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Blood flow to the brainstem and a possible link to high blood pressure (essential hypertension)

Blood flow to the brainstem and a possible link to high blood pressure (essential hypertension). Dr Phil Langton. Resting heart rate Max heart rate Resting CO Max CO. Miguel Indurain. ~30 bpm 200 bpm 5 litres 50 litres. Blood flow. Two circuits Requires work (not passive)

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Blood flow to the brainstem and a possible link to high blood pressure (essential hypertension)

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  1. Blood flow to the brainstem and a possible link to high blood pressure (essential hypertension) Dr Phil Langton

  2. Resting heart rate Max heart rate Resting CO Max CO Miguel Indurain ~30 bpm 200 bpm 5 litres 50 litres

  3. Blood flow • Two circuits • Requires work (not passive) • Distribution is dynamic • Distribution has multiple functions • Distribution is regulated • How is blood flow regulated? • Global vs regional (or local) flow…….

  4. Resistance to flow • MAP changes are small • Cardiac output changes ~5-fold BP=CO.TPR • So, TPR must alter in proportion to CO Qu. What are the units of TPR????

  5. Vessel calibre and resistance • Resistance - Proportional to length • Proportional to calibre • Resistance related to r4 • Is the calibre of an artery supplying resting muscle… • Fully relaxed? • Fully contracted?

  6. Rates of flow: resting to fully activated Consider: The sum of maximal flow rates exceeds max cardiac output! Discuss the implications of this…

  7. Determinants of Blood Pressure MAP = CO x R

  8. 125 100 mean blood pressure Arterial cross section (in man) 75 blood flow (ml/min/100g) Dilated: low resistance 50 Constricted: high resistance 25 autoregulatory range 0 0 30 60 90 120 150 180 210 mean blood pressure (mmHg) - small arterial blood vessels - • The ‘myogenic contraction’ of small arteries • Described by Bayliss (1902) • Thought important for autoregulation • Defined as ‘the tendency for local tissue blood flow to be independent of systemic blood pressure’

  9. 295 mm 190 mm Myogenic contraction [of small arteries] • An isolated cannulated artery (~0.2 mm dia.) • Typical myogenic contraction in absence of calcium or at room temperature threshold pressure 1.0 0.8 Diameter (normalised) in presence of calcium (normal myogenic response) 0.6 20 30 40 50 60 70 80 90 100 110 internal pressure (mm Hg)

  10. Myogenic depolarisation Characteristic feature of myogenic constriction From Knot and Nelson, (1998), J. Physiol. 508: 199-209

  11. Ca source in muscle Skeletal muscle smooth muscle SR SR = Intracellular calcium store

  12. Ca source in muscle Skeletal muscle smooth muscle Ca Ca entering through Ca channels SR = Intracellular calcium store

  13. 0.4 0.3 Steady-state Po 0.2 0.1 0 -70 -50 -30 -10 10 Membrane potential (mV) Likely importance of depolarisation Voltage-dependence of steady state open probability of calcium channels From Nelson et al., Am. J. Physiol.1990

  14. 0.05 0.04 0.03 Steady-state Po 0.02 0.01 0 -70 -66 -62 -58 -54 -50 -46 -42 Membrane potential (mV) Likely importance of depolarisation Voltage-dependence of steady state open probability of calcium channels [expanded voltage scale] From Nelson et al., Am. J. Physiol.1990

  15. A few important facts • Myogenic constriction of SMALL arteries • Not seen in arteries over a given size • Assumption: myogenic mechanism is present or absent • Threshold pressure for myogenic constriction • Little evidence below 40 mmHg • Temperature-sensitive • Myogenic constriction - absent or very attenuated at room temp • Temperature dependence of myogenic depolarisation has never been examined…….

  16. 105 95 85 75 Normalised arterial diameter at 80 mmHg (% of passive diameter) 65 55 45 0 100 200 300 400 500 600 m Passive Diameter at 80 mmHg ( m) Smaller arteries have more pronounced myogenic response Rat mesenteric

  17. 105 95 85 75 Normalised arterial diameter at 80 mmHg (% of passive diameter) 65 55 45 0 100 200 300 400 500 600 m Passive Diameter at 80 mmHg ( m) Smaller arteries have more pronounced myogenic response 325 micrometers No myogenic tone Rat mesenteric

  18. myogenic Not myogenic Non-myogenic arteries -40 (>320µm) -40 ) V m -50 ( l -50 a i t Resting membrane potential at 20 mmHg (mV) -60 n e t o -60 p -70 e n a r -80 -70 b m e -90 M -80 0 100 200 300 400 500 600 m Passive Diameter at 80 mmHg ( m) 20mmHg 80mmHg But muscle rmp still varies with diameter And even larger arteries depolarise to pressure 20 mmHg used as below threshold for myogenic response Rat mesenteric

