Microcirculation

An artery branches 6-8 x until becoming

arterioles; these are branching further

2-5 x towards capillaries.

Closed

capillaries

Capillaries

• diameter = 4-9 mm, 10 billions, surface = 500 - 700 m2

Capillary no, distance capill-cells (20-30 µm)~ metabolic activity of the tissue

• “pores” in the capillary membranes:

1. intercellular cleft / gap: 6-7 nm, S~1/1000 of the total capillaries

surface, allow the thermal motion of only small molecules

2. plasmalemmal / transcytosis vesicles = caveolae: role in

endocytosis, transcytosis (coalesce to form vesicular channels/pores)

3. special types of pores:

- large clefts in intestinal membranes, larger in liver capillaries

(endothelial discontinuity...)

- fenestrae in glomerular capillaries (20 to 100 nm), that appear

to be sealed by a thin diaphragm, but they are permeable to larger

molecules

- no pores, but tight junctions, in brain capillaries (BBB)

• permeability is not uniform along the whole capillary:

arterial end < venous end < venules (greater no of pores/clefts)

“Pores” in the capillary membranes Exchange between blood & interstitial fluid takes place in the capillaries by diffusion, filtration, pinocytosis (transcytosis).

(leaky junctions)

Cerebral endothelium: Tight-junction epithelium &

blood-brain barrier

Pericytes

• Capillary walls are closely associated with elongated, highly branched cells = pericytes

• Mesh-like outer layer between endothelium and interstitial fluid, more developed at the capillary venous end and venules level

• Functions: exchange, growth & repair processes, local control of blood flow at microcirculation level

Average function of the capillary system

• For the billions of capillaries which operate intermittently in

response to the local conditions in the tissue, there are…

• average rate of capillary blood flow

• average capillary pressure

• average rate of transfer of substances

Blood flow in the microcirculation

• Vasomotion

= intermittent contraction/relaxation of the metarteriols and

precapillary sphincters (5-10/min)

- partly an intrinsic contractile behavior of the vascular

smooth muscle

-depends on local and humoral factors, mostly on O2 conc.

-influenced by sympathetic tone

Blood flows intermittently/randomly or it may oscillate rhythmically at

different frequencies as determined by contraction and relaxation

(vasomotion) of the precapillary vessels.

Changes in transmural pressure = intravascular press. ▬ extravasc. press*

affect the contractile state of the precapillary vessels:

increase of transmural pressure terminal arteriole/precapillary

constriction

CHANGES IN CAPILLARY DIAMETER ARE PASSIVE AND ARE CAUSED BY

ALTERATIONS IN PRECAPILLARY AND POSTCAPILLARY RESISTANCE.

Average velocity of capillary blood flow ~1 mm/sec (zero-several mm/sec).

Blood flow in the microcirculation

*Transmural pressure is essentially equal to intraluminal pressure because extravascular pressure is usually negligible.

r of resistance vessels ~ contractile force of the vasc. smooth muscle ~ distending force produced by the intraluminal pressure. Intravascular pressure diminished vessel diameter and tension in the vessel wall decreased (Laplace's law) terminal arteriole response: vasodilation

When perfusion pressure is progressively reduced, a value of the transmural pressure = critical closing pressure is reached; at this pressure the vessel is occluded and blood flow ceases even though a positive pressure gradient from the afferent to the efferent end of the vessel may still exist. Also, small arterioles may be occluded because of infolding of the endothelium.

Laplace's law

T = P x r , in which P, intravascular pressure; r, radius of the vessel; T, wall

tension as the force per unit length tangential to the vessel wall (a force that tends to pull apart a theoretical longitudinal slit in the vessel).

