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)• Distribution is dynamic• Distribution has multiple functions• Distribution is regulated

• How is blood flow regulated?– Global vs regional (or local) flow…….

Resistance to flow

• MAP changes are small

• Cardiac output changes ~5-fold

BP=CO.TPR• So, TPR must alter in

proportion to COQu. What are the units

of TPR????

Vessel calibre and resistance

• Resistance - Proportional to length

• Proportional to calibre– Resistance related to r4

• Is the calibre of an artery supplying resting muscle…

a) Fully relaxed?b) Fully contracted?

Rates of flow: resting to fully activatedConsider: The sum of maximal flow rates exceeds max cardiac output!

Discuss the implications of this…Range of flows between rest and maximal function

0

100

200

300

400

500

600

heart

CNS

skele

tal m

uscle GIT

liver

kidne

ysk

in

saliv

ary gl

and fat

bloo

d flo

w (m

l/min

/100

g tis

sue)

maximalresting

Determinants of Blood Pressure

MAP = CO x R

• 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’

- small arterial blood vessels -

autoregulatory

range 0 30 60 90 120 150 180 210

0

25

50

75

100

125

(in man)mean blood pressure

mean blood pressure (mmHg)

bloo

d flo

w (m

l/min

/100

g)

Dilated: low resistance

Constricted: high resistance

Arterial cross section

Myogenic contraction [of small arteries]

• An isolated cannulated artery (~0.2 mm dia.)

Typical myogenic contraction

in absence of calcium or at room temperature

in presence of calcium(normal myogenic response)

20 30 40 50 60 70 80 90 100 110

0.6

0.8

1.0

Diam

eter

(nor

mal

ised)

internal pressure (mm Hg)

threshold pressure

190 mm

295 mm

Myogenic depolarisation

From Knot and Nelson, (1998), J. Physiol. 508: 199-209

Characteristic feature of myogenic constriction

Ca source in muscle

SR

SR = Intracellular calcium store

Skeletal muscle

smooth muscle

Ca source in muscle

Ca

SR = Intracellular calcium store

Skeletal muscle

smooth muscle

Ca entering through Ca channels

Likely importance of depolarisation

-70 -50 -30 -10 10

0

0.1

0.2

0.3

0.4

Stea

dy-s

tate

Po

Membrane potential (mV)

From Nelson et al., Am. J. Physiol. 1990

Voltage-dependence of steady state open probability of calcium channels

Likely importance of depolarisation

-70 -66 -42-46-50-54-58-62

Membrane potential (mV)

0

0.05

0.04

0.03

0.02

0.01Ste a

d y-s

tat e

Po

Voltage-dependence of steady state open probability of calcium channels

[expanded voltage scale]

From Nelson et al., Am. J. Physiol. 1990

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…….

0 100 200 300 400 500 60045

55

65

75

85

95

105

Passive Diameter at 80 mmHg ( m)

Nor

mal

ised

art

eria

l dia

met

er a

t 80

mm

Hg

(% o

f pas

sive

dia

met

er)

m

Rat mesenteric

Smaller arteries have more pronounced myogenic response

Smaller arteries have more pronounced myogenic response

0 100 200 300 400 500 60045

55

65

75

85

95

105

Passive Diameter at 80 mmHg ( m)

Nor

mal

ised

art

eria

l dia

met

er a

t 80

mm

Hg

(% o

f pas

sive

dia

met

er)

m

325 micrometers

No myogenic tone

Rat mesenteric

But muscle rmp still varies with diameter

Passive Diameter at 80 mmHg (mm)

0 100 200 300 400 500 600-90

-80

-70

-60

-50

-40

Res

ting

mem

bran

e po

tent

ial

at 2

0 m

mH

g (m

V)

Not myogenicmyogenic

Non-myogenic arteries(>320µm)

20mmHg 80mmHg-80

-70

-60

-50

-40

Mem

b ra n

ep o

ten t

ial(

mV

)

And even larger arteries depolarise to pressure

20 mmHg used as below threshold for myogenic response

Rat mesenteric

Temperature – myogenic depol absent at 22 oC

22°C37°C

20 80-50

-45

-40

-35

-30

-25

Pressure (mmHg)

Mem

bran

ePo

t ent

ial(

mV)

20 80-50.0

-47.5

-45.0

-42.5

-40.0

-37.5

-35.0

Pressure (mmHg)

Mem

bran

ePo

tent

ial(

mV)

B (I) (II)

*** **

Cerebral Mesenteric

A Pressure

Temperature

MembranePotential

20 mmHg 80 mmHg20 mmHg 80 mmHg80 mmHg

-46 mV -45 mV -44 mV -30 mV -32 mV

10 mV

100 s

22 oC 37 oC 22 oC 37 oC 37 oC0 mV

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.

End of part 1

• Questions?

