(Hypertension. 1996;27:202-208.)
© 1996 American Heart Association, Inc.
Articles |
Does the Renin-Angiotensin System Determine the Renal and Systemic Hemodynamic Response to Sodium in Patients With Essential Hypertension?
From the Groningen Institute for Drug Studies (of Groningen Utrecht Institute for Drug Exploration), Department of Medicine, Division of Nephrology, State University Hospital, Groningen, Netherlands.
Correspondence to D. de Zeeuw, MD, PhD, Department of Medicine, Division of Nephrology, State University Hospital, Hanzeplein 1, 9713 RB Groningen, Netherlands.
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Abstract |
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Abstract Many patients with essential hypertension respond to a high dietary sodium intake with a rise in blood pressure. Experimental evidence suggests that the renal hemodynamic response to sodium determines, at least partially, this rise in blood pressure. Our aim was to clarify the role of the renin-angiotensin system in the renal and systemic adaptation to a change in dietary sodium. We studied changes in mean arterial pressure (MAP) (millimeters of mercury), effective renal plasma flow (ERPF), body weight, and immunoreactive renin in 17 patients with essential hypertension and 15 normotensive control subjects, randomly crossing over between a 3-week sodium-restricted (50 mmol/24 h) and a sodium-replete (200 mmol/24 h) diet period. In addition, the effects of renin inhibition by remikiren (600 mg, single oral dose) were studied during the high sodium period. In normotensive control subjects, high sodium intake had no effect on MAP or body weight, whereas ERPF increased (490±19 to 535±21 mL/min, P<.05) and immunoreactive renin decreased (32±6 to 14±1 pg/mL). In hypertensive subjects, high sodium intake induced a heterogeneous response of MAP (median change, 2.6 mm Hg; range, -4.7 to +21.2; P=NS) and ERPF (median change, 21 mL/min; range, -33 to +98; P=NS). Body weight increased from 81.3±1.9 to 82.5±2.0 kg (P<.05), and immunoreactive renin decreased from 18±3 to 10±1 pg/mL (P<.05). Interestingly, the patients with a distinct rise in MAP showed a blunted ERPF response to high sodium intake (r=-.70, P<.01) and an increase in body weight (r=.76, P<.001). Moreover, the increase of ERPF was more pronounced in patients with a larger fall in immunoreactive renin (r=.77, P<.001). After administration of remikiren, a heterogeneous response in ERPF was observed: the patients with the blunted ERPF response to high sodium intake showed the largest ERPF rise (r=.70, P<.01). The remikiren-induced rise in ERPF correlated (r=.68, P<.01) with the fall in MAP (114±2 to 110±2 mm Hg). In conclusion, in patients with essential hypertension a rise in blood pressure in response to high sodium intake appears to partially be the result of insufficient renal vasodilation. This seems to be due to an inadequate (intrarenal?) renin-angiotensin system response to increased sodium intake.
Key Words: renal hemodynamics • blood pressure • sodium • renin inhibition • remikiren
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Introduction |
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A healthy individual is able to consume different amounts of sodium without sustained changes in blood pressure. In many patients with essential hypertension, on the other hand, blood pressure is more susceptible to changes in dietary sodium.1 2 3 4 A difference in the renal hemodynamic response to sodium appears, at least in part, to determine how the sodium intake affects blood pressure. Hollenberg and Williams and coworkers5 6 7 showed that a subset of patients with essential hypertension could be characterized by a blunted renal vascular response to sodium and a concomitant sodium sensitivity of blood pressure. Campese et al8 found abnormal renal hemodynamics in black sodium-sensitive patients with hypertension compared with sodium-resistant patients.
Since the RAS is involved in systemic and renal hemodynamic regulation as well as sodium homeostasis, we searched to establish the role of the RAS in the renal and systemic hemodynamic adaptation to an increase in dietary sodium.9 10 11 12 We therefore first studied the effects of a change in sodium intake on these parameters. In addition, the effects of acute interference in the RAS with the specific renin inhibitor remikiren during high dietary sodium intake was studied both in patients with uncomplicated essential hypertension and in healthy control subjects. Our premise was that a blunted renal vascular response to sodium, possibly due to a relatively inadequate suppression of (intrarenal) angiotensin II, would be accompanied by a rise in blood pressure. If so, then renin inhibition should induce, particularly in these patients, a more pronounced renal vasodilation.
