Circulatory Physiology I

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					           Circulatory Physiology I: we don't have it yet
Circulatory Physiology II: Dynamics and Control of the Body Fluids

  Circulatory Physiology III: Arterial Pressure and
                   Hypertension

                         First course

        Randy Thomas (IBISC FRE 2873 CNRS/Univ. Evry)




                      http://saphir.physiome.fr/
                                         SAPHIR:
"a Systems Approach for PHysiological Integration of Renal, cardiac, and respiratory functions"



         oxygen                                                                    thirst
                            muscles
         delivery                                        kidney
                                                                                    ADH
                                                                                   control

      local blood                                             capillary          angiotensin
         flow                                                 membrane             control
        control                   circulatory                 dynamics
                                  dynamics                                           aldosterone
                                                                                        control
       autonomic
        control                                              tissue fluids,
                                                               pressures,           electrolytes
                        pulmonary red cells,                      gel                  & cell
                        dynamics viscosity heart                                       water
      heart rate…                         hypertrophy

                                                Guyton, Coleman, Granger (1972) Ann. Rev. Physiol.

              Guyton's modular Systems Model for blood pressure regulation
                                                                                                     2
                            SAPHIR (cont.)



                                                                     Na, K, Cl,
                                                                     glucose,
                                                                     urea,
                                                                     blood pH,
                                                                     HCO3, CO2,
                                                                     O2, Ca++,
                                                                     Mg++,
                                                                     mannitol,
                                                                     blood
                                                                     hemoglobin,
                                                                     COP,
                                                                     phosphate,
                                                                     sulfate,
                                                                     NH4+



Ikeda, N., et al., "A model of overall regulation of body fluids".
       Annals of Biomedical Engineering, 1979. 7:135-166.




                                                                                   3
                         Outline




Guyton's 'engineering' approach to BP regulation
   •   Why regulate blood pressure?
   •   What are the problems for BP control?
   •   The hierarchy of pressure control systems.
   •   Relevant principles of Control Theory
   •   Quantitative evaluation of all aspects of BP
       regulation: the Guyton model(s)




                                                      4
          1. Guyton's 'engineering' approach to BP regulation
Why does the body need to regulate blood pressure?

1. To ensure adequate blood flow to each organ
   •   autoregulation of individual organs works best with a
       steady pressure at input
   •   SO - the Most important function of BP regulation is to
       MAINTAIN A STEADY PRESSURE HEAD
2. (corollary of (1)): avoid interference/competition among
   the organs for blood supply
   •   e.g., in sympathectomized dogs, exercise leads to
       dramatic fall of BP in the brain..
3. Adjust BP to bodily needs (sleep, exercise…)
4. Keep BP high enough to supply all organs (>80mmHg),
   but low enough to avoid damage to the vascular system



                                                                 5
          1. Guyton's 'engineering' approach to BP regulation
          What are the problems for control?


1. Maintain an appropriate long-term baseline level of BP.
   •   this role is assured almost entirely by the kidneys, which
       control blood volume and extracellular fluid volume
2. Provide appropriate short-term changes in the circulatory
   system in the face of the many acute stresses we
   encounter
   •   entirely independent of blood volume changes (too slow)
   •   must ensure adequate perfusion of all organs, but esp. the
       brain and the heart
   •   depends on controlling strength of the heart, capacity of
       blood vessels, and total peripheral resistance (TPR)
   •   accomplished via nervous control and hormonal signals



                                                                    6
               1. Guyton's 'engineering' approach to BP regulation
        The hierarchy of pressure control systems.

1. The two major parameters of BP control: TPR and CO
   Art. Press. = Cardiac Output X Total Peripheral Resistance + Right atrial pressure

   -- but this simplistic approach is "useless"!
2. The body's approach: a hierarchy of short- and medium-term damping
  and long-term control
   • short-term (seconds to minutes)
            • cardiovascular reflexes mediated by the nervous system

   • intermediate-term (minutes to hours)
            • capillary fluid shift from circulation to interstitial fluid
            • delayed compliance of the vasculature
            • hormonal controls (angiotensin, vasopressin,..)

   • long-term (hours, days, weeks..)
            • in response to numerous signals from elsewhere in the body, the
              kidney manages overall fluid and solute balance, which determines the
              baseline level of blood pressure … --> with INFINITE GAIN!

