THE AUSTRALIAN NATIONAL UNIVERSITY

1. THE AUSTRALIAN NATIONAL UNIVERSITY Neural Regulation ofBlood PressureChristian StrickerAssociate Professor for Systems PhysiologyANUMS/JCSMR - ANUChristian.Stricker@anu.edu.auhttp://stricker.jcsmr.anu.edu.au/BPControl.pptx

3. Aims The students should • know the sensors, integrators and effectors of the regulating reflexes; • be cognisant of the anatomy of the reflex pathways; • understand which and how the three system parameters HR, SV and TPR are regulated; • be able to explain the nature and effect of the arterial baroreflex (AB) and the cardiopulmonary reflexes (CP); • realise that AB controls HR, SV and TPR, and CP mainly venous return; • know how AB establishes beat-to-beat control; and • appreciate how these reflexes can be modulated by respiration and asphyxia/shock.

4. Contents • Overview of control of blood pressure • Principles of negative feedback • Regulated variables • Arterial baroreflex (AB) • Components: detectors (high pressure baroreceptors) and afferents, efferents (sympathetic and parasympathetic output to cardiovascular system), integrator. • Cardiopulmonary reflexes (CP) • Low pressure baroreceptors • Atrial stretch and release of ANP • Respiratory and chemoreflex modulation of baroreflex activity.

5. Topic Coverage • In this session, we ONLY look at BP control on the short-term (seconds). • Long-term BP control via volume control will be done in relation to kidney (see later “Volume regulation”). • How vessels locally regulate resistance will be subject of the next lecture.

6. Overview of BP Control • In Block 1, mean arterial pressure was defined as is mean arterial pressure (MAP), TPR total peripheral resistance, CO cardiac output, SV stroke volume and HR heart rate. • controlled by 3 variables: TPR, SV and HR. • Which system can control these parameters? • Autonomic nervous system: • HR: sympathetic (+), parasympathetic (-; vagal) at level of heart • SV: sympathetic (+), parasympathetic (-) at level of heart; sympathetic (+) at the level of TPR (afterload); and others. • TPR: sympathetic (+) ONLY at level of vessels (and other factors like volume, etc.).

7. Principles of Feedback Control • Positive and negative feedback. • Feed-forward: central command before exercise starts. • Functional characteristic is feedback time: from few 100 ms to hours or even longer.

8. Overview of Reflex Control Levick, 5th ed., 2010 • Two reflexes involved: • arterial baroreflex (AB) and • cardio-pulmonary reflexes (CP). • Modulated by respiration, chemoreceptors and muscle activity.

9. Arterial Baroreceptor Reflex (AB) Mostly negative feedback to brainstem, sympathetic nervous system and heart: Depressor reflex. If BP↑ → HR↓, SV↓, TPR↓ and vice versa if BP↓. Most important contributor to short-term homeostatic control of BP (s - min).

10. Locations of AB Sensors Levick, 5th ed., 2010 • Pressoreceptors in aortic arch and carotid sinus. • Afferent nerves: IX (carotid sinus) & X (aortic arch).

11. AB Sensor Properties Modified from Levick, 5th ed., 2011 • True mechanoreceptors (wall tension in vessel). • Sensitive over large BP range • Low pressure range: A-fibres; high pressure range: C-fibres. • Linear response in “normal” range. • Respond better to pulsatile than steady pressure: adaptation under steady (static) conditions, much less under pulsatile (dynamic): poor at relaying absolute BP information.

12. AB Set-Point and Sensitivity • Set-point = maximal slope in HR vs BP plot. • Maximal sensitivity 80 – 100 torr. • Exercise resets set-point: work in higher range without incurring depressor response; i.e. at same BP, a higher HR can be achieved. • Reset in proportion to work intensity. • AB active but HR is per-mitted to increase (muscle spindles). Levy, 5th ed., 2010

13. AB Efferent Activity • SY output over whole sympathetic chain (T1 – L3). • Parasympathetic output via VA and lumbosacral cord (S2 – S4). • Both systems are activated wholly. • VA and SY outputs act together but in opposite directions: • VA↓ → SY↑ or • VA↑ → SY↓. • For > 180 torr, VA is maximised and SY minimised. Kollai & Koizumi, Pflügers Arch (1989), 413:365-371

14. Central AB Pathways Levick, 5th ed., 2010 • Control area in brainstem (several nuclei) receives input from / sends outputs to many brain parts (hypothalamus). • VA relay simpler (NTS → NA) than that of SY pathway.

15. Medullar Interactions Levick, 5th ed., 2010 • VA→ SY inhibition (dashed lines) via • caudal inhibiting rostral vasopressor area (via GABA) and • raphe nucleus to spinal cord (via serotonin).

16. AB Function • AB helps to stabilise BP control beat by beat (fast response) within narrow range – if taken away, BP fluctuates widely. • Effect via VA↑ and SY↓ activity when BP↑: HR↓, SV↓ and TPR↓ and vice versa. • VA and SY work together in opposite direction. • During exercise, set-point shifted such that BP can rise without HRinhibition. • Can be modulated via inputs from respiratory and other centres. • Activated in orthostasis, dehydration, blood loss, shock, etc.

