Sodium RestrictionLowers High Blood PressureThrougha
DecreasedResponseof the Renin SystemDirect EvidenceUsing Saralasin
FrancescoP. Cappuccio,NirmalaD. Markandu,
GiuseppeA. Sagnellaand GrahamA. MacGregor
were studiedwhileon their normal
patientswith essentialhypertension
Twenty-nine
andon theSthdayof
diets,on thesth dayof a highsodiumdiet(around350mmol/day)
on changingfromthe
Thefallin meanarterialpressure
a lowsodiumdiet(10mmol/day).
highsodiumto the lowsodiumdietwas9.0 + 1.6mrnHgandthe risein the plasma
reninactivityin the sameperiodwas 2.52 + 0.41ng/ml/h,thesetwo variablesbeing
was givenon
correlated(r = -0.45; P < 0.02).An infusionof saralasin
significantly
wasfound
negativecorrelation
the sth day of the low sodiumdiet.A highlysignificant
betweenthe fall in blood pressureon sodiumrestrictionand the changein blood
was still significant
pressurewith saralasin(r : -0.52; P < 0.005);this correlation
(r : -0.41; P : 0.03)while it
when correctedfor the severityof the hypertension
if controlledfor plasmareninactivityon the low sodiumdiet
becamenon-significant
providedirectevidencethatthe fall in bloodpressure
(r : -033; NS).Theseresults
whichis seenon reducingsodiumintakein manypatientswithessentialhypertension
system.
of the reninangiotensin
is, at leastin part,directlymediatedby the reactivity
1985'3:243-247
Journalof Hypertension
Keywords: Sodium restriction, hypertension, renin system, saralasin-
lntroduction
Patients and methods
Although sodium restriction reduces blood pressure in Twenty-nine patients with essential hypertension,
many patients with essential hlpertension [1-3], the referred to the Blood Pressure Unit by local family
mechanism through which it acts is not clear 14-6). In doctors, were studied. Patients with renal failure (plasma
creatinine > L20 pmoVl), ischaemic heaft disease, or
essential hypertension there is a wide range of blood
taking oral
elisea.s€;, rr
sgle$lsvassular
sodium restriction
pressure responserdurifig-short-term
were
from the
excluded
any
drug
or
other
in
blood
contraceptives
[7,8]. Several authors have suggested that the fall
previously
received
had
blood
not
either
to
the
study.
Subiects
is
related
restriction
with
sodium
pressure
blunting of the renin response that occurs in many pressure lowering treatment or, if they had, it was
stopped 3 months prior to the study. Patients were
patients with essential hlpertension [7-12].
\(e therefore conducted a study looking at the changes members of alarger sample which had been previously
in blood pressure with alteration in sodium intake and investigated as reported elsewhere [!]; they were
looking directly at the importance of the renin system on consecutively seen in the Blood Pressure Unit and
recruited for the present study when saralasin became
the low sodium diet by infusing 1-Sar-8-ala-angiotensinII
available. All subjects were followed 3 months in
(saralasin), a competitive inhibitor of angiotensin II.
From the Blood Pressure Unit, Departmentof Medicine, Charing
Cross and WestminsterMedical School, London WG 8RF, UK.
BloodPressure
Unit,
Requests
for reprintsto: Dr G.A.MacGregor,
Medical
Department
of Medicine,CharingCrossand Westminster
School,LondonWO8RF,UK.
@ Gower Medical Publishing Ltd ISSN 0263-6352 243
244 Journal of Hypertension19g5,Vol 3 No 3
the Blood Pressure Unit on no treatment. At the end of
this run-in period, subjects were admitted to the study if
their supine diastolic blood pressures were greater than
90 mmHg and less than 130 mmHg. There were 13 males
and'1.6females; 22 were white and seven black. The mean
age of the group was 45.9 + Z.|years (mean t s.e.m.;
range21,-70years) and mean supine arterial pressurewas
730.3 + 2.5 mmHg. Informed consenr was obtained
from each subiect. Patients were studied for three
consecutive dietary periods: on their normal diets
(approximately 150 mmol sodiudby),
then on a high
sodium intake (around 350 mmoVday) for 5 days,
followed by a low sodium intake of 10 mmoVday for J
days. High sodium diet was achieved by supplementing
the normal dier wirh 20 Slow sodium tablets (CIBA 10
mmol/tablet). Low sodium diet was provided by the
metabolic ward kitchen. Potassium intake was not altered
for either diet. Throughout the srudy all subjects were
allowed to go about their normal activities; theywere not
admitted to hospital but were discouraged from vigorous
exercise. During the study all patients were seen in the
Blood Pressure Unit at the same time of the day, by the
same nurse in the same room. Blood pressure was
measured between 10 a.m. and72 noon in the same arm
by nurses using semi-automatic ultrasound sphygmomanometers (Arteriosonde) [13] with attached recorder,
on the final day of the normal diet and on the 5th day of
high and low sodium diets. The measurements were
therefore free from any observer bias. Supine and
standing blbod pressures were taken as the mean value
of five readings obtained at 7-2 min intervals with the
patients in the corresponding positions; supine blood
pressure was measured before standing blood pressure.