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Methods |
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Patients and Protocol
Thirty-two subjects were included in the study. The normotensive control group of 15 subjects all had a sitting diastolic blood pressure of less than 90 mm Hg. Seventeen subjects had moderate essential hypertension (sitting diastolic blood pressure, 95 to 115 mm Hg) without clinically relevant end-organ damage. Excluded were patients with secondary hypertension, patients who were overweight (more than 120% of their ideal body weight), and patients with a history or evidence of alcohol or drug abuse. Women with childbearing potential or taking birth control pills were also excluded. All subjects gave their informed consent, and the study was approved by the Ethical Committee of our hospital.
The normotensive subjects were younger than the hypertensive subjects (39 years; range, 22 to 64 years versus 51 years; range, 35 to 67), and they weighed less (73±2 kg versus 82±2 kg, P<.05) compared with the hypertensive subjects. All normotensive subjects were male and white, whereas the hypertensive group consisted of 14 men and 3 women (14 whites, 1 black, and two Asians).
Before entry into the study, all antihypertensive medication had been withdrawn for at least 3 weeks until blood pressure had stabilized. The minimum study duration was 6 weeks, including a random crossover after 3 weeks between a sodium-restricted (50 mmol/24 h) and a sodium-replete (200 mmol/24 h) diet. Subjects visited the outpatient clinic once weekly. Subjects entered the actual study week only if sodium excretion stabilized below 70 mmol/24 h (low sodium period) or above 180 mmol/24 h (high sodium period) on two consecutive occasions. The study weeks in the low sodium and high sodium periods were similar, and they each consisted of 2 study days on which placebo or drug (remikiren, 600 mg) was administered on a double-blinded, randomized basis. These 2 study days were separated by 3 washout days.
Each study day was as follows: after an overnight fast all subjects stayed in the hospital in a supine position during the study day except when voiding. From 8 AM to 6 PM blood pressure was recorded and renal hemodynamics as well as urinary excretion of sodium and creatinine were measured. The run-in period lasted from 8 AM until 11 AM. From 11 AM until 1 PM baseline data were obtained. After the administration of remikiren or placebo at 1 PM, effects were monitored for 5 hours. Urine was collected at hourly intervals. During the study day a constant infusion of 150 mL glucose 5%/h was administered in a forearm vein, and meals (every second hour in identical portions) and drinks (150 mL/h) were supplied. This added to a total amount of 3000 mL fluids, 50 mmol sodium, and 100 mmol potassium over the study day during low sodium periods and to 200 mmol sodium during high sodium periods. At 1 PM an extra 100 mL of water was given to improve swallowing of the test compounds. Blood was drawn at 1, 2, 3, 4, and 6 PM for determination of immunoreactive renin, at 12 AM and 6 PM for serum electrolytes, and every hour from 11 AM until 6 PM for the measurement of ERPF and GFR.
Methods
Blood pressure was recorded by an automatic
noninvasive
device (Dinamap, Criticon Inc) every 10 minutes during the entire
study day. MAP was calculated as diastolic blood pressure
plus one third of the difference between systolic and
diastolic pressure. For each hour the mean value was
calculated.
Urinary sodium and creatinine were measured by a standard autoanalyzer technique (SMA-C, Technicon). Blood samples for measurement of immunoreactive renin were collected into prechilled evacuated tubes containing EDTA as anticoagulant. After separation, plasma was stored at -20°C until analysis. Immunoreactive renin was determined with the use of the renin IRMA Pasteur kit, with coefficients of variation of 15.9% (interassay) and 6.6% (intra-assay), both at 31 pg/mL.13 GFR and ERPF were measured by constant infusion of 125I[iothalamate] and 131I-hippuran, respectively.14 The day-to-day coefficients of variation of this method were 2.2% and 5.0%, respectively. GFR and ERPF were corrected for standard body surface area (1.73 m2). Filtration fraction was calculated as the ratio of GFR to ERPF. RVR was calculated as the ratio of MAP to ERPF. The fractional excretion of sodium was calculated as the ratio of the respective clearances to GFR.