Consequences of Laplace's law: T=p x r

Even the capillaries are thin-walled, they can withstand high internal pressures without bursting because of their narrow lumens. At normal aortic (100 mm Hg) and capillary (25 mm Hg) pressures, the wall tension of the aorta is about 12,000 times greater than that of the capillary: 100 mmHg × r of 1.5 cm for the aorta vs. 25 mmHg × r of 5×10-4 cm for the capillary

In a person standing quietly, capillary pressure in the feet may reach 100 mm Hg. Under such conditions, capillary wall tension increases to a value that is only 0.003 that of the wall tension in the aorta at the same internal pressure. According to Laplace's equation, wall tension increases as vessels dilate, even when internal pressure remains constant (T=p x r). In aneurysm (local widening) of the aorta, the wall tension may become high enough to rupture the vessel.

Endothelium synthesize substances that affect the contractile state of the arterioles: 1. Endothelium-derived relaxing factor (EDRF) - nitric oxide (NO), vasodilator formed and released in response to stimulation of the endothelium by various agents (e.g., acetylcholine, ATP, serotonin, bradykinin, histamine, substance P); NO can also interfere with platelet aggregation. 2. Endothelium-derived hyperpolarizing factor (EDHF) - vasodilator 3. Prostacyclin, a vasodilator that also inhibits platelet adherence to the endothelium and platelet aggregation, aiding in the prevention of intravascular thrombosis 4. Endothelin, a 27-am.ac. powerful vasoconstrictor substance, require just ng for vasoconstr., released in large quantities in lesioned endothelium 5. Also, synthesize structural components: glycocalyx, basal lamina

endoth. enzymes: AG converting enz, carbonic anhydrase (lungs) thromboxane, von Willebrand factor (f VIII) adhesive molecules involved in cell migration during inflammation

Prostacyclin (PGI2) is formed from arachidonic acid (AA) by the action of cyclooxygenase (Cyc-Ox) and prostacyclin synthetase (PGI2 Syn) in the endothelium and elicits relaxation of the adjacent vascular smooth muscle via increases in cAMP. Stimulation of the endothelial cells with acetylcholine (Ach) results in the formation and release of an EDRF (NO). EDRF stimulates guanylyl cyclase (G Cyc) to increase cGMP in the vascular smooth muscle to produce relaxation. The vasodilator agent nitroprusside (NP) acts directly on the vascular smooth muscle. Substances such as adenosine, H+, CO2, and K+ can arise in the parenchymal tissue and elicit vasodilation by direct action on the vascular smooth muscle.

Endothelium- and nonendothelium-mediated vasodilation

Arterioles - A, before and B, after the microinjection of norepinephrine. Right inset - capillary with red cells during a period of complete closure of the feeding arteriole.

Vasomotion is influenced by sympathetic tone

Angiogenesis creates new blood vessels

Relation angiogenesis – growth, development, wound healing

– endurance exercise training

Angiogenic vs. antiangiogenic factors/cytokines: mitogens like VEGF, FGF vs. angiostatin and endostatin

Therapeutic role: cancer, coronary artery disease/myocardial ischemia

Arterial pressure • Flow in the arterial side of the circulation is pulsatile, reflecting the

changes in arterial pressure throughout a cardiac cycle; once past the arterioles, pulse waves disappear.

• Systolic pressure (SP): highest during a cardiac cycle, highest in aorta ~ 120 mmHg

• Diastolic pressure (DP): lowest during a cardiac cycle ~ 80 mmHg

! As diastolic pressure in LV ~ 0 mm Hg, DP in large arteries remains relatively high because of their capacity to store energy in the elastic walls.

The pressure pulse wave

= a moving wave of pressure that assists the continuous flow…

- determined by the ejection of blood in aorta

- transmitted through the fluid-filled arteries

- 10-15x more fast than the blood

- its velocity is increasing from aorta (3-5 m/sec) to large arteries (7-10 m/sec), small arteries (15-35 m/sec), along with the decrease in the vessels compliance

Pulse pressure Pulse pressure = P systolic – P diastolic =120 - 80= 40 mmHg

= f (stroke vol., low arterial compliance)

Example in aging: ↓ compliance cause ↑ pulse pressure.