Pulse rate was measured with a Cambridge 3048 pulse
monitor. Body weight was recorded at each visit. During
the study, 24 h vine collections were obtained during
the last 2 days of each dietary period.
Saralasin (1-Sar-8-ala-angiotensin II), a competitive
inhibitor of angiotensin II, was infused on the 5th day of
the low sodium diet by using an incremental infusion of
O.O5trgkg,minfor 2Omin,0.25 pgkg/minfor 20 min and
finally 7.25 p.glklmin for 20 min. Parients were infused
sitting upright in a chair which could, if necessary, be
tipped back, with a L h control period before and after
infusion. Blood pressure was measured every 1-3 min
with an Arteriosonde. Blood was taken in fasting
conditions, without stasis, after the patient had been
sining upright for l0 min between 10 a.m. and 12 noon,
for electrolltes, urea, creatinine and plasma renin activity
on the last day of the normal, high and low sodium diets.
On the 5th day of the low sodium diet, plasma renin
activity was measured by radio-immunoassay [14] before
saralasininfusion. Mean arterial pressure was calculated
as diastolic pressure plus one-third of pulse pressure.
The blood pressure response to saralasin was calculated
as the change in mean arterial pressure between rhe 20
min before infusion and the last 10 min at the highest rate
of infusion. As plasma renin activity levels are known to
be distributed abnormally in the population, Iog
transformation of the values was used. Student's
rwo-tailed paired t-tesrs, simple and partial correlation
analyseswere carried out using the University of London
computer and the Nonh Westem Universities'Statistical
Package for the Social Sciences.
Results
On their normal diets,the mean supine arterialpressure
in the 29 patiens was 130.3 + 2.5 mmHg, the mean
urinary sodium excretion was 155.8 + lO.Z mmol/24 h
and meanplasmarenin activitywas0.95 + 0.14ng/ml/h.
On the 5th day of the high sodium diet there wzrs no
significant change in the mean supine afterial pressure
(129.9 + 2.4 mmHg),urinary sodiumexcretionrose to
a mean of 287.2 + 16.0 mmoU24 h and plasma renin
activityfellto 0.50 + 0.09nglml/h. Measuremenrs
on the
5th day of the low sodium diet showed rhat the mean
supine arterial pressure fell to 720,9 + 2.0 mmHg,.
meanurinarysodium excretionwas18.5 + 1,.7mmoll24:
h and mean plasma renin activity rose significantly to
3.03 + O.41 ng/ml/h (P < 0.001). The mean fall in
blood pressure from high to low sodium diet was
9.0 + 1..6mmHg (P < 0.001). A significant negadve
correlationwasfound berweenthe fall in blood pressure
on low sodium diet and the rise in plasmarenin activitF
7r : -0.45; P < O.02;Fig. 1). Full detailsof systolicand
diastolicblood pressurechangesand other variablesthat
were measuredare shown in Table 1.
Risein plasma
reninactivity
(ng/ml/h)
10
0
-10
-20
F a l l i nM A P ( m m H g )
Fig. 1. Relationshipbetweenfall in mean arterialpressure(MAp)on
changingfrom the high sodium to the low sodiumdiet and renin
changes in 29 patientswith essentialhypertension(r : -0.45;
P < 0.02).O : white: A : black.