  19. A 20 mmHg 20 mmHg 80 mmHg 80 mmHg 80 mmHg Pressure Temperature 22 oC 37 oC 22 oC 37 oC 37 oC 0 mV 10 mV 100 s Membrane Potential -46 mV -45 mV -44 mV -30 mV -32 mV Temperature – myogenic depol absent at 22 oC (II) B (I) ° 22 C Cerebral Mesenteric ° 37 C -25 -35.0 ) ) V V m m ( ( -37.5 -30 l l a a i i t t -40.0 n n e -35 e t t o o -42.5 P P -40 e e n n -45.0 a a r r b b -45 -47.5 m m e e *** ** M M -50 -50.0 20 80 20 80 Pressure (mmHg) Pressure (mmHg)

  20. Interpretation & conclusions • Myogenic constriction and depolarisation are lost at room temperature • Larger arteries are not ‘myogenic’ but do depolarise when pressured • The more negative resting potential of larger arteries may explain their lack of response to pressure.

  21. End of part 1 • Questions? Coming next part 2 ‘Blood flow to the brainstem and a possible link to high blood pressure (essential hypertension)’,

  22. [Essential] Hypertension (EH) • Average resting blood pressure is 120/80 (mmHg) • Hypertension = systolic above 140 or diastolic above 90 mmHg • ~1/3 people in England have hypertension Men Women % with high blood pressure 31% 28% Data source: www.heartstats.org • Half of those treated remain hypertensive

  23. Sympathetic nervous system in EH Grassi G www.sns-web.org

  24. Why Skeletal Muscle Flow? • ~40% of body mass is skeletal muscle (skm) • Resistance to flow altered to manage changes in MAP (e.g. during posture changes) • Large variation in flow ~100 fold change • Known association between exercise, oxygen use and muscle BF • Requirement for targeted blood flow – to active (& not inactive) muscle

  25. There is a Graded Association Between Hypertension and Sympathetic Drive (Grassi 1998) Mean Arterial Pressure (mmHg) Symp Nerve Activity (bursts per 100 heart beats) Severe Essential Hypertensive Secondary Hypertensive Mildly Essential Hypertensive Normotensive (Grassi 1998. J Hypertens, 16:1979-1987)

  26. The Cushing Mechanism & Neurogenic Hypertension MAP mmHg cerebral vascular resistance Intra-Cranial PressuremmHg The Cushing Response (1901) (Bull.Johns Hopk. Hosp., 12: 290-292). conscious dog systemic arterial pressure intra-cranial pressure Harvey Cushing (Baltimore, 1903)

  27. R α 1 r4 Vertebral Artery Flow & Mean Arterial Pressure Q= P/R 180 Mean Ante-Mortem Blood Pressure (mmHg) 120 If radius reduced by half, resistance increases by 16-fold P 60 20 40 Rate of Flow in Both Vertebral Arteries (ml per second) Dickinson (1960) J. Clin. Sci.,19, 513

  28. Normotensive Hypertensives Smaller Diameter Vertebral Arteries in Humans With Hypertension vertebral arteries Dickinson (1965). Neurogenic Hypertension. Blackwell

  29. Animal Model of Human Hypertension:The Spontaneously Hypertensive Rat (SHR) • Genetically pre-programmed hypertension • Dependence on renin-angiotensin system • Responsive to human anti-hypertensive medication • Does it have narrowed cerebral vessels?

  30. SHR & WKY Rats WKY = Normotensive Control Rats SHR = Spontaneously Hypertensive Rats • = SHR ⁰ = WKY (Dickhout & Lee 1998 Am. J Phys 43:794-800)

  31. Hypothesis There is a difference in cerebrovascular architecture consistent with high vascular resistance in pre-hypertensive SHRs.

  32. Method Pentabarbitone overdose (IP) Cannulation of left ventricle Perfusion (20-24 oC): Saline flush + hydralazine Fix – 100ml 4% formalin Resin (Pu4ii, Vasqtec) 1 hour Curing at 10 oC 24 hours Maceration (KOH / acetic acid) 10 days Detergent washes and rinsing Freeze dried; sputter coated Method used: Kruker et al., 2006. Microscopy research and technique 69:138–147 Visualised in SEM (5kV)

  33. Left vertebral Right vertebral Basilar caudal rostral

  34. Basilar

  35. Basilar artery of SHR smaller 63% reduction in conductance

  36. Vascular Maps of SHR and WKY SHR WKY

  37. BASILAR BASILAR re. to WKY RIGHT VERTEBRAL rel. to WKY CONDUCTANCE  RADIUS4 • Conductance of feeding vessel taken as 1 • Conductance of SHR appears lower than WKY Decr Cond. LEFT VERTEBRAL rel. to WKY

  38. Summary & Conclusions SHR has smaller median basilar diameter SHR basilar - more heavily branched Right vertebral of SHR distinctly small Right vertebral of SHR more heavily branched than left in SHR and WKY Estimated conductance of SHR lower than WKY, especially if normalised to WKY Differences are apparent between vascular casts of SHR and WKY that are consistent with higher cerebrovascular resistance in the SHR

  39. Questions?

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