Friction effect

Mean arterial pressure MAP = average arterial pressure with respect to time

- representative for the driving pressure*

= diastolic pressure + 1/3 pulse pressure

MAP = 80 mmHg + 1/3(120-80 mmHg)= 93 mmHg

for HR = 60-80 beats/min

MAP value more close to the DP.

Why?

Diastole lasts twice as long as systole.

What happens with MAP value if HR increases?

SP=112 mm Hg

DP=68 mm Hg

(112/68)

Pulse pressure=?

MAP=?

44

82.6

Arterial pressure is estimated by sphygmomanometry

• AP in brachial artery of the arm

• Sphygmomanometer: inflatable cuff, pressure gauge

When the cuff is inflated so that it stops arterial

blood flow, no sound can be heard through a stethoscope placed over the brachial artery distal to the cuff.

Korotkoff sounds are created by pulsatile blood flow through the compressed artery.

Blood flow is silent when the artery is no

longer compressed.

Exchange of nutrients and other substances

between the blood and interstitial fluid

• Diffusion… back and forth – continual mixing – random movement

• Diffusion results from thermal motion of water molecules and dissolved substances

• What diffuses…

– Lipid-soluble substances [through cell membrane]: O2, CO2

– Water-soluble, non-lipid-soluble substances [only through

intercellular pores]: H2O, Na+, Cl-, glucose

– Great velocity of thermal motion tremendous diffusion

[rate of H2O diffusion through the capillary mb.= 40 ÷ 80 x the rate

at which plasma itself flows linearly along the capillary]

Diffusion depends on lipid-solubility, molecular size / MW,

concentration difference between the two sides of the

membrane...

D I F F U S I O N

Diffusion between capillary and interstial fluid

Arterial end

Lymfatic capillary

Venous end

Blood capillary

Effect of molecular size on passage

through the pores

dintercell. cleft = 6-7 nm ~ 20 x dwater

< dplasma protein molecules

interstitial fluid contains almost the same

constituents as plasma except for the proteins

Capillary pores do not restrict the fast diffusion of water,

NaCl, urea or glucose; they pass as much as they are

available in the blood (flow limited transport)

Minimal diffusion of molecules with MW > 60.000 (diffusion

limited transport).

Relative permeability of muscle capillary pores to

different-sized molecules

Substance MW Permeability coefficient

Water 18 1

NaCl 58,5 0,96

Urea 60 0,8

Glucose 180 0,6

Sucrose 342 0,4

Inulin 5000 0,2

Myoglobin 17000 0,03

Hemoglobin 68000 0,01

Albumin 69000 0,0001

Reflection coefficient - relative impediment to the passage of a

substance through the capillary membrane

= 0 for water

= 1 for albumin

Filterable solutes have reflection coefficients between 0 and 1.

Net rate of diffusion through the capillary membrane

- net rate of diffusion is proportional to the concentration difference

between the two sides of the membrane

- e.g., concentration difference for O2, CO2

glucose

- O2, CO2 : lipid-soluble, readily pass through the endothelial wall

possible diffusion shunt of gas around the capillaries, or directly

between adjacent arterioles and venules

diffusion of O2 from the arterioles can decrease blood O2 content

at this level to about 80% of that in the aorta

Arterial end

Lymfatic capillary

Venous end

Blood capillary

Interstitium

Interstitium:

-solid structures (collagen fiber bundles, proteoglycan [PG] filaments)

-interstitial fluid is derived by filtration and diffusion from the capillaries

-interstitial/tissue “gel”: the interstitial fluid entrapped within the PG filaments mainly diffuses through the gel (velocity ~ 95%-99% for free fluid flow)

-free fluid vesicles in the interstitium: normally <1%, ↑ ↑ in edema

D I F F U S I O N

Arterial end

Lymfatic capillary

Venous end

Blood capillary

F I L T R A T I O N

Exchanges between capillary and interstial fluid: capillary filtration is regulated by the hydrostatic and osmotic forces across the endothelium

Four primary forces determine fluid movement

through the capillary membrane: ‘Starling forces’

(Ernest Starling, 1896)

1. Capillary pressure (Pc) – hydrostatic pressure which tends to force fluid outward through the capillary mb.

2. Interstitial fluid pressure (Pif) – hydrostatic press. in the interstitial fluid which tends to force fluid outward(+)/inward(-) through the capillary mb.

