Microcirculation: introduction

1) Capillaries are the site of diffusion of nutrients and waste between blood and tissue 2) Transcapillary exchange of fluid

Maintains plasma & interstitial flluidVolumeOpposes edema formation ( Capillary

Starling forces)Lymphatic structure & functionEdema formation

Microvascular unit

Arteriole

Venule

Metarteriole

Capillaries Arteriovenous shunt (S)

Pre-capillary sphincters exist at the origin of each capillary

Structures in the microcirculation

StructureSmooth Muscle Innervated Function Control

Arteriole Yes Yes Resistance Local & neural

Metarteriole Sparse Occasionally Resistance Local

Precapillary sphincter Yes No Resistance Local

Capillary No No Exchange None (passive)

Venule Yes Yes Capacitance Neural

Capillary Structure

Capillaries:Site of exchange by diffusion (some diffusion occurs in venules also).Capillary walls are porous to small molecules:

Intercellular cleftsFused vesicle channels

The Permeability Surface area term for diffusion across a capillary wall

The rate of diffusion of a molecule is proportional to area & concentration gradient, & inversely proportional to distance:

n = amount, t = time, D = diffusion coefficient, A = area, dC = concentration gradient, dx = distance.

dxdCAD

dtdn

Applied to the circulation, the equation for diffusion of molecules across the capillary wall is:

Where P is permeability of the capillary & S is surface area. Under most conditions P is constant & determined by the structure of the capillary wall.Physiologically, the area S available for diffusion can be increased by recruiting more capillaries, which also decreases the distance (shorter intercapillary distance).

dxdCSP

dtdn

Transcapillary exchange of lipid soluble substances

Lipid soluble substances such as CO2, O2 & many anesthetics penetrate the capillary

wall by diffusing via the lipid component of the endothelial cell membranes.

Capillary area for diffusion of lipid soluble molecules is maximal.

Transcapillary movement of macromolecules & cells

Molecules > 40 A can be transported across the endothelium by pinocytosis.Leucocytes & lymphocytes migrate through intercellular clefts by ameboid movement.

Transcapillary exchange of water soluble substances

H2O, monosaccharides, amino acids, small peptides & organic acids and inorganic ions (Na+, K+, Ca++, etc) diffuse rapidly through intercellular clefts.The area for diffusion of water soluble molecules is less than for lipid soluble molecules.Capillaries have two types of endothelium:Discontinuous endothelium capillaries have large clefts & gaps in basement membrane, relatively high permeability.Continuous endothelium: basement membrane is continuous, intercellular clefts are ~ 40 angstroms diameter & have tight junctions. Molecules larger than 40 A, like proteins, cannot cross the wall by diffusion.

Continuous endothelium (muscle, skin, lung, CNS)

Discontinuous endothelium (liver, spleen, glomerulus, small intestine, endocrine glands, bone marrow)

Flow & diffusion limits on exchange`

Flow limited exchange: exchange of molecules that diffuse rapidly is limited by the rate of blood flow (examples: H2O and small molecules)

Diffusion limited exchange: exchange limited by diffusion because eitherThe molecules diffuse slowly (macromolecules) orDiffusion distances are large

flowFlow-limited; Diffusion is rapid

flowDiffusion limited;Diffusion is slow

With edema increased diffusion distance may limit supply of nutrients to tissues

Transcapillary exchange of fluid impacts plasma & interstitial fluid volumes

Total body water content is maintained nearly constant by control mechanisms that operate through thirst (input) and kidney function (output)Total body water can be divided into

Extracellular fluid (ECF)PlasmaInterstitial fluid including lymph

Intracellular fluid (ICF)The distribution of fluid between plasma and interstitium depends on:1. Osmotic pressure due to plasma proteins2. Capillary hydrostatic pressure3.Osmotic pressure due to proteins in interstitial fluid4. Interstitial fluid hydrostatic pressure(These are the Starling Forces)Imbalances in these factors may produce edema & decrease blood volume.Edema is “a palpable swelling produced by expansion of the interstitial fluid volume.”

Osmosis

Osmotic pressure is pressure created by a difference in solute concentration across a semi-permeable membrane.

Osmosis is the passive diffusion of water from a region of low solute concentration (dilute solution, low osmotic pressure) to a region of high solute concentration (concentrated solution, high osmotic pressure).

Osmotic pressure due to protein molecules is called oncotic pressure.

Definition of an osmole

Osmotic Pressure depends on the concentration of particles in a solution..

An osmole is a unit that refers to the total number of particles dissolved in a solution. One osmole = 6.02 x 1023 particles (Avogadro’s number).

One gram molecular weight of glucose dissolved in water will liberate one osmole of particles.

One mole of NaCl dissolved in water will yield two osmoles (Na+ and Cl-) of particles.

One osmole of glucose in one liter of water will yield a one osmolar solution.

Osmolarity is the number of osmoles/liter of solution.Osmolality is the number of osmoles/kilogram of solvent.The difference between osmolarity & osmolality for biological solutions is insignificant.