Low Sodium Diet, Renin and Blood PressureCappuccioet a/. 245
hypertension
withessential
of sodiumintakein 29 patients
TableL Effectsof alteration
Normaldiet
+ 3.6
169.4
1 1 0 .+
8 2.5
+ 3.4
169.3
't19.1+ 2.7
76.9+ 2.2
85.8+ 2.3
7 0 . 0! 2 . 5
0 . 9 5+ 0 . 1 4
155.8
t '10.2
64.8+ 3.5
(mmHg)
Supinesystolicbloodpressure
(mmHg)
Supinediastolicbloodpressure
(mmHg)
systolicbloodprgssure
Standing
(mmHg)
bloodpressure
diastolic
Standing
Supinepulse(beats/min
)
pulse(beats/min
Standing
) ,
Weight(kg)
Plasmareninactivity(ng/ml/h)
h)
sodium(mmol/24
Urinary
(mmol/24
h)
Urinarypotassium
Highsodium
diet
Lowsodium
diet
170.0
t 3.3
109.9+ 2.4
169.8
r 3.3
+ 2.5
1't8.3
78,1+ 2.2
85.7+ 2.5
70.4+ 2.5
0.50+ 0.09+
287.2+ 16.0++
6 4 . 4+ 3 . 6
154.5+ 2.7**
104.2+ 2.1-152,4+ 2.9*
+ 2j*
112.1
82.1+ 2.494.1+ 2.7*
68.3r 2.4".
3 . 0 3+ 0 . 4 1 *
1 8 . 7+ 1 . 7 - 49.4+ 1.9--
Resultsgiven as mean + s.e.m.
*p < 0.05;-.P < 0,001,for differencesbetweeneffectsof low sodiumdiet and both high sodiumdiet and normaldiet.
tp < 0.005;++P< 0.001,for differencesbetweeneffectsof high sodiumdiet and normaldiet.
t
Before saralasininfusion, on the last day of the low
sodium diet, mean sitting arterial pressure was
120.7 + 2.0 mmHg and during the last 10 min of
maximal infusion rate the value fell to 1t6.8 + 2.9
mmHg (r < 0.05); individual changes ranged from
-26.7 to *11.7 mmHg (Fig. 2). The changein blood
pressurewith saralasinon the low sodium diet showeda
highly significant correlation with the fall in blood
pressure on going from high to low sodium diet (r :
Pre
Saralasin
(1.251t1/kg/min)
160
-o.52; P < 0.005), thus indicating that the greater the
fall in blood pressure on sodium restriction, the less the
fall in blood pressure with saralasin (Fig. 3). There was
also a highly significant correlation between the blood
pressure fall with saralasin and the plasma renin activity
on the low sodium diet (r : 0.71;P < 0.001;Fig. 4), as
well as for the rise in plasma renin activity on going from
high to low sodium diet (r = 0.72; P < 0.001). The
severity of hypertension (mean blood pressure on
normal diet) was also related to the blood pressure
sensitivity to sodium restriction (r = O.43;P ( 0.02), to
the blood pressure changes with saralasin (r : -0.41;
P < 0.05) and to changes in plasma renin activity on
going from high to low sodium diet (r : -O.44;
P < O.O2). To rule out any spurious correlation,
because of the close interrelationships among these
150
6 140
E
130
l
Y
E rzo
-o
E
11n
+
rF
q)
100
Fig.3. Relationshipbetweenfall in mean arterialpressure(MAP)on
changing from the high sodium(HS)to the low sodium (LS)diet and
infusion(5thdayof 10 blood pressure responseto saralasin(1.25 pg/kg/min) inlused on
to saralasin
Fig.2. Bloodpressureresponse
mmol Na* diet) in 29 patients with essentialhypertension the 5th day of the low sodium diet in 29 hypertensives(r : -0.52;
(mean+ s.e.m.;*P < 0.05).
P < 0.005).O : white; A : black.
246 Journal of Hypertension1985,Vol 3 No 3
subjects on a normal sodium intake. The importance of
the compensatory rise of plasma renin activity and
angiotensin II in the maintenance of blood pressure in
o)
.I
normotensive subjects was also demonstrated by a
E
greater fall in blood pressure wirh captopril in these
E n
normotensive subjects on a low sodium diet [20]. pressor
osensitivity to angiotensin II is known to decrease with
reduction in sodium intake and to vary between padents,
.c
a) -10
thus complicating the relationship found between
c
measurements of the activity of the renin-angiotensin
_c.
system and the blood pressure fall with sodium
O
restriction [21].