3. Plasma colloid osmotic pressure (Pp) – osmotic pressure caused by the plasma proteins, which tends to cause osmosis of fluid inward through the capillary mb.

4. Interstitial fluid colloid osmotic pressure (Pif) - osmotic pressure caused by the proteins in the interstitium, which tends to cause osmosis of fluid outward through the capillary mb.

Mean capillary (hydrostatic) pressure

• Mean capillary pressure measurement:

- direct micropipette cannulation of the capillaries: 25mmHg

- indirect functional measurement: 17mmHg

• Mean functional capillary pressure = 17,3 mmHg (nearer to

the pressure in the venous end):

- precapillary sphincters are closed during a large part of the

vasomotion cycle

- venous capillaries are several times as permeable as the

arterial capillaries

- there are far more venous capillaries then arterial ones.

Colloid osmotic pressure

• Only those molecules or ions that fail to pass through the

pores of a semipermeable membrane exert osmotic pressure

• Proteins are the only significant dissolved constituents that do not

readily penetrate the pores of the capillary membrane.

Dissolved proteins of the plasma and interstitial fluids that are

responsible for the osmotic pressure = colloid osmotic pressure

or oncotic pressure (P).

Pp = 28 mmHg

19 mmHg from dissolved proteins (80%-albumin, 20%-globulin)

9 mmHg from the cations associated with plasmatic proteins

(Gibbs-Donnan effect)

Pif = 8mmHg (protein concentration in IF is 40% of that in

plasma, no Donnan effect here)

Qf - fluid movement across the capillary wall

k - filtration constant for the capillary membrane

Pc - capillary hydrostatic pressure (mm Hg)

πi - interstitial fluid oncotic pressure (mm Hg)

Pi - interstitial fluid hydrostatic pressure (mm Hg)

πp - plasma oncotic pressure (mm Hg)

Net filtration occurs when the algebraic sum of the hydrostatic

and osmotic pressures across the capillaries is positive, and

net absorption occurs when the sum is negative.

Starling Equilibrium for Capillary Exchange

Pc=30 mmHg Pp =28 mmHg

Pif = -3 mmHg Pif = 8 mmHg

Poutward=13mmHg

Pc=10 mmHg Pp=28 mmHg

Pif = -3 mmHg Pif = 8 mmHg

Pc=17,3mmHg Pp=28mmHg

Pif = -3 mmHg Pif = 8 mmHg

Net outward force=0,3 Pinward=7mmHg

Arterial end Venous end

NET FILTRATION PRESSURE: outward inward net outward force (30+3+8 ) – 28 = 41 – 28 =13 mmHg

NET REABSORBTION PRESSURE: inward outward net inward force 28 -(10+3+8 ) =28 – 21= 7 mmHg

NET FILTRATION=2ml/min/entire body drained as LYMPH

Fluid exchange at the capillary

- Quick movement of fluid across the capillary endothelium - Filtration and absorption occur with very small imbalances of pressure across the capillary wall. only about 2% of the plasma flowing through the vascular

system is filtered, and of this, about 85% is absorbed in the capillaries and venules. The remainder returns to the vascular system in the lymph, along with the albumin that escapes from the capillaries.

Lymphatic system

Accessory rout for fluid drainage from interstitium (1/10 of the filtrated fluid, 2-3L/ day) together with proteins and macromolecules; act as an ‘overflow mechanism’; its function is essential for survival.

Lymphatic vessels in almost all tissues of the body (exception epidermis, brain, muscles endomysium and bones; here – minute interstitial channels = prelymphatics).

