Microcirculation: Solute and Fluid Exchange

Companion reading: Guyton & Hall, Chapter 16: The Microcirculation and the Lymphatic System: Capillary Fluid Exchange, Interstitial Fluid, and Lymph Flow.  pp. 162-174, Chapter 17: Local Control of Blood Flow by the Tissues; and Humoral Regulation. pp. 175-183

Objectives:

Define the mechanisms responsible for the movement of water and solute into and out of the vascular space.  This includes knowing the basic transport equations for volume flux and for solute flux.
Possess a working understanding of the forces governing transport, how they can be altered, what influence changes in the driving forces will have on volume balance and solute delivery.
Understand the role of the endothelium in the regulation of circulatory function and possess a working knowledge of the mechanisms resulting in autoregulation of blood flow.












I. Fluid Exchange:

A. Transcapillary fluid balance: Starling's Hypothesis.  The movement of fluid into and out of the circulatory system is governed by forces in the blood and tissue compartments.  The Starling Hypothesis states that these forces are balanced under normal, resting conditions:

(Pc - Pi) = s (Pp - Pi)

1. Driving Forces.
a. Capillary hydrostatic pressure, Pc.  20-27 mmHg (Guyton: 17 mmHg)
b. Interstitial hydrostatic pressure, Pi. -7 to -1  mmHg (Guyton: -3 mmHg)
c. Plasma solute osmotic pressure, Pp. 25 mmHg  (Guyton: 28 mmHg)
d. Interstitial solute osmotic pressure, Pi. 1 to 3 mmHg. (Guyton: 8 mmHg)
2. Selectivity or Reflection coefficient (s):  A measure of the ease of solute penetration through the capillary wall: the probability of the molecule crossing the wall.
a. s = 1.  Capillary is impermeable to solute; full osmotic pressure will be expressed.
b. s = 0.  The solute "sees" no restriction and passes across the wall unhindered; thus no expression of osmotic pressure.
c. 0 < s < 1.  The membrane is semipermeable to solute; some amount is "reflected" off the barrier and does not pass; the amount of imbalance is expressed as an osmotic pressure.  If s were 0.75, for example 75% of the time the solute would not pass and 75% of the osmotic effect would be exerted.  For most colloids (proteins) s = 1: for small solutes like NaCl or glucose, s = 0.  The implication is that for continuous vessels the osmotic gradient between blood and tissue results from the retention of plasma proteins in the vessel lumen.
B. Ultrafiltration:Fluid movement, Jv:  The rate of fluid movement (Jv) is a result of the hydrostatic and osmotic forces, as well as the geometry of the membrane and the available area for exchange:
Jv = Lp S [( Pc - Pi) - s(Pp - Pi)]
or
Jv = Kf [( Pc - Pi) - s(Pp - Pi)]
or, as in Berne and Levy:
J = k[(Pc + Pi) - (Pi + Pp)], assuming s = 1

An amount of fluid moves across the wall when an imbalance in the forces exists.

1. Filtration:  when Jv has a positive sign there is net movement of water out of the vessel.

2. Absorption:  The net movement of water is into the vessel when Jv has a negative sign.

3. Hydraulic Conductivity, Lp.  The coefficient, Lp, is indicative of the leakiness of the capillary wall to the movement of water and is a characteristic for each exchange vessel:  units = cm/(s cmH2O).

4. Capillary Filtration Coefficient, CFC or KfIs the hydraulic conductance per unit surface area for exchange: units (ml/[s mmHg]).  This is the usual parameter because most times S is unknown.

The ultrafiltrate, of the fluid that moves across the capillary wall, has the same concentration of small, uncharged solutes as plasma, an appropriate Donnan ratio concentration for ions and vanishingly low concentrations of proteins and large molecules.

II. Lymphatics: The "second circulation" filtered fluid does not normally stay in the circulation:
A. Daily filtered load about 20 liters/day.
1. Capillary/venular readsorption: 16-18 liters/day re-adsorbed by low pressure venules and capillaries.
2. Lymphatic drainage: 2- 4 liters/day are taken up by the lymphatic capillaries.
B. Blood volume exchanges: Total blood volume on the order of 5 L; plasma volume 2.75 L.  Thus 7 complete volume changes a day across the capillary membranes.

C. Fluid in the lymphatic system.

1. Route: Fluid taken up by the lymphatics is transported as lymph back to circulatory system via lymphatic ducts that eventually connect with the subclavian veins at the junction to the internal jugular veins in the neck.

2. Mechanism: Fluid flux is facilitated by pumping action on the lymphatics located between contracting muscles.  Lymphatics, like veins, possess valves to prevent back flux.  Lymphatic exist in all tissues except bone, cartilage and CNS.
 