17. Cardiopulmonary Reflexes (CP) Collection of various reflexes based on sensor types. Low-pressure receptor reflexes. Most afferent input is also inhibitory. Work predominantly on VR

18. Cardiopulmonary Reflexes (CP) • Cardiac de-afferentiation (transplant) reveals tonic inhibition of HR and TPR only. • Intracoronary injection of solute causes bradycardia, vasodilation and hypotension: • Depressor reflex • Important to know some specific reflexes as some can cause only SY↑ activity: • Activation of veno-atrial stretch receptors causes tachycardia and diuresis.

19. Locations & Types of CP Sensors Levick, 5th ed., 2010 • Mostly small, unmyelinated (80%) fibres from • cardiac mechano-receptors (wall tension in ventricle); • ventricular chemosensors (mediate pain via SY fibres): SY activity↑; • coronary artery baroreceptors (perfusion pressure); and • Some myelinated (20%): veno-atrial mechanoreceptors.

20. 2. Veno-Atrial Stretch Receptors • Measure atrial blood volume, i.e. central venous pressure/volume in low pressure part of circulation (central veins, atria); control venous return (VR). • Upon activation (via infusion - ‘Bainbridge effect’) • tachycardia: SY activity↑ to SA node without change inVA activity; and • diuresis and natriuresis: control of blood volume via renal vasodilation (renal Na+ excretion↑), anti-diuretic hormone release↓ (hypothalamus) and release↑ of atrial natriuretic peptide (ANP) by atrial cells. • Part of long-term volume regulation response (see volume control in kidney section, later).

21. Modulation by Respiration & Arterial Chemoreceptors

22. Respiratory Modulation • During inspiration, HR↑: • Inspiratory centre inhibits vagal output (motoneurones shortly unresponsive to AB input) → disinhibition of SA node → HR↑. • Converse is true during expiration. • Emotional faint: VA output↑ → HR↓↓. Levick, 5th ed., 2010

23. Arterial Chemoreceptors (+) • Carotid and aortic bodies (see respiration, later): sense and . • If < 80 torr (asphyxia, clinical shock, …): • TPR↑ as renal, splanchnic and muscle vascular beds are constricted; • Splanchnic veins constrict → pooling↓ → PMSF↑ → SV↑ → CO↑. • BP↑ as TPR↑ and CO↑. • Tachycardia due to resp. rate ↑ (lung stretch receptors inhibit VA output).

24. Take-Home Messages • Under resting conditions, VA output on heart is more effective than that of SY. • Both, VA and SY nerves are tonically active and oppose each other; VA effect is fast, SY effect appreciably slower. • AB provides important short-term regulation of BP: • If BP↑, high pressure receptors in aortic arch and carotid sinus cause HR↓, SV↓ and TPR↓ and vice versa. • Cardiac de-afferentiation reveals tonic inhibitory effect on HR and TPR – part of CP reflexes. • Veno-atrial stretch receptors help control BP↑ mainly via circulating blood volume↓ / VR↓; i.e. renal vasodilation, hypothalamic release↓ of ADH and atrial release↑ of ANP. • When BP falls < 80 torr, peripheral chemoreceptors modulate BP via vasoconstriction plus tachycardia.

25. MCQ Jack West, a 28 year-old bike rider was involved in a car accident on the road to the snowfields. He suffered a broken femur and was immediately transferred to Cooma Base Hospital. On admission, his HR was 112 bpm, and his blood pressure 65 / 45 torr. Which of the following statements best describes the state of the arterial baro- and cardiopulmonary reflex? • Arterial baroreceptor activity↓; sympathetic outflow↓; parasympathetic outflow↑; low pressure mechanoreceptor activity↓. • Arterial baroreceptor activity↑; sympathetic outflow↑; parasympathetic outflow↓; low pressure mechanoreceptor activity↓. • Arterial baroreceptor activity↓; sympathetic outflow↑; parasympathetic outflow↓; low pressure mechanoreceptor activity↓. • Arterial baroreceptor activity↑; sympathetic outflow↓; parasympathetic outflow↑; low pressure mechanoreceptor activity↑. • Arterial baroreceptor activity↑; sympathetic outflow↑; parasympathetic outflow↓; low pressure mechanoreceptor activity↑.

26. That’s it folks…

27. MCQ Jack West, a 28 year-old bike rider was involved in a car accident on the road to the snowfields. He suffered a broken femur and was immediately transferred to Cooma Base Hospital. On admission, his HR was 112 bpm, and his blood pressure 65 / 45 torr. Which of the following statements best describes the state of the arterial baro- and cardiopulmonary reflex? • Arterial baroreceptor activity↓; sympathetic outflow↓; parasympathetic outflow↑; low pressure mechanoreceptor activity↓. • Arterial baroreceptor activity↑; sympathetic outflow↑; parasympathetic outflow↓; low pressure mechanoreceptor activity↓. • Arterial baroreceptor activity↓; sympathetic outflow↑; parasympathetic outflow↓; low pressure mechanoreceptor activity↓. • Arterial baroreceptor activity↑; sympathetic outflow↓; parasympathetic outflow↑; low pressure mechanoreceptor activity↑. • Arterial baroreceptor activity↑; sympathetic outflow↑; parasympathetic outflow↓; low pressure mechanoreceptor activity↑.