Data Analysis
For practical purposes, data are discussed and
presented
as if each patient switched from a low to a high sodium diet. In fact,
low and high sodium diets were randomly assigned. The low and high
sodium diet comparison was performed with the use of the placebo data
in the respective sodium diet periods. The effect of remikiren was
tested by comparing each individual remikiren day with its concurrent
placebo day, adjusted for baseline values. Data are expressed as
mean±SEM unless otherwise indicated. All values presented are
the mean of the 5-hour postdose study period and are not peak values.
Mean values were compared by Student's t test for paired
data. If considered appropriate, a paired nonparametric
Wilcoxon signed rank test was used. To evaluate relationships
between variables, Pearson's correlation coefficients were
calculated. Multiple regression analysis was performed to
assess parameters that independently contributed to the
observed changes in the parameters of interest. After
univariate analysis, a model was created containing
all predicting variables with values of P<.30. After
this model was tested, all variables with values of
P<.05 were put into a final model. All single remaining
parameters were then separately added to this model to test
their contribution. This was done in all subjects together (n=32), with
normotension or hypertension as a categorical variable, and in the
separate normotensive and hypertensive subgroups. Values of
P<.05 (two-sided) were considered to indicate
statistical significance.
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Results |
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Responses to the Change in Sodium Intake
The Table
shows the overall results. All subjects
in both study groups adhered well to the low and high sodium diets, as
reflected by urinary sodium excretion. In the normotensive group the
average MAP did not change after the subjects switched to high sodium
intake. In the hypertensive group, average MAP rose slightly. However,
the response of blood pressure was heterogeneous: in some
patients a clear rise in MAP was observed, whereas in others no change
or even a slight fall occurred (median change, 2.6 mm Hg; range,
-4.7 to 21.2 mm Hg) (Fig 1). In both study groups
heart rate did not change.
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A clear difference between normotensive and
hypertensive subjects was
observed with respect to the renal hemodynamic
response. During the low sodium diet, ERPF was greater in normotensive
control subjects than in hypertensive subjects (490±19 versus
424±21
mL/min, P<.05); it increased during high sodium intake to
535±21 mL/min (P<.05) in the normotensive group and not
significantly to 451±25 mL/min in hypertensive subjects.
Interestingly, as shown in Fig 2, this difference in
ERPF response was partially explained by the more variable
individual response in hypertensive patients. In some a distinct
increase was observed, whereas we found no change or even a decrease in
ERPF in the others (median change, 21 mL/min; range, -33 to 98
mL/min). Baseline GFR was not different between the two study groups,
nor was the sodium-induced increase in GFR. Filtration fraction and
RVR were significantly lower in normotensive compared with hypertensive
subjects. This applied to both diets. The high sodium diet itself did
not induce significant changes in these parameters.
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Immunoreactive renin during low sodium intake was higher in the normotensive than in the hypertensive group and decreased in both groups after the increase in dietary sodium. Body weight was comparable on both sodium diets in normotensive subjects but increased in hypertensive subjects.
Determinants of Sodium-Induced Responses
What parameter could
explain the observed differences
in the adaptation to the higher sodium intake between the two groups
and particularly within the hypertensive group? Multiple regression
analysis in the combined control and patient groups, with
sodium-induced change in blood pressure as the dependent
variable, revealed that the change in blood pressure was inversely
related to the increase in ERPF (P=.008) and the change in
immunoreactive renin (P=.006) and positively related to the
subject category (normotensive or hypertensive; P=.004) but
not to age (P=.91), body weight (P=.77), race
(P=.89), sex (P=.84), and the initial ERPF
(P=.44). The multiple r of this model was .82. In
hypertensive patients the change in MAP correlated inversely with an
increase in ERPF (r=-.70, P<.01; Fig
3,
left panel). Thus, a greater rise in blood pressure was
observed in a patient in whom renal vasodilation in response to high
sodium intake was less impressive. This rise in MAP was accompanied by
an increase in filtration fraction (r=.79,
P<.001; Fig 3, right panel) and RVR
(r=.86,
P<.001). Multiple regression analysis demonstrated
that the change in blood pressure was not determined by age
(P=.94), race (P=.91), sex
(P=.89),
body weight (P=.73), initial ERPF (P=.22),
initial blood pressure (P=.13), or initial immunoreactive
renin (P=.66). Interestingly, a more pronounced increase in
ERPF occurred in those patients in whom high sodium had stronger
suppressed immunoreactive renin (r=-.77,
P<.001; Fig 4). A less pronounced increase
in ERPF (r=-.59, P<.05) and a rise in
blood pressure (r=.76, P<.001; Fig
5) were observed in those patients who gained more
weight during the high sodium diet. In normotensive subjects the
situation was different. MAP correlated with the decrease in
immunoreactive renin in response to high sodium (r=.82,
P<.001), such that in subjects with the largest decrease in
immunoreactive renin even a fall in blood pressure could be observed.