III. Regulation of Hydrostatic Forces:  What happens up stream and down stream of the capillaries matters
A. Capillary Flow: depends on the total resistance (RT) of the circuit: e.g. is the sum of precapillary resistance in the arterioles (Ra) and postcapillary resistance (Rv) in the venules.
Q = DP/RT = (Pa- Pv)/(Ra + Rv)
B. Capillary Pressure:  Depends on the ratio of venous resistance to total resistance.
Pc = [(Pa- Pv) (Rv/{Ra + Rv})] + Pv
Pc = [(Pa- Pv) (Rv/{RT})] + Pv
C. Resistance:
1. Systemic resistance, (Rv/{Ra + Rv}) = 0.2: Venous resistance is 20% of total.
2. Pulmonary circuit, (Rv/{Ra + Rv}) = 0.4: Venous resistance is 40% of total.
3. Ra and Rv change with vasomotor activity,  but the greatest changes occur on the pre-capillary (arteriolar) side of the circuit.  Thus an increase in RT results in a decrease in Pc.
IV. Edema:  The most common clinical manifestation of an imbalance of forces at the capillary wall is edema.  Edema is the excess accumulation of fluid in the interstitial space that has not been readsorbed into the capillaries or taken up by the lymphatics.  Causes include:
A. Obstruction:  Parasites, larvae microfilaria causing elephantiasis- or insufficiency of lymphatics from surgery or congenital lack.

B. Permeability or change in reflection coefficient:  Increased protein permeability will result in an imbalance.  Occurs in cases of trauma, thermal injury, and inflammation.  Life threatening manifestations occur in endotoxic shock, ARDS, following Interleukin 2 treatments.

C. Plasma Protein:  Reduction in the circulating amount of plasma protein, especially albumin in cases of liver dysfunction, malnutrition, or acute alteration of fluid status.

D. Capillary pressure:

1. Increased Pv: Venous obstruction, high plasma volume, congestive heart failure.
2. Increased Rv: Venoconstriction
3. Lowered Ra: Vasodilation
V. Solute Exchange:
Materials pass from tissue to the circulatory system and back again at the capillary wall.  The exact nature of the barrier and how the barrier properties are regulated are not known.  Materials that pass the vessel wall include respiratory gases, water ions, minerals, amino acids, carbohydrates, proteins and even cells.
The primary cell type across which exchange of water, solutes and gases occurs is the endothelium, which until recently was thought to be a passive barrier separating the blood from tissue.  As illustrated in the figure, endothelium is more than a Saran lining of the vasculature.
 
A. Capillary Permeability
1. Water: high P, uses cellular and paracellular pathways.
2. Lipid soluble substances: High P, cellular path
3. Ions, small polar substances: Moderate P, paracellular path; junctions, small pores?
4. Hydrophilic solutes: Moderate P, paracellular path; junctions, small pores?  The larger the substance, though, the smaller the P.
5. Plasma proteins, macromolecules: Low to trace P; vesicles or junctions?
B. Capillary "Type": Permeability varies with type of capillary; capillary type varies with organ function.
1. Tight (brain) <
2. Continuous (skeletal muscle, skin) <
3. Fenestrated (secretory glands, kidney, gut) <
4. Discontinuous (liver, spleen, bone marrow).
C. Fick's First Law of Diffusion: Simple case of moving materials from an area of higher concentration to an area of lower concentration across some distance.  The process is passive by Brownian motion.  Primary mechanism for the movement of respiratory gases, small solutes and nutrients.
Js ~ f(DC)

1. Diffusion from capillary to tissue:  Within a capillary the concentration is Cp, in the interstitium it is Ci, thus the gradient is Cp-Ci, the thickness of the endothelium is Dx, and the surface area of capillary available for exchange is S.  Also must include the mobility of the solute, the diffusion coefficient D and the solubility for the solute, a.

Js = - aD S Dc/Dx = PS (Cp -Ci)

where solute permeability coefficient P = aD/Dx: units cm/s.

NOTE:  Should a value for a not be given you may assume it equals 1.  Values for a relate solutes that are lipophilic, especially respiratory gases, anesthetic agents, and alcohols (remember that gases and alcohols can used to anesthetize: can you deduce why?).
2. Diffusion between open capillaries: The same basic process but now delivering material to more than one exchange element, so the number of vessels (n) are important as this will influence the area for exchange (A = n*S) and the distance between capillaries (DX ~ f(SQRT(n)).  So:
Js = - aDA dc/dx
a. Js  = mass/time = moles/s diffusing through a surface of n vessels, A (cm2)
b. D, the free diffusion coefficient is cm2/s
c. dc/dx, the concentration gradient, (mass/volume)/(distance) = moles/cm2 and is a function of local tissue consumption or production.
d. The flux then, since x is a function of the number of perfused vessels, will be faster if more vessels have blood flowing through them.
e. The solubility, or partition coefficient, a, in this case is unitless.
VII. Summary: Coordinated Control of blood and tissue transport
A. Recruitment: varying the number of open capillaries will regulate the delivery of solute and the removal of waste as well as vary the total area available for exchange.  Recruitment is achieved by dilation of the terminal arterioles.