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

Coming next part 2

• Average resting blood pressure is 120/80 (mmHg)– Hypertension = systolic above 140 or diastolic above 90 mmHg– ~1/3 people in England have hypertension

05

10152025303540

1

% with high blood pressure

MenWomen

31% 28%

Data source:

www.heartstats.org

• Half of those treated remain hypertensive

[Essential] Hypertension (EH)

Sympathetic nervous system in EH

Grassi G www.sns-web.org

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

There is a Graded Association Between Hypertension and Sympathetic Drive (Grassi 1998)

Normotensive Mildly Essential Hypertensive

Severe Essential Hypertensive

Secondary Hypertensive

Mean Arterial Pressure (mmHg)

(Grassi 1998. J Hypertens, 16:1979-1987)

Symp Nerve Activity (bursts per 100 heart beats)

Harvey Cushing(Baltimore, 1903)

The Cushing Mechanism & Neurogenic Hypertension

conscious dogsystemic arterial pressure

intra-cranial pressure

The Cushing Response (1901)

0

50

100

150

200

250

300

0 50 100 150 200 250

MAP mmHg

Intra-Cranial Pressure mmHg

(Bull.Johns Hopk. Hosp., 12: 290-292).

cerebral vascular resistance

Vertebral Artery Flow & Mean Arterial Pressure

Mean Ante-Mortem Blood Pressure (mmHg)

Rate of Flow in Both Vertebral Arteries (ml per second)

Dickinson (1960) J. Clin. Sci.,19, 513

120

60

180

20 40

P

If radius reduced by half, resistance increases by 16-fold

Q= P/R

R α 1 r4

vertebralarteries

Dickinson (1965). Neurogenic Hypertension. Blackwell

Normotensive Hypertensives

Smaller Diameter Vertebral Arteries in Humans With Hypertension

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?

SHR & WKY Rats

WKY = Normotensive Control RatsSHR = Spontaneously Hypertensive Rats

• = SHR ⁰ = WKY

(Dickhout & Lee 1998 Am. J Phys 43:794-800)

Hypothesis

There is a difference in cerebrovascular architecture consistent with high vascular

resistance in pre-hypertensive SHRs.

Method

Method used: Kruker et al., 2006. Microscopy research and technique 69:138–147

Pentabarbitone overdose (IP)

Cannulation of left ventricle

Perfusion (20-24 oC):Saline flush + hydralazineFix – 100ml 4% formalinResin (Pu4ii, Vasqtec)

Maceration (KOH / acetic acid)

Freeze dried; sputter coated

Visualised in SEM (5kV)

Detergent washes and rinsing

1 hour

10 days

Curing at 10 oC 24 hours

Left vertebral

Right vertebralBasilar

caudal

rostral

Basilar

SHR WKY200

225

250

275

300

325

350

Diameter of basilar arteries

Dia

met

er (µ

m)

Number of basilar branches per generation

05

1015202530354045

1 2 3 4 5 6

Generation number

num

ber o

f bra

nche

s WKY

SHR

0th Generation (basilar or vertebral

1st Gen.

1st Gen.

2nd Gen. 3rd

3rd 3rd

3rd

4th4th

0th Generation (basilar or vertebral

1st Gen.

1st Gen.

2nd Gen. 3rd

3rd 3rd

3rd

4th4th

Basilar artery of SHR smaller

63% reduction in conductance

Vascular Maps of SHR and WKYMedian diameters of left and right vertebral arteries

0

50

100

150

200

250

300

350

SHR WKY

Dia

met

er (m

icro

met

ers)

Left VA

Right VA

Basilar

WKYSHR

Relative conductance for median diameter basilar branches

-6

-5

-4

-3

-2

-1

01 2 3 4 5 6

Generation

Log

[con

duct

ance

(re

l to

basi

lar

med

ian)

]

WKY

SHR

BASILAR Conductance for median diameter basilar branches relative to WKY median

-6-5-4-3-2-10

1 2 3 4 5 6Generation

Log

[con

duct

ance

(rel

to

basi

lar m

edia

n)]

WKY

SHR

BASILAR re. to WKY

Conductance for median diameter left vertebral branch generations relative to WKY Left VA

-6

-5

-4

-3

-2

-1

01 2 3 4 5 6

Generation

Log

[con

duct

ance

(rel

to

basi

lar m

edia

n)]

WKY

SHR

LEFT VERTEBRAL rel. to WKY Conductance for median diameter right vertebral branch generations relative to WKY Right VA

-6

-5

-4

-3

-2

-1

01 2 3 4 5 6

Generation

Log

[con

duct

ance

(rel

to

basi

lar m

edia

n)]

WKY

SHR

RIGHT VERTEBRAL rel. to WKY

CONDUCTANCE RADIUS4

Conductance of feeding vessel taken as 1 Conductance of SHR appears lower than WKY

DecrCond.

Median diameters of left and right vertebral arteries

0

50

100

150

200

250

300

350

SHR WKY

Dia

met

er (m

icro

met

ers)

Left VA

Right VA

Basilar

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

Questions?