Terminal lymphatic vessels - close-end network of highly permeable lymph capillaries, anchored through fine filaments to the surrounding connective tissue

Juncture of subclavian vein and internal jugular vein

Terminal lymphatic capillaries collecting lymphaticlymphatic vessels

thoracic (left lymph) duct/right lymph duct

Lymphatic system

Special structure of the lymphatic capillaries:

- Endothelial cells (EC) with actomyosin filaments & anchoring filaments to the surrounding connective tissue (lymphatic capillary pump)

- the edges of adjacent EC overlap in a minute valve, allowing an inward flap; the backflow in the lymphatic capillary closes the flap valves.

Structure of lymphatic vessels:

- valves along lymphatic vessels up to the point where they empty into the blood circulation;

- smooth muscle that contracts in response to stretch

system of pumps & valves (lymphatic pump)

Lymphatic system

Lymphatic capillary

Lymph composition

- almost the same as interstitial fluid

- proteins: 2 g/L in lymphatic capillaries 6 g/L in liver lymphatics

3-4 g/L in intestines lymphatics

3-5 g/L in thoracic duct

- nutrients from GIT (1-2% fats after a fatty meal)

- lipid-soluble vitamins (A, D, E, K)

- lymphocytes

- globulins synthesized in lymphatic nodes

- clotting factors

- microorganisms

2/3

Lymph flow

- 2 mL/min = 120 mL/hour = 2-3 L/day

- Interstitial fluid pressure Lymph flow

< (-6) mmHg minim

(-2) ÷ 0 mm Hg maxim (20 fold increase)

>1,5 ÷ 2 mm Hg maxim, constant

- Factors that increase lymph flow:

- intrinsic: ↑Pc, ↓Pp, ↑ Pif, ↑ permeability of the capillaries,

lymphatic pump (valves & smooth mm.)

- extrinsic: skeletal mm contraction, body movements,

pulsations of arteries adjacent to the lymphatics,

external compression of the tissues

- Lymph flow increase 10- to 30-fold during exercise and

decrease to almost zero during periods of rest

Roles of the lymphatic system

1. Control the concentration of proteins in IF (prevent the

increase in Pif); return the ‘filtered’ proteins to the

blood;

2. Control the volume of IF;

3. Control the pressure of IF (favours the fluid filtration

into the interstitium and maintenance of lymph flow).

4. Lymph nodes filter the lymph and removes foreign

particles such as bacteria

The Venous System

Functions of the Venous System

- Circulatory function:

-blood return to the heart;

-constriction/enlargement, storing/making available the blood when required,

-regulate cardiac output through venous return, venous pump (peripheral veins)

- Blood reservoir: 64% from total blood volume

Blood flow converges in the venules and veins:

Smallest venules: -similar to capillaries -thin exchange endothelium, little connective tissue - show a convergent pattern of flow

Larger venules: -contain also smooth muscle -drain blood into larger veins Veins: -diameter, volume …(hold more then 50% of the blood), -less elastic, more distensible tissue -lie closer to the surface of the body; venipuncture -below the heart there are veins with internal one-way valves -drain blood into venae cave RA (central venous pressure)

Blood flow through the venous system

Venous valves of the leg

Valves create one-way flow in the veins below the heart

Chronic excess venous press. venous valve incompetence varicose veins

Blood flow through the venous system

Venous Pressures

Central venous pressure (CVP): Right atrial pressure Peripheral venous pressure

Right atrial pressure - central venous pressure (CVP)

- zero pressure reference level: tricuspid valve in a person standing/laying down, at which gravitational pressure factors caused by changes in body position usually do not affect the pressure measurement by more than 1-2 mmHg

- CVP depends on: 1) ability of right heart to pump: normally, maintains a decreased CVP, favoring the venous return 2) venous return of the blood from the peripheral veins into the right atrium, directly depends on: - blood volume, - large vessel tone/peripheral venous pressures, - arterioles tone: their dilation decreases the peripheral resistance and allows rapid flow of blood from the arteries into the veins.