                                                                                        7
1. Guyton's 'engineering' approach to BP regulation
The hierarchy of pressure control systems




from Guyton, A. C. (1980). Circulatory Physiology III. Arterial
   Pressure and Hypertension. Philadelphia, W.B. Saunders.        8
1. Guyton's 'engineering' approach to BP regulation
The hierarchy of pressure control systems.




from Guyton, A. C. (1980). Circulatory Physiology III. Arterial
   Pressure and Hypertension. Philadelphia, W.B. Saunders.        9
               1. Guyton's 'engineering' approach to BP regulation
                 Relevant principles of Control Theory


Three types of control:
    - proportional feedback
    - integral feedback
    - feed-forward control


Quantitative modeling, using
control systems diagrams:




                                        Guyton, A. C. (1980). Circulatory Physiology III. Arterial
                                        Pressure and Hypertension. Philadelphia, W.B. Saunders.
                                                                                                     10
                         1. Guyton's 'engineering' approach to BP regulation
                           Relevant principles of Control Theory -2




Gain:
   (max-final)/(final-normal)




 Guyton, A. C. (1980). Circulatory Physiology III. Arterial Pressure and Hypertension. Philadelphia, W.B. Saunders.
                                                                                                                      11
                        1. Guyton's 'engineering' approach to BP regulation
                          Relevant principles of Control Theory -2


    Infinite Gain of the Kidney-blood volume feedback control system




Guyton, A. C. (1980). Circulatory Physiology III. Arterial Pressure and Hypertension. Philadelphia, W.B. Saunders.
                                                                                                                     12
        Modular systems-model of blood pressure: Kidney module


          INPUTS
AUM: sympathetic
vasoconstrictor effect on
arteries
VIM: Blood viscosity
                                   afferent,                                 volume
                                   efferent,                               reabsorption
PA: aortic pressure                                 glomerular
PPC: plasma COP
RBF: Renal Blood Flow               & total          filtration
REK: percent of normal
renal function
                                   resistanc
CNE: third factor effect               e
AHM: ADH multiplier                                                            sodium
AM: aldosterone multiplier
                                                                              excretion
         OUTPUTS
NOD: rate of renal Na+
excretion
VUD: rate of urine output
                                               renal blood flow
                                                                                                    CNE
                             AUM                                                                     AHM
                                                                                                     AM
                                          VIM   PPC                  REK
                                             PA             RBF                           NOD
                                                                                            VUD
                 Guyton, A.C., T.G. Coleman, and H.J. Granger, "Circulation: Overall regulation."
                                 Annual Reviews of Physiology, 1972. 34:13-44.

                                                                                                           13
      The Infinite-Gain feature of the
kidney - blood volume - pressure regulator:

       The (acute) renal function curve




from Guyton, A. C. (1980). Circulatory Physiology III. Arterial
   Pressure and Hypertension. Philadelphia, W.B. Saunders.        14
           The Infinite-Gain feature of the
     kidney - blood volume - pressure regulator:

The (acute) renal function curve and Net sodium intake




      from Guyton, A. C. (1980). Circulatory Physiology III. Arterial
         Pressure and Hypertension. Philadelphia, W.B. Saunders.        15
      The Infinite-Gain feature of the
kidney - blood volume - pressure regulator:

The acute vs. chronic renal function curves




from Guyton, A. C. (1980). Circulatory Physiology III. Arterial
   Pressure and Hypertension. Philadelphia, W.B. Saunders.        16
      The Infinite-Gain feature of the
kidney - blood volume - pressure regulator:

    Shifting the Renal Function Curve…




from Guyton, A. C. (1980). Circulatory Physiology III. Arterial
   Pressure and Hypertension. Philadelphia, W.B. Saunders.        17
Several renal transporters implicated in health problems

                     ENaC

                         TSC



                                          AQP2-3




                                           ROMK1
                                           NKCC2
                                            CaSR




             AQP1
             UT-B
                                      ClC-Ka
                     AQP1
                     UT-A2      AQP2-4
                               UT-A1,A3




                                                           18
Distal Tubule JNa too high --> Hypertension




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http://saphir.ibisc.fr/




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