The Capillary by MikeJenny

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									                                          The Capillary

I.      Body fluid compartments
        A.     Distribution of body water
               1. Body fluids are apportioned between intracellular, interstitial, and vascular
                   (plasma) compartments (Fig 1).
               2. The plasma and interstitial compartments together constitute the extracellular
                   fluid.

      Fig.1
                      Plasma      Interstitial             Intracellular Fluid
                                    fluid
                      ~3 L         ~12 L                        ~25 L




                          Capillary           Cell membrane

       B.      Capillary diffusion
               1. The capillary is formed from a single layer of endothelial cells.
               2. The driving force for solute movement is a concentration gradient.
               3. The lipid bilayer of the endothelial cell membrane forms a barrier to diffusion
                  of hydrophilic molecules. These cross the capillary wall primarily by diffusing
                  through the intercellular channels (Fig. 2). Water crosses the capillary
                  membrane through both intercellular channels and specialized water channels
                  (aquaporins) in the endothelial cell membrane.
               4. Lipophilic solutes, which include the respiratory gases, diffuse very rapidly
                  across the endothelial cell membranes.

                                           Electrolytes,              O2, CO2,
                                           hydrophilic solutes        lipophilic solutes

     Fig. 2                     Capillary endothelial
                                        cell



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B.   Osmotic relationships
     1. As a consequence of ion pumps and selective permeabilities in cell
        membranes there are differences in concentration between intracellular and
                                                                              -
        extracellular compartments with respect to major solutes (Na+, K+, Cl , etc.).
     2. The capillary is relatively non-selective in its permeability properties. Low
        molecular weight solutes pass through readily; protein molecules are the only
        ones with restricted permeability.
     3. Thus interstitial fluid has almost the same composition as plasma, except for
        the higher protein concentration in plasma.
     4. Cell membranes (and capillaries) are highly permeable to water, so the
        extracellular and intracellular compartments are in osmotic equilibrium; i.e.
        the extracellular fluid is isotonic with respect to intracellular fluid. Tonicity
        is an expression of the relative osmotic pressure difference between
        compartments. If the solute concentration of the extracellular fluid is
        increased (ingest salt) the extracellular compartment will become hypertonic
        with respect to the intracellular compartment and water will leave the cells. If
        the solute concentration of the extracellular fluid is reduced (ingest pure
        water) the extracellular fluid will become hypotonic with respect to the
        intracellular compartment and water will enter the cells.
     5. Osmolarity is a measure of the absolute concentration of osmotically active
        particles. A solution of one mole/liter of non-dissociable solute is equivalent
        to 1 osmole/liter (1 Osm). Normal osmolarity of body fluids is about 300
        mOsm. The osmotic pressure of a 1 Osm solution is 22.4 Atm, or 22.4 x 760
        = 17,024 mmHg. Thus a 300 mOsm solution has an osmotic pressure
        equivalent of 17,024 x 0.3 = 5,107 mmHg.
C.   Osmotic forces at the capillary
     1. The only molecular species for which there is a significant asymmetry
        between the plasma and interstitial fluid is protein. All of the other solutes,
                                                                             -       -
        which make up the major component of plasma osmolarity (Na+, Cl , HCO3 ),
        are present in approximately equivalent concentrations on both sides of the
        capillary membrane.
     2. Hence differences in protein concentration provide the only osmotic driving
        force at the capillary level.
     3. The plasma protein concentration is about 7 gm/100 cc plasma (7 gm%). The
        osmotic pressure generated by this protein is known as the oncotic pressure
        and is in the range of 25-28 mmHg.


