Download The Nervous System (NS)

Pathophysiology of Brain & Body USSJJQ-20-3
Hypertension
Hypertension


A (the?) major ‘disease of civilisation’
 Multifactorial genetic/environmental
A spectrum, but transition defined as…


BP ≥ 140/90 mmHg
Major studies have demonstrated detrimental
effects…
Prevalence of Hypertension in the US
Percent hypertensive
80
66 %
60
51 %
38 %
40
18 %
20
3%
0
72 %
9%
18-29 30-39 40-49 50-59 60-69 70-79
80+
Age
Based on NHANES III (phase 1 and 2)
Hypertension defined as blood pressure 140/90 mmHg or treatment
JNC-VI. Arch Intern Med. 1997;157:2413-2446.
www.hypertensiononline.org
Risk of hypertension (%)
Lifetime Risk of Developing
Hypertension Beginning at Age 65
100
80
Men
Women
60
40
20
0
0
2
4
6
8
10 12 14 16 18 20
Years
Residual lifetime risk of developing hypertension
among people with blood pressure <140/90 mmHg
Vasan RS, et al. JAMA. 2002; 287:1003-1010.
Copyright 2002, American Medical Association.
www.hypertensiononline.org
Mortality According to Blood Pressure
in Men Age 50 to 69
Ratio (%) of actual to
expected mortality
250
200
150
68-82
83-87
88-92
93-97
98-102
100
50
0
158167
148157
138147
128137
98127
Systolic blood pressure (mmHg)
Society of Actuaries. Blood Pressure Study, 1939.
www.hypertensiononline.org
Age-adjusted annual
incidence of CHD per 1000
Blood Pressure and Risk for
Coronary Heart Disease in Men
60
60
50
50
40
40
Age 65-94
30
30
20
20
10
0
Age 35-64
<120 120- 140- 160- 180+
139 159 179
Systolic blood pressure (mmHg)
Age 65-94
10
0
Age 35-64
<75
75- 8595- 105+
84
94
104
Diastolic blood pressure (mmHg)
Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart
disease (CHD) at baseline
Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.
www.hypertensiononline.org
Risk of CHD Death
According to SBP and DBP in MRFIT
Relative risk of
CHD mortality
4
Systolic blood pressure (SBP)
Diastolic blood pressure (DBP)
3
2
1
0
Decile
SBP (mmHg)
DBP (mmHg)
1
2
3
(lowest 10%)
<112 112- 118<71
71-
76-
4
5
6
7
121-
125-
129-
132-
79-
81-
84-
86-
CHD=coronary heart disease
He J, et at. Am Heart J. 1999;138:211-219.
Copyright 1999, Mosby Inc.
8
9
10
89-
92-
>98
(highest 10%)
137- 142- >151
www.hypertensiononline.org
Relative risk of
stroke death
Risk of Stroke Death According
to SBP and DBP in MRFIT
9
8
7
6
5
4
3
2
1
0
Decile
SBP (mmHg)
DBP (mmHg)
Systolic blood pressure (SBP)
Diastolic blood pressure (DBP)
1
2
3
(lowest 10%)
<112 112- 118<71
71-
76-
4
5
6
7
121-
125-
129-
132-
79-
81-
84-
86-
He J, et at. Am Heart J. 1999;138:211-219.
Copyright 1999, Mosby Inc.
8
9
10
89-
92-
>98
(highest 10%)
137- 142- >151
www.hypertensiononline.org
Isolated Systolic Hypertension
and CVD Risk in Framingham
2.5
Age-adjusted annual CVD
event rate per 1000
100
ISH BP 160/<95 mmHg
BP <140/95 mmHg
80
82
2.4
60
40
20
0
43
33
18
Men
Women
CVD=cardiovascular disease ISH=isolated systolic
hypertension
P<0.001 for difference between both men and women with ISH
and blood pressure (BP) <140/95 mmHg
www.hypertensiononline.org
Wilking SV et al. JAMA. 1988;260:3451-3455.
Hypertension and the Kidneys
History

Stephen Hales (1773)


Richard Bright (1836)


First measurement of BP
 Importance of Blood Volume
Left Ventricular Hypertrophy
 Linked to increased peripheral resistance…
 …due to “altered condition of the blood”
FA Mahomed (1872)


Routine measurement of BP in clinical diagnosis
Tigerstedt & Bergman (1898)


Extracts of rabbit kidney
Raised blood pressure


Prolonged effect
Named agent renin

Harry Goldblatt (1934)

Renal artery constriction in dogs


Produced hypertension
Not diminished by sympathetic section
 Humoral agent responsible


Menendez & Page (1938)

Argentina & USA



Triggered hypertension research ever since!
Identified short-acting pressor substance
Termed hypertensin (Argentina) and angiotonin (USA)
1957

