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(Hypertension. 2001;37:923.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Impaired Sodium Excretion During Mental Stress in Mild Essential Hypertension
From the Department of Medicine IV/Nephrology, University of Erlangen-Nürnberg, Germany.
Correspondence to Prof Dr med Roland E. Schmieder, Universität Erlangen-Nürnberg, Medizinische Klinik IV/4, Klinikum Nürnberg Süd, Breslauer Straße 201, D-90471 Nürnberg, FRG. E-mail roland.schmieder{at}rzmail.uni-erlangen.de
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Abstract |
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In hypertensive rats, environmental stress causes sodium retention by an exaggerated increase in renal sympathetic nerve activity, which is modulated by angiotensin II. We tested whether similar effects can be observed in humans. In 66 normotensive subjects (half of them with a family history of hypertension) and 36 subjects with mild essential hypertension, urinary sodium excretion and renal hemodynamics were examined at rest and during mental stress treated either with placebo or ACE inhibition in a double-blind, randomized, cross-over design. Despite a marked increase in glomerular filtration rate in response to mental stress (
glomerular filtration rate, 4.3±7.7 mL/min in
normotensives without versus 5.6±8.4 mL/min in normotensives with a
family history versus 10.1±5.7 mL/min in patients with mild essential
hypertension; P<0.002), the
increase in urinary sodium excretion was blunted in patients with mild
essential hypertension (urinary sodium excretion, 0.12±0.17
mmol/min versus 0.10±0.14 mmol/min versus 0.05±0.14
mmol/min; P<0.05). ACE
inhibition corrected the natriuretic response to mental
stress in subjects with mild essential hypertension (urinary sodium
excretion, 0.05±0.14 mmol/min with placebo versus 0.13±0.19
mmol/min with ACE inhibition;
P<0.01); thus, after ACE
inhibition, urinary sodium excretion increased similarly in all 3
groups. In conclusion, impaired sodium excretion occurs during mental
stress in human essential hypertension but not in subjects with
positive family history of hypertension. This abnormality in sodium
handling during activation of the sympathetic nervous system appears to
be mediated by angiotensin II.
Key Words: sodium • hypertension, essential • stress • renin-angiotensin system
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Introduction |
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The kidney acts as a major long-term regulator of blood pressure by controlling extracellular sodium and water balance.1 According to Guyton’s2 hypothesis, failure of the kidneys to excrete the sodium load at a normal blood pressure level is the primary cause of essential hypertension. Sodium and water retention leads to elevated blood pressure, which in turn restores sodium excretion ("pressure natriuresis concept").
In spontaneously hypertensive rats, environmental stress provokes sodium retention mediated by an exaggerated increase in renal sympathetic nerve activity, thereby contributing to the development of hypertension.3 4 Similarly, Light et al5 have shown in a pilot study in humans that natriuresis during mental stress is impaired in subjects at high risk for essential hypertension, for example, subjects with a parental history of hypertension or with borderline systolic hypertension. These data suggest that very early in the course of human essential hypertension, an impaired sodium excretion during activation of the sympathetic nervous system occurs.
Interestingly, nerve-mediated antinatriuresis during environmental stress can be abolished by the administration of an angiotensin (Ang) II antagonist in normotensive rats.6 Thus, Ang II appears to modulate nerve-mediated antinatriuresis in rats. In this study, we investigated the effects of ACE inhibition on renal sodium handling and renal hemodynamics during mental stress in patients with mild essential hypertension and in normotensive healthy volunteers with and without a positive family history of hypertension.
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Methods |
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Study Population
Young white male students, 18 to 40 years old, were screened for participation in the study at the campus of the University of Erlangen-Nuremberg. Thirty-three normotensive control subjects without (nFH) and 33 with a positive family history of hypertension (pFH) and 36 subjects with mild essential hypertension (EH, World Health Organization stage I) were enrolled in the study.
Normotension was defined by systolic blood pressure
(SBP) <140 mm Hg and diastolic blood pressure (DBP)
<90 mm Hg on 4 blood pressure readings. If the average SBP was
140 mm Hg or the DBP was 90 mm Hg, the subjects were
classified as having mild EH. A positive family history of hypertension
was defined as SBP 160 mm Hg or DBP 95 mm Hg of the
father, the mother, or one of the siblings before the age of 60 years.
Blood pressure readings were taken in the sitting position after 5
minutes of rest with a standard mercury sphygmomanometer on 2 different
occasions at least 2 weeks apart (according to World Health
Organization recommendations).
None of the subjects had ever received cardiovascular medication, none followed any specific dietary guidelines, and none had a secondary form of hypertension or target organ damage caused by hypertension. All participants underwent a clinical examination including 12-lead ECG, fundoscopy, sonography of the kidneys and adrenal glands, Doppler sonography of the renal arteries, and routine laboratory tests. Written informed consent was obtained from each individual, and the study protocol was approved by the local ethics committee.