                                      2
              4. Since the molar concentration of protein in the plasma is very low ( 1mM)
                  the protein accounts for only a very small fraction of the total osmolarity of
                  the plasma. Changes in plasma protein concentration affect oncotic pressure
                  but not osmolarity.
II.     Formation of interstitial fluid
        A.    The capillary-lymphatic system
              1. Assuming a cardiac output of about 5 L/min it can be calculated that during a
                  24 hour period some 4000-5000 liters of plasma flow through the systemic
                  capillaries.
              2. Of this large volume, there is a net transfer of 2-4 liters/day of relatively
                  protein-free fluid that passes through the capillary membranes into the
                  interstitial space.
               3. If plasma volume is to remain constant an equivalent volume of fluid must be
                  returned to the vascular compartment. This is the function of the lymphatic
                  system.
               4. The lymphatic vessels originate as closed-ended tubes in close proximity to
                  capillaries. As they travel centrally the lymph channels coalesce to form the
                  major lymph ducts (thoracic duct, right lymph duct) which connect to the
                  venous system in the thorax.
               5. Thus in the steady state the rate of interstitial fluid formation is equal to the
                  rate of lymph flow into the circulation (Fig 3).

      Fig. 3
                                                         Heart
                       Systemic
                         veins
                                                                                        Systemic
                  Lymph                                                                  arteries
                  vessels
                                                     Capillaries
             Lymph
         flow, 2-4L/day
                                                                        Interstitial fluid
                                                                     production, 2-4L/day




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          B.     Mechanics of lymphatic return
                 1. The rate of entry of interstitial fluid into the terminal lymphatics is a function
                     of the interstitial fluid hydrostatic pressure.
                 2. Lymph flow is mainly driven by rhythmic contraction of smooth muscle in the
                     walls of the larger lymph vessels. The lymph vessels contain valves, similar
                     to venous valves, which maintain a unidirectional flow.
                 3. Lymph flow is strongly facilitated by external compression, such as with
                     contraction of skeletal muscles.
III.      Transcapillary fluid exchange
          A.     General considerations
                 1. The magnitude and direction of fluid flow across the capillary is determined
                    by the sum of oncotic and hydrostatic pressures across the capillary wall.
                 2. The hydrostatic pressure inside the capillary (PC) is greater than the
                    hydrostatic pressure in the interstitial space (PIF) and thus provides a driving
                    force for filtration.
                 3. The oncotic pressure in the capillary (C) is greater than the oncotic pressure
                    of the interstitial fluid (IF) and thus provides a driving force for reabsorption
          B.     Quantitative treatment (Fig. 4)
                 1. The net hydrostatic pressure difference (P) between the plasma and
                    interstitial fluid is PC - PIF.
                 2. The net oncotic pressure difference () between the plasma and interstitial
                    fluid is C - IF.
                 3. The magnitude and direction of flow (F) is a function of the net pressure
                    gradient, or F = K(P - ).
                 4. This expression can be expanded to
                    F = K[(PC - PIF) - (C - IF)] , or
                    F = K(PC - PIF - C + IF) (Starling equation)
                 5. The proportionality constant, K, is the hydraulic conductance of the capillary
                     (capillary filtration coefficient).

                    Arteriole                     Capillary                      Venule
       Fig. 4
                                      Pc = 20                 c =25
                                                              25 25
                                       Pif = -4                if = 5
                                                                            Lymph


                                                     4
     C.   Hydrostatic pressures
          1. By direct micropuncture techniques it has been shown that the mean capillary
             hydrostatic pressure is in the range 20-25 mmHg.
          2. As a consequence of frictional resistance along the length of the capillary the
             pressure at the arterial end is 10-15 mmHg higher than it is at the venous end.
          3. The rate of transcapillary fluid movement (in either direction) is a linear
             function of PC. Flow is zero at that point where net hydrostatic and oncotic
             pressures are equal (Fig. 5).




               Filtration
Fig. 5
                         +
                         0
          Reabsorption_             10       15   20    25     30 35 40
                                                                 Pc, mmHg




          4. The value of the hydrostatic pressure in the interstitial space is less certain
              because of technical difficulties in measuring it. The best estimates indicate
             that it is subatmospheric, with values ranging from -1 to -5 mmHg. However
             there is some variability in this regard. PIF is generally less than zero in
             muscle, lung, and subcutaneous connective tissues. PIF tends to be greater than
             zero in tissues in which absorptive epithelia transport large quantities of water
             into the interstitial spaces (GI tract, kidney).

