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

1. Circulatory Physiology I: we don't have it yet Circulatory Physiology II: Dynamics and Control of the Body FluidsCirculatory Physiology III: Arterial Pressure and HypertensionFirst course Randy Thomas (IBISC FRE 2873 CNRS/Univ. Evry) http://saphir.physiome.fr/

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

3. 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.

4. 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)

5. 1. Guyton's 'engineering' approach to BP regulationWhy does the body need to regulate blood pressure? • 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 • (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.. • Adjust BP to bodily needs (sleep, exercise…) • Keep BP high enough to supply all organs (>80mmHg), but low enough to avoid damage to the vascular system

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

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

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 The hierarchy of pressure control systems. from 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 • 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. 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. 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. afferent, efferent, & total resistance renal blood flow volume reabsorption glomerular filtration sodium excretion Modular systems-model of blood pressure: Kidney module 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 CNE AHM AUM AM VIM PPC REK RBF NOD PA VUD Guyton, A.C., T.G. Coleman, and H.J. Granger, "Circulation: Overall regulation." Annual Reviews of Physiology, 1972. 34:13-44.

14. The Infinite-Gain feature of thekidney - 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. The Infinite-Gain feature of thekidney - 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.

16. The Infinite-Gain feature of thekidney - 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. The Infinite-Gain feature of thekidney - 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. 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

19. Distal Tubule JNa too high --> Hypertension

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