Normal plasma osmolality

Plasma solutes, millimoles/liter

Cations Anions

Na+ 135 Cl- 108

K+ 3.5 HCO3- 24

Ca++ 2 Lactate 1

Sum 140.5 Albumin 0.6

Sum 133.6

Glucose 5

Urea 5

Grand total 284.1

mM = millimole = 1/1000th of a molemOsm = milliosmole = 1/1000th of an osmoleNormal plasma osmolality = 280 to 296 mOsm/liter

Starling forces in capillaries

OUT IN

F = K [(Pcap + i) – (Pi + cap)]

F = net movement of fluid across the capillary wall (ml/min)

Pc ap = capillary hydrostatic pressure (mmHg)

cap = capillary oncotic pressure* (mmHg)

Pi = interstitial fluid hydrostatic pressure (mmHg)

I = interstitial fluid oncotic pressure (mmHg)

K = filtration constant: (determined by capillary surface area and permeability to water (ml/min)/mmHg)

*oncotic pressure = osmotic pressure due to proteins

Calculation of net filtration pressure

F = K [(Pcap + i) – (Pi + cap)]

net filtration pressure

F ~ Pcap – cap

Blood flow

Pc ap = 37 mm Hg

i= 0 Pi = 1 mm Hg

cap = 25 mm Hg

Arterial end: Pcap > cap

Net filtration pressure = (37 + 0) - (1 + 25) = 11 mm Hg

Venous end: Pcap < cap

Net filtration pressure = (17 + 0) - (1 + 25) = - 9 mm Hg

Pcap =17 mm Hg

cap = 25 mm Hg

i= 0 Pi = 1 mm Hg

Negative value for net filtration pressure indicates net force favors absorption

Starling forces & lymph flow in various tissues

Pcap Pi cap i Lymph flow NFP**

Hind limb (dog) 13.0 -5 21 4 0.015 +1.0

Skeletal muscle (rest) 10.1 -3 20 8 0.005 +1.1

Intestine (rest) 16.0 2 23 10 0.08 +1.0

Intestine (digesting) 16.0 3 23 5 0.10 -5.0

Liver 7.0 6 22 20 0.10 -1.0

Lung 7.0 -5 23 12 0.10 +1.0

Cardiac muscle 23.1 15 21 13 0.12 +0.1

Glomerulus 50.0 15 28 0 2.0 +7.0

Peritubular capillary* 25.0 7 32 7 2.0 -7.0

*in the kidney** NFP = net filtration pressurePressures are all mm Hg; lymph flow units are ml/min per 100 g tissue

Factors that influence lymph flow

Lymph flow is increased by Interstitial hydrostatic pressure Lymphatic contractions (smooth muscle) & valves Sympathetic stimulation of lymph vesselsSkeletal muscle pump

Lymphatic circulation

systemic capillaries

Venous system

Interstitial fluid

Filtration 20 liters/day

Absorption 16 to 18 liters/day

Lymph flow2 to 4 liters/day

systemic arteries

Right heartPulmonary circulation

Left heart

2 to 4 liters of fluid per day is filtered out of the capillaries, taken up by the lymphatics and returned to the systemic circulation.

Terminal lymphatics are highly permeable to proteinLymphatics are the only route for return to circulation of protein that leaves capillaries

Arteriolar Tone and Capillary Hydrostatic Pressure

Arteriolar constriction decreases Pcap

Arteriolar dilation increases Pcap

Changes in PCap will affect filtration & absorption

Effect on mean arterial pressure:

MAP = CO x TPR

Constriction of arterioles in one organ or tissue may be offset by dilation elsewhere, without causing a change in TPR and MAP

Widespread arteriolar constriction in many tissues will increase TPR and MAP (if CO doesn’t change).

Arterial pressure Capillary hydrostatic pressure

dilation

constriction

CapillaryArtery Arteriole

Absorption of interstitial fluid into the circulation compensates in hemorrhage

MAP = CO x TPR

Hemorrhage

sympathetic nerve activity

heart rate cardiac contractility

Restore MAP

TPR

Cardiovascular reflexes

hypotension

absorption of fluid into capillaries

Restore blood volume

CO

Vasoconstriction(skin, kidney, GI tract)

capillary hydrostatic pressure

hematocrit

Three physiological roles of arteriolar tone

Support arterial blood pressureDirect distribution of flow between organs & tissuesInfluence capillary filtration & absorption

Edema safety factors

Capillary hydrostatic pressure, mm Hg

30

Lym

ph fl

ow

B

30

Pi,

mm

Hg

C

30

(ca

p -

i), m

m

Hg

A

A: As capillary hydrostatic pressure & filtration increase, tissue protein is diluted, i decreases, so cap - i increases, limiting further filtration.(The y-axis in panel A is cap - I, the oncotic pressure gradient influencing filtration)

B: As filtration increases, lymph flow increases, limiting accumulation of fluid in the interstitium.

C: As filtration increases, fluid added to the interstitium increases Pi, decreasing the hydrostatic pressure gradient favoring filtration (Pcap – Pi)

Edema formation

Edema is a pathological accumulation of excess fluid in the interstitial spaceCauses of edema:

Decreased plasma oncotic pressureKidney disease urinary excretion of plasma proteinLiver disease inadequate albumin synthesisIncreased capillary permeability to proteins

Tissue traumaAnaphylactic shock

Increased venous & capillary hydrostatic pressureCongestive heart failureBlockage of lymphatics Tumors Parasites