- RA press.: normal ~ 0 mmHg = atmospheric press. around the body increases ~ 20÷30 mmHg under abnormal conditions (heart failure,

massive blood transfusion, which increases blood volume/venous return).

decreases up to -3÷-5 mmHg below atm. press. ~ intrathoracic pressure - when heart pumps with exceptional vigor blood volume decreases/severe hemorrhage.

Venous pressure in periphery

Resistance to blood flow when large veins are distended is almost zero. Large veins that enter the thorax and the large abdominal veins are compressed at different points by the surrounding tissues blood flow impeded at these points small increase in resistance to blood flow at this level pressure in the

more peripheral small veins in a person lying down is usually +4 to +6 mmHg greater than CVP.

Compression points between peripheral veins and large central veins:

- Rib collapse: in the arm veins, the pressure at the level of the first rib is usually about +6 mmHg because of compression of the subclavian vein as it passes in sharp angulation over this rib.

-Atmospheric press. collapse: neck veins of a person standing upright collapse almost completely because of atmospheric pressure on the outside of the neck

pressure in these veins remains at zero; also, any press. increase will increase blood flow, any press. decrease will rise the resistance

- Abdominal pressure collapse: abdominal veins are often compressed by different organs and by the intra-abdominal pressure (+6 mmHg15-30 mmHg).

Compression points that tend to collapse the veins entering the thorax.

Intra-abdominal pressure: - normally up to +6 mm Hg, - can rise to +15 to +30 mmHg (pregnancy, large tumors, excessive fluid in the abdominal cavity/ascites) drainage of the blood from the legs only

when the pressure in the veins rise above the abdominal pressure (e.g., if the intra-abdominal pressure is +20 mm Hg, the lowest possible pressure in the femoral veins is also +20 mm Hg).

RA pressure: - >0 mmHgblood begins to back up in the large veins veins enlargement - rise at +4 to +6 mmHg (e.g., during heart failure) opening of the veins

at the collapse points - >+6 mmHg rise in peripheral venous press. in the limbs and elsewhere.

Peripheral venous pressure depends on:

Gravitational/hydrostatic pressure -occurs in the vascular system because of weight of the blood in the vessels - ! Also affects arterial pressure in the peripheral arteries and capillaries. In a standing person, for a MAP of 100 mmHg at the level of the heart, the arterial press in the feet is about 190 mmHg…

• after standing still for 15 – 30 min., blood volume decreases with 10-20% (fluid leakage, legs swell...)

Gravitational/hydrostatic pressure occurs in the vascular system because of weight of the blood in the vessels (1 mmHg for each 13.6 millimeters). For a standing person: •pressure in the RA remains ~ 0 mmHg (heart pumps any excess blood) •pressure in the veins of the feet ~+90 mmHg if standing still at least 30 sec., <+20 mmHg if walking (venous/muscular pump) • pressure between 0-90 mmHg at other levels of the body: +40 mmHg in the femoral a., +35 mmHg in the hands (+6+29...) -10 mmHg in the sagittal sinus (hydrostatic ‘suction’ between the top and the base of the noncollapsible skull cavity; risk of air embolism if sagittal sinus is opened during surgery).

Gravitational/hydrostatic pressure

Effect of Gravitational Pressure on Venous Pressure

Clinical estimation of venous pressure. -observing the degree of distention of the peripheral veins (neck veins): in sitting position, the neck veins are never distended in the normal quietly resting person, but distend when the RA pressure > +10 mm Hg.

Direct measurement of venous pressure and RA pressure (CVP) -by inserting a catheter through the peripheral veins and into the right atrium (central venous catheter) to assess the heart pumping ability.

Reference point for circulatory pressure measurement (located at/near the tricuspid valve).

Factors involved in venous return

1. Pressure gradient • Central venous pressure: RA pressure

• Venous pressure in periphery: 2. Hydrostatic/gravitational pressure (1 mmHg for 13.6 mm)

• Body position

• Standing person: standing still or walking...

3. Heart activity: • Aspiration pump together with the venous pump/muscle pump