B. Local Blood Flow Control:  Blood flow distribution can be controlled centrally (neural mechanisms) and at the local level.   In organs that maintain a constant flow in the face changing vascular pressure are said to "autoregulate".  To do this they have to alter vascular resistance (remember, to keep flow constant if pressure changes, resistance has to change in the opposite direction = Q = *P/R).  There are two hypotheses as to the mechanism whereby autoregulation is achieved: the Metabolic Hypothesis and the Myogenic Hypothesis

For example, if pressure increases we predict that flow should increase as well.  In autoregulating organs only a brief rise in flow is seen followed by a return to control levels.  This means that the organ tends to maintain a fairly constant condition.  Two theories to explain this phenomenon.
 1. Metabolic Hypothesis: The concentration of inhibitory metabolites in the microvascular bed depends on the level of blood flow through the bed.  When vascular pressure is increased there is a brief elevation in blood flow which removes the inhibitory metabolites allowing the resistance vessels to contract.  As they constrict, the radius decreases thereby elevating R so Q decreases.

 2. Myogenic Hypothesis:  The increase in pressure results in a quick stretch of the vessel wall thereby stimulating vascular smooth muscle to contract.  On contraction the radius is decreased, R is increased and Q decreases.


The metabolites involved in autoregulation are Adenosine, H+, and CO2.  Different organs autoregulate to greater or lesser extents and the mechanisms they use vary.  The heart, kidney and brain are examples of organs showing strong autoregulation, the splanchnic circulation hardly auto regulates at all.  In the skin what autoregulation there is appears to be largely due to myogenic mechanisms while in the heart and brain the metabolic mechanisms predominate.

There are 2 additional terms describing changes in blood flow with which you will be expected to know:
 

1. Active hyperemia:  An increase in blood flow above control levels usually induced by an increase in cellular activity (metabolism, exercise).  In this case rapidly accumulated metabolites (CO2, H+ ) result in arteriolar dilation (facilitating the opening of new capillaries), resulting in better tissue perfusion (e.g. enhanced substrate delivery and waste removal).  The dilation persists until the metabolites are removed.

2. Reactive hyperemia:  The overshoot of blood flow following an ischemic episode (decrease blood flow);  it may result from both metabolic and myogenic mechanisms acting during the period of reduced flow (metabolite accumulation and dilator response to a decreased pressure).


C. Microvessel Permeability:
Microvessel permeability can be altered by inflammatory mediators inducing the formation of leaks to macromolecules.  In addition, permeability properties can be altered less dramatically to regulate normal transport.  Recent studies from this University and others have demonstrated that many vasoactive substances, known to regulate vascular smooth muscle tone, can also regulate microvessel permeability.  At present agents which dilate vascular smooth muscle in the systemic circulation, whether by endothelium dependent or independent means, tend to increase capillary permeability to water and in some cases to solute.  These include atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), sodium nitroprusside (SNP), acetylcholine (ACh), substance P (Sub-P), bradykinin (BKN), low O2 , Adenosine (ADO), and adenosine triphosphate (ATP).

By contrast, vasoconstrictors angiotensin II (AII) and norepinephrine (NE), at low doses either do not alter basal permeability properties or attenuate the increases in permeability induced by the vasodilators.

D. Lymphatic Activity:  Just as we have recently demonstrated that vasoactive agents thought to influence only arterial vessel tone, several groups have found that these agents also regulate the activity of the lymphatics.  Vascular smooth muscle (VSM) is of two classes, phasic and tonic.  Most VSM is of the tonic variety in that it does not generate action potentials.  Phasic smooth muscle (found in the portal vein and in the lymphatics) generates action potentials like visceral smooth muscle and can thus initiate waves of contraction.  This mechanism will produce sufficient force to propel the contents of the vessel of lymphatic toward the heart.  Retrograde flow in the lymphatics is hindered by the presence of valves and nodes.  Vasodilators tend to diminish the force and frequency of lymphatic pumping (which will result in an elevated Pi ) while vasoconstrictors tend to increase the force and frequency of pumping (which will tend to decrease Pi ).