No correlations were found between the change in blood pressure and
age, body weight, initial blood pressure, initial ERPF, or the
sodium-induced change in ERPF in normotensive subjects. On the
other hand, age (P=.01) and the sodium-induced decrease
in renin (P=.03) predicted the rise in ERPF.
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Responses to Renin Inhibition
Overall results are shown in
the Table
. During the high sodium
diet, the renin inhibitor remikiren induced a slight but
not significant fall in average MAP in both study groups. The response
in the hypertensive group compared with the normotensive group was less
uniform (Fig 1), showing a clear fall in blood pressure in some
hypertensive patients. Heart rate and body weight did not change in
either group.
The renal hemodynamic response to remikiren was quite
uniform in normotensive subjects: remikiren induced a further
significant increase in ERPF, whereas GFR remained fairly stable. The
increase in ERPF after remikiren, however, was not significant for the
hypertensive group (451±25 to 464±23 mL/min). This was again due
to
the greater variability in response (median change, 18 mL/min; range,
-30 to 56 mL/min) (Fig 2). Filtration fraction and RVR
decreased
significantly in the normotensive but not in the hypertensive group.
Remikiren induced an increase in immunoreactive renin during high
sodium intake in both groups. This increase was more pronounced in
normotensive subjects (P<.05).
Urinary volume in the 5 hours after renin inhibition did not change in the normotensive group (1326±50 to 1388±60 mL/5 h) but increased in the hypertensive group (1017±49 to 1148±56 mL/5 h, P<.05).
Sodium excretion rose significantly in the normotensive as well as the hypertensive group (14.7±1.2 to 16.6±1.3 and 13.4±1.1 to 15.4±1.1 mmol/h, respectively; both P<.05). Fractional sodium excretion showed a similar rise (1.14±0.1% to 1.45±0.13% in normotensive subjects and 1.23±0.13% to 1.40±0.15% in hypertensive subjects; both P<.05). Urinary sodium excretion did not differ between the two groups.
Determinants of Remikiren-Induced Responses
In hypertensive
patients, multiple regression analysis
demonstrated that a greater fall in blood pressure during renin
inhibition was determined independently by a smaller increase in ERPF
in response to high sodium (P=.001) and by more pronounced
remikiren-induced increases in both ERPF (P=.01) and
immunoreactive renin (P=.02). This model appeared highly
predictive for the fall in blood pressure (multiple r=.89).
Other factors, such as baseline blood pressure and ERPF, did not
explain the fall in blood pressure. Furthermore, remikiren induced a
more pronounced rise in ERPF in case no increase in ERPF in response to
high sodium intake had occurred (r=.70, P<.01).
The reactive rise in renin, induced by remikiren, correlated with the
sodium-induced suppression in renin (r=.76,
P<.001). In normotensive subjects, on the other hand, the
response of blood pressure and ERPF to change in dietary sodium did not
explain the absence or presence of the effects induced by renin
inhibition. Differences in the status of the RAS could also not explain
differences in the degree of response of any of the studied
parameters after renin inhibition. The reactive rise in
renin, induced by remikiren, again correlated with the
sodium-induced suppression in renin (r=.79,
P<.001).