     D.   Oncotic pressures
          1. The plasma oncotic pressure is 25-28 mmHg.
          2. The interstitial fluid oncotic pressure varies depending on the protein
             permeability of the particular capillary bed. A value of 5 mmHg would be
             typical for skeletal muscle.
          3. The oncotic pressure is not a simple linear function of the protein
             concentration, as would be expected from the Van’t Hoff law for ideal
             solutions (Fig. 6) ( = cRT, where c is solute concentration).




                                             5
Fig. 6                 60
          oncotic            Normal plasma
          pressure,
                       40
           mmHg
                       20
                                                     Predicted by
                         0                           Van’t Hoff law, =cRT
                             0   2    4    6      8 10 12 14 16
                                               [Protein], g/100 cc



           4. When C is plotted as a function of plasma protein concentration the curve
              deviates upward (Fig. 6). Thus with a normal plasma protein concentration of
              ~7 gm/100 cc plasma the oncotic pressure is 30-40% higher than would be
              expected on the basis of the Van’t Hoff law.
           5. This upward deviation is due to a Gibbs-Donnan effect. At physiological pH
              protein molecules have a high negative charge, obligating the presence of
              positively charged counterions to remain with them. Thus per unit volume of
              plasma the total number of osmotically active particles is considerably greater
              than the number of protein molecules.
     E.    Balance of forces at a typical capillary
           1. Assume a typical case where C is 25 mmHg, IF is 5 mmHg, and PIF is
              -3 mmHg
           2. Assume that the value of PC is 25 mmHg at the arterial end of the capillary
              and 10 mmHg at the venous end of the capillary (Fig 7).
           3. The filtration pressure at the arterial end of the capillary is 8 mmHg whereas
              the filtration pressure at the venous end is -7 mmHg.
           4. Thus, on the average, there is a net filtration pressure of ~1 mmHg which
              accounts for the daily production of 2-4 L of interstitial fluid.




                                           6
                           Arterial end                           Venous end
                               Pc       25                        10
Fig. 7
                               c       25                        25
                               Pif       -3                        -3
                              if        5                          5
                            25 - (-3) = 28                10 - (-3) = 13
                              25 - 5 = 20                    25 - 5 = 20
                                      +8                              -7
                 Net filtration pressure = 1mmHg                        Lymphatic capillary


      F.    Determinants of capillary hydrostatic pressure (PC)
            1. The value of PC is essentially determined by the volume of blood in the
               capillaries.
            2. The latter is a function of the rate of flow into the capillary and the rate of
               flow out of the capillary.
            3. The resistance to the flow of blood from arteries into the capillaries (pre-
               capillary resistance) is 5-8 times greater than the resistance between capillaries
               and veins (post-capillary resistance).
            4. Consequently, all other things being equal, a rise in venous pressure will have
               a much greater effect on PC than an equivalent rise in arterial pressure.
            5. PC is also sensitive to the radii of the pre-capillary resistance vessels. Thus
               arteriolar dilation causes PC to increase and arteriolar constriction causes PC
               to decrease.
            6. In summary, the most important physiological determinants of PC are
                a. venous pressure
                b. arteriolar resistance
IV   Perturbations of transcapillary fluid exchange
     A.     General considerations
            1. Under normal conditions the distribution of extracellular fluid between plasma
               and interstitial compartments is fairly constant.
            2. This distribution involves a dynamic balance between capillary filtration,
               capillary reabsorption, and lymphatic removal of interstitial fluid.
            3. Excessive accumulation of fluid in the interstitial space is termed edema.