Agreed composite term Angiotensin
Juxtaglomerular Apparatus
Bowman’s Capsule
Efferent Arteriole
DCT
PCT
Macula
Densa Cells
Granular Juxtaglomerular (JG) Cells
Afferent Arteriole
The Renin-Angiotensin System
1. ↓ Renal Perfusion
Pressure
(baroreceptor)
2. ↓ Na at Macula
Densa cells
3. ↑ Sympathetic
nerve activity (ß-1)
Angiotensinogen
+
NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH
1
2
3 7
8 9 10
Renin
Angiotensin I
NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu-COOH
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
Angiotensin II – Support of Blood Pressure
Cardiac & Vascular
Hypertrophy
↑ Cardiac
Contractility
Sympathetic
Facilitation:
Central
Nerve terminal
(ganglionic?)
Vasoconstriction
Angiotensin II
Direct Renal
Sodium Retention
Aldosterone
Secretion
↑ Thirst
ADH Release
Role of RAS in hypertension
 Critical in some forms…
 EG Renovascular (Goldblatt)
 See later…
 But role in essential hypertension unclear
 Essential hypertension more than 90% of all cases
 ‘essential’ euphemism for ‘unknown cause’
 Renin can be low, normal or high !
 But no doubting importance of kidney in
essential hypertension…
Features of essential hypertension






↑ BP
Normal Cardiac Output, CO
↑ Total Peripheral Resistance, TPR
↑ renal resistance
↓ Renal Blood Flow, RBF
Normal Glomerular Filtration Rate, GFR
 Effect of ↓ RBF offset by ↑ BP
 ↑ BP ‘needed’ for normal renal function


Could also be the basis for ↑ BP with age in highsalt cultures
Because ↓ renal ‘reserve’ (# nephrons)
Experimental models of hypertension

Goldblatt hypertension (see later)


Spontaneously Hypertensive Rat (SHR)



Dog, rat, rabbit
Cross-transplantation indicates ‘pressure’ travels with
kidney
mRen-2 (high renin) transgenic rat
Dahl strains (rat)


Na+-sensitive or Na+-resistant
Experimentally, hypertension can be associated with
shifts in renal output curves (which way?)


Kidneys do not excrete adequate Na+ at normal BP
Na+ balance established at ↑ BP (and BV)
How BP normally varies with Na+ intake
Na+ intake/
output
(x normal)
1
0
100
Blood Pressure (mmHg)
200
Theoretical normal BP dependence on
Na+ intake
Na+ intake
(x normal)
1
0
100
Blood Pressure (mmHg)
200
Experimental manipulation of the curve
Role of Na+

Intake <1g/day for most of our evolution



Deliberate addition ~10,000 years ago
Agriculture
Now approaching 10g/day ?!

Low-salt tribes – BP does not rise with age



Yanomamo Indians
Salt intake <0.5g/day
BP 100/64 at 50y
‘Stress-free’, simple, non-accultured lifestyle?



No. Eg, Yanomamo Indians ‘aggressive’
Other nomadic, non-accultured tribes with high-salt 
hypertensive
Role of Na+

Japanese: 1950s/1960s



Migration studies also indicate link


High level of cerebral haemorrhage
Correlated with regional salt intake
ie migration from low to high salt intake regions
increases BP
A small number of studies indicate no
relationship


High-salt nuns (peaceful lifestyle?)
Kuna Indians (genetic change?)
BP changes with Age; effect of dietary Na+
Dietary Na+ and BP rise: INTERSALT
Na+ excretion and Stroke
Genetic Aspects

Control of Blood Pressure multifactorial

Mutations/polymorphisms in rare Mendelian hyper/hypotension
‘Simple’ Views of Hypertension

Theoretical basis for hypertension


BP = SV x HR x TPR
With contribution of BV (mainly via MSFP)


‘spectrum’ of hypertension ranging from…
Pure vasoconstrictor



Effects mediated via ↑ TPR
To…
Pure volume-loading

Effects mediated via ↑ BV

Vasoconstrictor hypertension

Eg renin-secreting tumour




↑ circulating Ang II
Intense vasoconstriction
↑↑ in TPR
↓ VR and CO


↑ Na+ and H2O retention


Still get ↑ BP as ↑↑ TPR > ↓ CO
Mediated by aldosterone and angiotensin
Normal Na+/H2O balance achieved at ↑ BP

Volume-loading hypertension

Eg primary aldosteronism (eg a tumour)


↑ circulating aldosterone
↑ Na+ and H2O retention



eg right-shift of renal output curve ↑ Na+ and H2O
retention
↑ BV
↑ CO

(Transfers to ↑ TPR)

↑ BP

Na+ and H2O balance achieved at ↑ BP

Goldblatt hypertension

Experimental, mixed vasoconstrictor/volumeloading

One-kidney, one-clip

Remove one kidney, constrict renal artery of the
other






↓ in renal perfusion pressure
Activation of RAS
↑ vasoconstriction
↑ Na+/H2O reabsorption
↑ BV
↑ systemic BP



↑ systemic BP restores renal perfusion pressure
RAS therefore returns to normal
Normal Na+/H2O balance restored
 But only at this higher systemic BP

Two-kidney, one-clip

Constrict renal artery of one kidney










↓ in renal perfusion pressure
Activation of RAS
↑ vasoconstriction
Expect ↑ stimulus for Na+/H2O reabsorption
↑ systemic BP
However, ‘good’ kidney fully exposed to ↑ BP
Leads to ↑ urine production
 Precise mechanism unknown
Therefore, limited ↑ BV to drive ↑ BP
RAS therefore remains activated
 Remember, it was the ↑ BV that sustained the ↑ BP
in the one-kidney model that turned ‘off’ the RAS
Now the ‘good’ kidney acting as ‘pressure-relief valve’

Goldblatt hypertension has human
pathological equivalent
 Renovascular hypertension
 Caused by renal artery stenosis
 Stenosis is a narrowing of the lumen
 Narrowing of one artery equivalent to ‘one-clip, twokidney’ model
 Can be corrected by surgery