Pathophysiology of Brain & Body - USSJJQ-20-3

1. Pathophysiology of Brain & Body - USSJJQ-20-3 Blood Pressure and its Control

2. The Need for Blood Pressure • Pressure gradient is required to move fluid • Pressure is generated by a ‘pump’ (provides energy) pushing against a resistance (inc gravity and inertia) • BP higher than needed to overcome gravity • Higher BP  targeted, efficient distribution • Implies sufficiently high resistance needed • Resistance supplied primarily by arterioles • Mostly, vessels actively seek to limit flow • Efficient blood distribution comes at a price • Heart has to work harder to generate the relatively high pressure • Pressure subjects vessels to stress

3. The Heart is Intermittent Pump, Yet Blood Flow is Continuous • Your heart doesn’t generate pressure for 2/3rds of your life • So what keeps the blood flowing for that 60 yrs? • The major arteries are very elastic • Some of the energy during systole is ‘captured’ by stretching of the major arteries • During diastole, the arteries recoil passively and continue to maintain pressure and so drive blood around the circulation • That ability to maintain pressure/flow can be affected by… • Hardening of arteries (less elastic) • Lower resistance to flow (exercise)

4. Determinants of Blood Pressure1) Cardiac Output • CO = SV x HR (l/beat x beats/min  l/min)

5. Determinants of Blood Pressure2) Total Peripheral Resistance • TPR is resistance offered by all blood vessels to blood flow • Main resistance vessels are the arterioles • Resistance prop to 1/radius4 • Radius controlled by smooth muscle cont. via… • Neural activity (vasomotor centre in medulla) • Myogenic activity (intrinsic reaction to stretch) • Circulating factors (eg angiotensin) • Local factors (eg NO) • TPR units are mmHg / l /min • BP = CO x TPR • (l/min x mmHg/l/min  mmHg) • Analogous to V = IR (Ohm’s Law)

6. Determinants of Blood Pressure3) Role of Blood Volume (often ignored) • BP = CO x TPR • But CO = VR; ie Heart is a ‘demand’ pump • So BP depends on VR ! • VR influenced by • Respiratory ‘push-pull’ pump • Skeletal muscle contraction • Mean Systemic Filling Pressure • ‘Average’ BP if heart isolated from circulation • Depends on BV (higher volume  higher MSFP) • BV distribution between venous/arterial • Large veins ‘capacitance’ vessels; ~65% BV • Venoconstriction  shift; important in exercise

7. The Kidneys, Body Water, BV and BP • 40 litres(70kg, 25y male) • Average intake/output 2.3 l/day • Intake • Metabolic reactions 10% • Drink 60% • Food 30% • Output • Urine 60% • Sweat 4% • Faeces 4% • Evaporation 32% • Skin & resp tract • No salt lost via these routes

8. Fluid Compartments • 40 litres Total • 25 litres Intracellular • 15 litres Extracellular • 3 litres Plasma • 12 litres Interstitial • Usually includes cerebrospinal etc • >90% as a gel

9. Fluid Movements (ml/min) 125 12,000,000 Kidneys 2 240,000 1.5 1.5 • Intake/output 1.5 • Bulk flow from non-renal capillaries 2 • Bulk flow at renal glomeruli 125 • Water diffusion at body capillaries 240,000 • Water diffusion across RBCs 12,000,000 • Illustrates dynamic equilibrium • Renal adjustment of plasma composition affects other compartments • Renal adjustment of plasma volume affects blood pressure

10. Short-term BP Control • Seconds • Baroreceptor reflex • Carotid sinus, aortic arch • Inhibits vasomotor centre • Chemoreceptor input • Aortic arch, carotid bodies • Stimulate CV centre when O2, pH drop • CNSischaemic response • ‘Last ditch’ attempt when CNS perfusion pressure drops • Massive sympathetic outflow • Minutes/hours • Renin-angiotensin • vasoconstriction • Vascular stress-relaxation (delayed compliance) • Veins ‘relax’ around increased BV • Capillary fluid shift • Jv= Kf([Pc − Pi] − σ[πc − πi]) • Individual mechanisms show finite gain (park this thought…)

11. Finite Gain Control Systems • When circumstances change… • systems don’t re-establish original conditions… • …unless they can correct original stimulus for change • Eg central heating • Room temp balance of heat production/loss • When external temp falls, average room temp falls even though heating still on! • Or even water level in cistern with a hole in it!