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     4. Edema can occur through either an increase in the rate of formation of
        interstitial fluid or a reduction in the rate of fluid removal from the interstitial
        space.
B.   Significance of the negative interstitial hydrostatic pressure
     1. The hydrostatic pressure in the interstitial space reflects the volume of fluid in
        this space.
     2. The negative pressure is maintained as a consequence of
        a. capillary reabsorption driven by the oncotic pressure gradient
        b. imbibition of fluid by the extracellular matrix gel
        c. lymphatic removal of interstitial fluid (quantitatively the most important
            factor)
     3. Edema will not occur so long as the rate of lymphatic flow can keep pace with
        the rate of fluid filtration.
     4. Increased net filtration can be produced by either an increase in PC or a
        decrease in C.
     5. Provided that the pressure in the interstitial space is subatmospheric there will
         be no visible edema. The tightly compacted cells with their dense
         extracellular matrix render the interstitial compartment very non-compliant.
         That is, it cannot accommodate an increase in volume without a large increase
         in PIF.
      6. However, once enough fluid enters the interstitial space to elevate PIF
        above zero the cells separate and the interstitial space can then accommodate
        a large volume with little change in pressure (interstitial compliance
        increases).
C.   Role of the lymphatic system
     1. Lymph flow is critical in maintaining a relatively constant interstitial fluid
        volume.
     2. An important function of the lymphatic system is to remove protein from the
        interstitial space.
     3. There is a continual slow leak of protein from the capillaries and if the
        interstitial space in a localized region becomes a static compartment there will
        be an eventual dissipation of the transcapillary protein concentration gradient.
     4. Thus obstruction of lymphatic channels produces edema through both
        a. reduced rate of fluid removal
        b. reduction of the oncotic pressure gradient.



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         D.   The capillary filtration coefficient (K)
              1. The capillary filtration coefficient reflects the ease with which water
                 molecules flow through the capillary wall in response to a given pressure
                 gradient.
              2. The value of K is determined by both the absolute permeability of the capillary
                 and the surface area available for filtration. Thus factors which can change the
                 number of open capillaries (vasoconstriction, vasodilatation) will also change
                 the value of K.
            3. Large increases in K can occur as a result of chemical and physical injury to
               capillaries (inflammation, burns).
V.   The pulmonary capillary
     A.     Hydrostatic and oncotic pressure
            1. Pulmonary capillaries differ from most systemic capillaries in that:
               a. being part of a low pressure system, the mean value of Pc is much lower
                  (~10 mmHg) than it is in systemic capillaries.
               b. the pulmonary capillary is much more permeable to protein, so that IF is
                     quite high (~19 mmHg).
              2. Inserting typical values into the Starling equation it is seen that there is a net
                 positive filtration pressure favoring the continual flow of fluid into the
                 interstitial compartment (Fig. 8).
              3. The lung has a well-developed lymphatic system which can, over a wide
                 pressure range, remove interstitial fluid as fast as it is formed. As long as
                 lymph flow can match the rate of capillary filtration the fluid content of the
                 lungs will remain unchanged.




                                                             c = 25
Fig. 8          Capillary          Pc = 10


                                   Pif = -3                  if = 19
                                                                                           Lymph
              Interstitial space
                                              Alveolar space




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        B.     Capillary hydrostatic pressure and lung fluid content
               1. There is only a small resistance between the pulmonary capillary and the left
                  atrium; hence left atrial pressure is a reasonably close approximation to
                  pulmonary Pc.
               2. Over the left atrial pressure range 0-25 mmHg the fluid content of the lung is
                  constant. Within this range lymph flow can keep pace with filtration as Pc
                  rises.
               3. With pressures in excess of ~25 mmHg capillary filtration rate exceeds
                    maximum lymph flow, marking the onset of pulmonary edema (Fig. 9).

      Fig. 9
                             9
                             8
               Lung water
                             7
                content,
                             6
               wet wt/dry wt
                             5
                             4
                             3

                                     0     10        20       30   40
                                     40 Left atrial pressure, mmHg


Suggested reading

Berne, R.M. and Levy, M.N., Principles of Physiology, chap. 22.




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