1. Randy Thomas (IBISC FRE 2873 CNRS/Univ. Evry) 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 http://saphir.physiome.fr/

2. 2 Guyton, Coleman, Granger (1972) Ann. Rev. Physiol. kidney muscles circulatory dynamics capillary membrane dynamics thirst ADH control angiotensin control aldosterone control electrolytes & cell water tissue fluids, pressures, gel red cells, viscosity autonomic control pulmonary dynamics local blood flow control oxygen delivery heart rate… heart hypertrophy SAPHIR: " a Systems Approach for PHysiological Integration of Renal, cardiac, and respiratory functions " Guyton's modular Systems Model for blood pressure regulation

3. 3 SAPHIR (cont.) Ikeda, N., et al., "A model of overall regulation of body fluids". Annals of Biomedical Engineering, 1979. 7:135-166. Na, K, Cl, glucose, urea, blood pH, HCO3, CO2, O2, Ca++, Mg++, mannitol, blood hemoglobin, COP, phosphate, sulfate, NH4+

4. 4 Outline Guyton's 'engineering' approach to BP regulation Why regulate blood pressure?Why regulate blood pressure? What are the problems for BP control?What are the problems for BP control? The hierarchy of pressure control systems.The hierarchy of pressure control systems. Relevant principles of Control TheoryRelevant principles of Control Theory Quantitative evaluation of all aspects of BP regulation: the Guyton model(s)Quantitative evaluation of all aspects of BP regulation: the Guyton model(s)

5. 5 Why does the body need to regulate blood pressure? 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 inputautoregulation 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 HEADSO - 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..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

6. 6 What are the problems for control? 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 volumethis 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)entirely independent of blood volume changes (too slow) must ensure adequate perfusion of all organs, but esp. the brain and the heartmust 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)depends on controlling strength of the heart, capacity of blood vessels, and total peripheral resistance (TPR) accomplished via nervous control and hormonal signalsaccomplished via nervous control and hormonal signals

7. 7 The hierarchy of pressure control systems. 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"! -- 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) short-term (seconds to minutes) cardiovascular reflexes mediated by the nervous systemcardiovascular reflexes mediated by the nervous system intermediate-term (minutes to hours) intermediate-term (minutes to hours) capillary fluid shift from circulation to interstitial fluidcapillary fluid shift from circulation to interstitial fluid delayed compliance of the vasculaturedelayed compliance of the vasculature hormonal controls (angiotensin, vasopressin,..)hormonal controls (angiotensin, vasopressin,..) long-term (hours, days, weeks..) 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!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!

8. 8 The hierarchy of pressure control systems 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. 9 The hierarchy of pressure control systems. 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.

10. 10 Relevant principles of Control Theory 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.

11. 11 Relevant principles of Control Theory -2 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.

12. 12 Relevant principles of Control Theory -2 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.

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

14. 14 The Infinite-Gain feature of the kidney - blood volume - pressure regulator: The (acute) renal function curve 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.

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

16. 16 The Infinite-Gain feature of the kidney - blood volume - pressure regulator: The acute vs. chronic renal function curves 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.

17. 17 The Infinite-Gain feature of the kidney - blood volume - pressure regulator: Shifting the Renal Function Curve… 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.

18. 18 Several renal transporters implicated in health problems AQP2-4 UT-A1,A3 AQP1 UT-A2 AQP1 UT-B ROMK1 NKCC2 CaSR AQP2-3 TSC ClC-Ka ENaC

19. 19 Distal Tubule J Na too high --> Hypertension

20. 20 http://saphir.ibisc.fr/