Physiological regulatio n in pathogenesis cardiovascular disease and in general

1. Physiological regulation in pathogenesis cardiovascular disease and in general Stanislav Matoušek, M.D.

2. Regulated and unregulated variable Unregulated variable Regulated variable Cold café Hypertension • Fallen bridge • Broken leg

3. What are we going to cover? • 1. Basicterminology of regulation theory • 2. Typesof feedback loops in the body (positive, negative) • 3. Origin of disturbance/diseaseinregulatedsystem • 4. History of regulated systems and their description • 5. Different types ofgovernors (automated regulators) • 6. Regulation of cardiac outputandblood pressure • heart • vessels • kidney regulator

4. Basic terminology

5. Regulation or (automatic) control • if an environmental variable (such as temperature) ....changes and the system can nearly compensate for those changes ...then the system is said to be regulated. • Principia cybernetica web • Regulation is every process that minimizes differencebetween the realand the desired (reference) value of the regulated variable. Zdenek Wunsch, Basics of medical cybernetics (1977) in Czech

6. Regulation valve of central heating Open-loop regulation Feedback regulation Output signalof the controlled system is measured and fed back for use in the control computation. Regulator does not measure output variable (temperature) when it „computes“ the control action to take.

7. Open loop temperature/ °C time / hours

8. Open loop temperature/ °C time / hours

9. Open loop temperature/ °C Error of the output variable Outside disturbance time / hours

10. Feedback temperature/ °C time / hours

11. Feedback temperature/ °C time / hours

12. Feedback temperature/ °C Error of the output variable Outside disturbance time / hours

13. The Effect of Feedback temperature/ °C The output error is (5x) smaller then without the feedback time / hours

14. Open loop vs. closed loop Open loop regulated system: Feedback (=closed loop) regulated system:

15. Feedback in physiology

16. RAAS system

17. General structure of control system

18. Room temperature regulation Outside temperature Room temperature Set tem-perature Heater body Heating Hot water valve open/closed Thermostat setting vs. actual temperature Thermo-meter Measured temperature

19. Examples in physiology Regulation of blood sugar Normal glycemia β cell Insulin Glycemia GLUT 4 tissue cell Glc upta ke β cell

20. Types of feedback in the body (positive, negative)

21. Regulation in human body • There are two systems specialized in control and regulation in the body: • endocrine system • nervous system • Besides these two, every cell and tissue has many local feedback regulated processes

22. Local regulation

23. Systemic regulation

24. Negative feedback Keeps the value of the regulated entity close to the equilibrium. Ca++ - + PTH

25. Positive feedback Rare – amplification of small original „disturbance“; Does not create any equillibrium Kalikrein Prekalikrein + + + + faktor XII faktor XII a

26. Disturbance/disease in regulated system (body)

27. Diabetes mellitus Diabetes type II Normal glycemia Insulin βcells Glycemia - Glc entering cells GLUT 4 in tissue + βcells Diabetes type I

28. Disease in general • Block in the feedback loop • Too high a disturbance • „Weak actuator“ • Incorrectly set reference point

29. History of regulation and feedback control

30. Float valve of ancient Greece and Rome. History in engineering

31. Steam Engine by James Watt

32. James Watt – fly-ball governor 1788

33. System stability

34. Maxwell stability criteria Problem of long-distance telephoning (use of electronic amplifiers) Bell Telephone Laboratories: H. Nyquist (1932) Nyquist criterium of stability 20 century

35. Today

36. History in biological sciences • Living organism’s ability to keep life processes in balance and thus confront the disturbances is so apparent that was already noted in Antiquity. Zdenek Wunsch in Basics of Medical Cybernetics Another important aspect seen as a source of diseases are the organism’s internal imbalances. This idea, while surely correct in its essence, is remarkably trans-cultural. Stanislav Komarek in Salvation of the Body

37. Ancient Greece • Empedocles from Agrigent (504-443 BC)

38. Ancient Rome Galenos

39. Ancient China

40. Late 18th century and 19th century Lavoisier: Dynamic balance of known substances in metabolism (oxygen, food compounds, heat) is needed in body Fredericq (1885): Living organism is a system able to respond to disturbing influence by a compensatory activity that neutralizes or repairs the developing perturbation. The higher the level of the living organism, the more common, more perfect and more complicated these regulatory activities become.

41. Homeostasis – Walter Cannon • from the earlier idea of Claude Bernard of milieu interieur, • popularized it in his book The Wisdom of the Body,1932. • Four general features of homeostasis: • Constancy in an open system, such as our bodies represent, requires mechanisms that act to maintain this constancy. • Steady-state conditions require that any tendency toward change automatically meets with factors that resist change. An increase in blood sugar results in thirst to dilute the sugar. • The regulating system -number of cooperating mechanisms acting simultaneously or successively. e.g. Blood sugar is regulated by insulin, glucagons, and other hormones, thirst. • Homeostasis is the result of organized self-government.

42. Cybernetics – Norbert Wiener • 1948 bookCybernetics: Or Control and Communication in the Animal and the Machine. • The book formalizes the notion of feedbackand has gained large influence in many fields: control engineering, computer science, biology, philosophy, sociology and philosophy.

43. Advent of computational biology – Arthur Guyton and Thomas Coleman

44. Thomas Coleman and laboratory of biocybernetics of our institute

45. Little intermezzo

46. Reminder of high-school calculus

47. Derivative

48. Important functions

49. Integral

50. Different types of governors / controllers