Study Design
The study protocol followed a randomized,
double-blind cross-over design. Participants were randomly allocated
either to receive placebo for 1 week (baseline examination) followed by
a washout period of 7 days, and then ACE inhibition with 2.5 mg
cilazapril once daily for another week (ACE inhibitor
phase) or the same regimen with the sequence reversed. Pill counts were
performed to ensure compliance, and patients were informed that serum
drug levels would be measured (but eventually not done). Evaluation of
urinary sodium excretion (UNa), renal hemodynamics, and
the humoral status of the renin-angiotensin system was
performed at the end of the placebo and the ACE inhibitor
phase, respectively. Participants were asked to refrain from smoking
and drinking coffee or alcoholic beverages on the day before the
studies.
Experimental Methods
To activate the sympathetic nervous system
with mental stress, we used a modified time reaction task device
(Wiener Determinationsgerät) with a computerized feedback system to
hold stimulus intensity constant over 30 minutes of stress
testing.7 In this test, the
speed of the task is adjusted to the performance of each
participant to keep stress intensity constant over a prolonged period
of time. The rationale of using a stress test with low stimulus
intensity was to measure renal hemodynamics in parallel
to sodium excretion. Only low stress stimulus intensity provides a
hemodynamic response sustained up to 30
minutes,7 8 and the
constant infusion technique requires at least 20 minutes to achieve a
new steady-state
condition.8
To determine glomerular filtration rate (GFR) and renal plasma flow (RPF), we applied the constant infusion technique without urine sampling as previously described.8 Filtration fraction (FF) was calculated by dividing GFR by RPF. Blood pressure was measured every minute (Dinamap). Parameters of the renin-angiotensin-aldosterone system were all determined by radioimmunoassay.
Statistics
All data were analyzed with the PC version of
the Statistical Package for Social
Sciences.9 One-way ANOVA was
used to detect any significant difference among the 3 groups, and the
Bonferroni method was applied for subsequent tests. Paired
t tests were done for
comparisons within groups between rest and stress values and between
treatment phases. Pearson’s correlation coefficients were calculated
when indicated. Results are given as mean±SD in the text and as
mean±SEM in the figures.
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Results |
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Baseline Characteristics
The baseline characteristics are given in Table 1. By study design, blood pressure was higher in hypertensive patients than in normotensive control subjects. Baseline renal hemodynamics, 24-hour UNa, and plasma concentrations of the renin-angiotensin-aldosterone system components were similar at baseline. With respect to these parameters, no difference was noted between normotensives with and those without a family history of hypertension.
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Central and Renal Hemodynamics
During Mental Stress
In response to mental stress, SBP, DBP, and heart rate
increased, whereas RPF decreased slightly, with no difference among the
groups
(Table 2). GFR and FF increased in all 3 groups. However, in
hypertensive subjects, the increase was significantly greater. With
regard to both parameters, no difference was found between
normotensive subjects with and those without a family history of
hypertension.
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Ang II concentrations increased only in hypertensive subjects. The increase in GFR was greater, the more plasma Ang II concentration increased (r=0.31; P<0.001). Aldosterone values decreased similarly in all 3 groups.
ACE inhibition blocked the increase of Ang II concentration
in hypertensive subjects (Ang II, +4.6±5.3 pg/mL with placebo
versus +1.1±5.5 pg/mL with ACE inhibition,
P<0.05) and blocked the
increase in GFR (GFR, +10.1±5.7 mL/min with placebo versus
+8.7±6.1 mL/min with ACE inhibition,
P<0.02). As a consequence,
under ACE inhibition, no differences were found between the groups with
respect to the aforementioned
parameters.
UNa During Mental Stress
UNa at rest was similar among the 3 groups. Mental
stress produced a significant and similar rise of UNa in both
normotensive groups, whereas in hypertensive subjects, no significant
rise was observed (UNa, 0.12±0.17 mmol/min in nFH versus
0.10±0.14 mmol/min in pFH versus 0.05±0.14 mmol/min in EH;
P<0.05, or as median and 25%
and 75% quartile, 0.07 [0.02, 0.23] mmol/min in nFH versus 0.10
[0.02, 0.15] mmol/min in pFH versus -0.005 [-0.04,
0.11] mmol/min in EH,
P<0.05). In parallel,
fractional excretion of sodium increased in the normotensive subjects,
whereas it decreased in the hypertensive subjects (fractional
excretion of sodium, 0.32±0.52 in nFH versus 0.28±0.37 in pFH versus
-0.20±0.49 in EH, P<0.05).