Saralasin is a competitive inhibitor of angiotensin II
but it has agonist activity, when angiotensin II levels are
Fig. 4. Belationship
betweenchangein mean arterialpressure low 122,231.Using an incremental infusion rate up to a
(MAP)aftersaralasin
infusion
and levelsof plasmareninactivityon maximum of 1..25p.gA<glminand infusing parients while
the sth day of the low sodiumdiet in 29 patientswith essential sitting upright may minimize this
agonist aaivity. As --,i
(r = 0.71;P < 0.001).O: white;A : btack.
hypertension
shon-term infusion, saralasin blocks only the immediat,
effects of circulating angiotensin IL Therefore, saralasin
will underesrimate the participation of the renin system
variables, a partial correlation analysis was carried out. in the maintenance of blood pressure. Nevertheless, it
This analysis showed that the relationship between accurately reflects the relative importance of the renin
sodium sensitivify (considered as blood pressure fall on system in sustaining blood pressure when comparing
sodium restriction) and blood pressure change during
different individuals and will allow for differenies in
saralasin infusion was still significant when controlled for sensitivity to angiotensin II between patients. In our
the severity of hypertension (r : -0.47;p : g.gl) while
study, the fall in blood pressure with saralasinwas closely
it was no longer significant if corrected for the rise in correlated with the plasma renin activity before the
plasma renin activity from the high to the low sodium
infusion, as reported by others 124,251, but more
- 0 . 3 5 ;N S ) .
diet (r:
important is its inverse relation to the fall in blood
pressure with sodium restriction. The study therefore
provides direct evidence that the fall in blood pressure
which is seen on reducing sodium intake in patients with
Discussion
essential hlpertension is, at least in part, directly
Sodium restriction reduces blood pressure in many mediated by the reactivity of the renin s)stem and the
patients with essential hypertension [1-3] and appears to degree of rise of angiotensin II. This decreased
be more effective the higher the blood pressure [11]; responsiveness of the renin system in many patients with
nevertheless, the mechanism whereby it lowers blood
essential hypertension may account for the greater
pressure is not clear. Alteration in sodium intake causes decrease in blood pressure on reduction of sodiu
j
linle change in blood pressure in normotensive subjects intake seen in hypenensive patients compared t<t
[11]. Several authors have pointed out that the blood normotensive subjects [9]. It may also explain the
pressure response to a reduction of sodium intake could differences observed by some
[7,S] in the sensirivity of
be partly explained by a decreased responsiveness ofthe
hwenensive patienm to sodium restriction. Patients with
renin-angiotensin system [7-12,151.Some studies have essential hypertension tend to have a level of plasma
shown that patients with the grearesr fall in blood
renin activity below that observed in age-matched
pressure with sodium restriction have the least rise in normotensive subjects [26], although there appears to be
plasma renin activity [9]. This inverse relationship might a continuous distribution of plasma renin activitywithout
suggest drat in essential hypertension a blunted response any division into distino populations [27,28]. Hypertenof the renin-angiotensin system to sodium restriction
sive patients with a low plasma renin activity are resistant
lea<isto a-gr@
rhese pafi ents. to eleVation ofBl@l
stimuli
Epidemiological evidence has shown that on a normal [29,301.Severity of hypertension has been closely related
sodium diet, the higher the blood pressure, the lower the to blood pressure sensitivity to sodium restriction
[9,12],
plasma renin activiw [16].
but this is likely to be mediated by the lowered
Chinn et al. t17l demonstrated that circulating responsiveness of the renin-angiotensin system as blood
angiotensin II, both in normal subjects and in patients pressure rises [16]. Other mechanisms have also been
with essential hypertension, is within the range that is proposed as involved in blood pressure sensitivity to
known to modulate arterial pressure directly. Posternack alteration of sodium intake. The activation of the
et al. [78) demonstratecl that angiotensin II plays an active sympathetic nervous sysrem may possibly limit the fall in
role in sustaining normal blood pressure under blood pressure during sodium restriction, in view of an
conditions of considerablesodium depletion. MacGregor increase in plasma noradrenaline found by some
et al. Il9l also provided evidence, using a converring investigatorsI3I-341 in normorensive subjects,although
enzyme inhibitor (Captopril), that the renin angiorensin there do not appear to be any reports in hypenensive
system maintains blood pressure in normotensive subjects. Changes in the level of a circulating sodium
Low Sodlum Diet, Renin and Blood PressureCappuccioel a/.
rransport inhibitor [35] might also partly account for
differencesin sensitivityto sodium restriction.Our study,
while not excludingtheseor other possiblefactors,does
demonstratethe direct importanceof the responseof the
renin-angiotensin system to sodium restriction in
determining the observedblood pressure fall.
247
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ND,Roulston
JE,JonesJC,Morton
GA,Markandu
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JJ: Maintenance
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ND,SmithSJ,SagnellaGA,Morton
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GA,Markandu
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