12. Short-term BP Control • Finite gain • Cannot fully reverse BP change • Eg consider baroreceptor response to haemorrhage Error BP Correction Gain = Correction/ Error (Error > 0, so gain is finite) Haemorrhage Baroreceptor Activity Vaso- constriction What is the stimulus sustaining extra constriction? Must be the error

13. Long-term BP Control • Renal/body fluid/pressure mechanism • Demonstrates infinite gain • Always fully restores BP • (ienever leaves an ‘error’ signal; that’s finite gain) • Example • ↑ in BP • ‘pressure’ diuresis & natriuresis • ↓ in BV • ↓ in VR • ↓ in CO (or ↓in TPR via autoregulation) • ↓ in BP • Process continues until BP back to normal

14. Graphical Representation • Na+ and H2O intake/output curves Na+/H2O intake/ output (x normal) 1 0 100 200 Blood Pressure (mmHg) • Na+ and H2O intake not BP-dependent, output is • BP regulated at intersection of curves

15. Importance of Na+ • Bulk of blood is H2O, but BV (and so BP) regulated by Na+ • Thought experiment: if ↑ H2O content of body • ↓osmolarity of ECF • ↓ ADH secretion • H2O diuresis • No change in BV • Thought experiment: if ↑ Na+ content of body • ↑ osmolarity of ECF • ↑ ADH secretion + thirst • Antidiuresis+ ↑ fluid intake • ↑ in BV

16. Intake Changing Equilibrium BP • Thought experiment: Just change Na+intake Output Na+intake/ output (x normal) 1 0 100 200 Blood Pressure (mmHg) • ↑ Na+ intake alone ↑ BP

17. Output Changing Equilibrium BP • Thought experiment: Just change Na+output Na+intake/ output (x normal) 1 Intake 0 100 200 Blood Pressure (mmHg) • Right-shifting renal Na+ output alone ↑ BP

18. Changing renal Na+ output curve • Renal Na+ output determined by hormones • Angiotensin • ↑ Na+reabsorption • Direct effect, and indirect via aldosterone • Aldosterone • Steroid released from adrenal cortex • ↑ Na+reabsorption • ANP • AtrialNatriuretic Peptide • Released from right atrium of heart • ↓ Na+reabsorption • BP does not vary much with Na+intake • Because release of hormones is sensitive to BP and Na+ • Intake/output curves shift together  stable BP

19. Combined effect of ↑ Na+intake and hormone-mediated change in renal function Output Na+intake/ output (x normal) 1 Intake 0 100 200 Blood Pressure (mmHg) • ↑ Na+ intake left-shifts renal Na+ output → stable BP

20. Effect of ↑ Na+ intake • ↑ Na+ intake • ↑ body Na+, BV, BP • ↓ Angiotensin, ↓ aldosterone, ↑ ANP • Shift in renal output curve to left • Diuresis, natriuresis • ↓ body Na+, BV, BP

21. How BP varies with Na+ intake Na+ intake/ output (x normal) 1 0 100 200 Blood Pressure (mmHg) • ↑ Na+ intake left-shifts renal Na+ output → stable BP • pivotal role of RASin shifting output in response to input/BP

22. How BP varies with Na+intake: sodium-pressure curve Na+ intake (x normal) 1 0 100 200 Blood Pressure (mmHg) • alterations in sodium-pressure curves occurs in diseases such as hypertension

23. The Renin-Angiotensin System Angiotensinogen NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH 1. ↓ Renal Perfusion Pressure (baroreceptor) 2. ↓ Na at Macula Densa cells 3. ↑ Sympathetic nerve activity (ß-1) 1 2 3 7 8 9 10 + Renin NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu-COOH Angiotensin I 1 2 3 7 8 9 10 ACE Angiotensin II NH2-Asp-Arg-Val…Pro-Phe-COOH 1 2 3 7 8 Aminopeptidase Effects! Angiotensin III NH2-Arg-Val…Pro-Phe-COOH 2 3 7 8

24. Angiotensin II – Support of Blood Pressure Cardiac & Vascular Hypertrophy Vasoconstriction Direct Renal Sodium Retention ↑ Cardiac Contractility Aldosterone Secretion Angiotensin II Sympathetic Facilitation: Central Nerve terminal (ganglionic?) ↑ Thirst ADH Release

25. The role of Renal Autoregulation • Theory relies on change in renal output in response to change in blood pressure – • ie pressure makes you pee • Original output curves observed in isolated, perfused kidneys • But there are differences between isolated and in situ kidneys • Across a wide range of BP, the in situ kidney autoregulates RBF and GFR, but not the isolated GFR/RBF (ie tendency to produce urine) 1 0 100 200 Blood Pressure (mmHg)

26. Changing Pressure  Changing Pee • Change in output seen in isolatedkidney probably due to change in RBF/GFR • ie pressure directly makes the kidneys pee • Effects less likely to happen in situ • Change in output seen in the in situ kidney probably due to changes in Na+reabsorption • Sodium and water strongly linked • Ang, Aldo and ANP are BP-sensitive • Effects unlikely to happen in isolatedkidney • So because of autoregulation, shifts in renal output curves in the in situkidney are indirect, via hormones, but occur directlyin the isolated kidney by alterations in GFR