Thus, a blunted response of sodium excretion was noted in hypertensives
only
(Figure 1 and
Table 3).
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With ACE inhibition, UNa in response to mental stress
rose significantly in hypertensives (UNa, +0.05±0.14 mmol/min
with placebo versus +0.13±0.19 mmol/min with ACE inhibition;
P<0.05) and reached the level
of normotensive control subjects
(Figure 2). Thus, ACE inhibition normalized UNa during mental
stress in patients with EH.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our principal finding is that stress-induced natriuresis is impaired in patients with mild EH but was restored by ACE inhibition.
Which mechanism may account for the observed blunted natriuresis? Because the increase in glomerular filtration in response to mental stress was higher in hypertensive subjects, thereby confirming earlier results of our study group,10 an impaired increase in filtered sodium does not account for the blunted natriuretic response.
Differences in stimulation of the adrenal gland and consequently in aldosterone concentration are unlikely to explain the observed antinatriuresis in EH because the decrease in aldosterone concentrations during mental stress, which has been reported previously,11 was similar in all 3 groups. Furthermore, aldosterone-mediated changes in distal tubular sodium transport need >45 minutes to take place,12 but our stress phase lasted only 30 minutes.
The effect of the renal nerves on stress-induced sodium
retention has been shown to be mediated by 
1
receptors at the proximal tubular
site.13 In spontaneously
hypertensive and in DOCA-NaCl hypertensive rats, increased efferent
renal sympathetic nerve activity appears to be critical in the
initiation and development of EH by provoking sodium
retention.3 4 In
these animal models, the air jet as a model of environmental stress
leads to exaggerated activation of the renal sympathetic
nerves.
In Sprague-Dawley rats, it has been shown that renal nerve–mediated sodium retention during environmental stress can be inhibited by renal nerve ablation or Ang II type 1 receptor blockade, pointing to the crucial role of Ang II in modulating the antinatriuretic response.6 Ang II facilitates release of noradrenergic transmitters at the presynaptic site and acts postsynaptically with released norepinephrine in a synergistic manner.14 15 16 17 In addition, Ang II is known to influence renal sodium retention indirectly by a decrease in medullary blood flow and renal interstitial pressure and by an enhanced sodium reabsorption through an enhanced filtration fraction leading to augmented peritubular capillary colloid-osmotic pressure.18
In human hypertension, much less is known about the activity of the renal sympathetic nerves. Although direct renal nerve activity recording is not feasible in humans, Esler et al19 found under resting conditions an increased renal venous norepinephrine outflow in patients with EH pointing to an increased activation of the sympathetic nervous system. Interestingly, norepinephrine outflow from the kidney was greater than that from the heart or liver, thereby suggesting a disproportionally increased activation of the renal sympathetic nerves. Apart from the sympathetic nervous system, our finding of a correction of stress-induced natriuresis in hypertensives by ACE inhibition further points to the renin-angiotensin-system as an important underlying pathogenic mechanism in humans.
Recently, we have demonstrated that hypertensive subjects display an enhanced antinatriuresis in response to exogenously administered Ang II,20 confirming the hyperresponsiveness to Ang II, which has been described for the renal vasculature10 21 22 and for cardiac structure.23
In contrast to Light et
al,5 we did not find a
difference in stress-induced natriuresis between normotensive subjects
with and those without a family history of hypertension. This might be
explained by different stress stimulus intensity. The stress test used
in the current study elicited a rather mild increase in blood pressure
(BP) and heart rate (HR) in offspring of hypertensive parents
(BP systolic, 10 mm Hg; BP diastolic,
5 mm Hg; HR, 9±8 bpm) as opposed to the stress test used by
Light et al (BP systolic, 19 mm Hg; BP
diastolic, 8 mm Hg; HR, 22 bpm). Moreover, Light
et al not only included normotensive subjects but subjects with
borderline systolic hypertension as well. Additionally, an
impaired sodium excretion was only shown in the subgroup responding
with a higher increase in heart rate in response to mental stress but
not in those with a lower increase in heart
rate.5
A blunted stress-induced natriuresis in subjects with mild EH compared with normotensives despite similar central hemodynamic changes suggests that the renal response to mental stress is a better marker for early alterations in the course of EH than the central cardiovascular response.
Conclusions
Our data indicate that patients with EH show blunted
natriuresis during activation of the sympathetic nervous system that
appears to be mediated by an overproportional increase of Ang
II.
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Acknowledgments |
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This study was supported in part by Merck, Darmstadt, Germany. We thank Anja Friedrich, research nurse, for her outstanding technical assistance.
Received April 11, 2000; first decision May 2, 2000; accepted August 24, 2000.
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References |
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