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Discussion |
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In the present study patients with uncomplicated essential hypertension showed a heterogeneous response in ERPF upon an increase in dietary sodium intake. Moreover, our data indicate that when a higher sodium intake induces an increase in ERPF, blood pressure remains fairly stable, as in our normotensive control subjects, while in the case of nonresponsive renal vasculature blood pressure rises. The impaired renal hemodynamic response to sodium is reversible since the renin inhibitor remikiren, during high sodium intake, could still induce renal vasodilation in these patients. The use of this very specific blocker of the RAS provides evidence that inappropriate suppression of RAS in response to high sodium intake impedes an adequate renal vascular response, which as a result makes blood pressure more sensitive to sodium.
Several studies during the past decades have shown that blood pressure variation in response to changes in dietary sodium intake in patients with essential hypertension follows a more or less gaussian distribution.15 The individual blood pressure response to sodium, however, appears to be highly reproducible.16 17 These findings could be clinically important since sodium sensitivity of blood pressure in patients with essential hypertension has been associated with a higher risk of cardiovascular and renal complications, such as left ventricular hypertrophy and microalbuminuria.18 19 20 It has been shown that the increased sensitivity of blood pressure to sodium is more prevalent in blacks, in the obese, and in older patients.21 22 23 24 25 26 27 28 29 In the present study, however, multiple regression demonstrated that in our study groups, race, sex, age, or body weight did not explain the observed differences in the blood pressure response to sodium.
What then could have caused the rise in blood pressure in a subset of our patients? Several authors emphasized a primary disturbance within the kidney as a result of its central role in sodium and volume homeostasis and long-term blood pressure regulation.30 31 32 33 34 A rise in blood pressure is thought to compensate for the decreased capacity of the kidney to excrete sodium, thus enabling the kidney to maintain sodium balance. The fact that in the present study body weight increased only in those patients who showed a rise in blood pressure indeed indicates that volume expansion, probably due to impaired sodium handling and consequently sodium retention, may have contributed to this rise.35 36 37
Most strikingly, a discrepant response in effective ERPF was observed. High sodium intake induced an increased flow in both sodium-resistant patients and normotensive control subjects, whereas ERPF did not change in the sodium-sensitive patients. GFR, on the other hand, increased to a comparable extent. As a consequence, RVR and filtration fraction increased only in those patients who displayed a rise in blood pressure in response to high sodium intake. This probably indicates both an increased preglomerular and postglomerular vascular tone.38 Our findings confirm data from previous studies. Campese and coworkers8 19 first found decreased ERPF during high salt intake in black patients and recently also in a group of white salt-sensitive patients with essential hypertension. Hollenberg et al5 39 defined a distinct subset of essential hypertensive patients as nonmodulators who, as well as having at least 10 other characteristics of hypertension, failed to increase their renal blood flow during high sodium intake. Salt sensitivity of blood pressure appeared to be more prevalent in the non-modulators, although no direct relation could be observed, and these two terms are not identical.6 40 Taken together, the impaired sodium handling seems to be related to the incapacity of the kidney to increase its blood flow in response to a higher sodium intake. This could have resulted in disturbed renal tubular sodium reabsorption. Apparently, the GFR response and consequently the filtered load is not a limiting factor in renal sodium handling in essential hypertension.
Clearly, such nonresponsiveness of the renal vasculature may partially be the result of fixed vascular changes in the hypertensive kidney, known as arteriolar nephrosclerosis, but it is also likely that some functional enhancement of renal vascular tone is in play. The link between elevated blood pressure, even in the prehypertensive state, and abnormal renal vasoconstriction has been shown in many different studies.38 41 42 The fact that ERPF even during low sodium intake is reduced in the hypertensive group compared with the normotensive group indeed could indicate that such structural damage has developed during the course of the hypertensive disease. Schmieder et al43 recently showed not only a decline in ERPF with increasing age but moreover found that this decline is greater in hypertensive patients. This supports our data, since in our hypertensive group we found a lower ERPF in the older subjects. Interestingly, however, the sodium-induced increase in flow did not relate to age. The observed renal vasoconstriction is therefore at least to some extent functional.
Since the RAS is an important determinant of renal vascular tone and its activity is modulated by dietary sodium, it is conceivable that a disturbed interaction between sodium and the RAS causes an impaired renal hemodynamic response.9 39 The high sodium diet resulted in a variable suppression of the RAS and, interestingly, a more pronounced decrease in renin coincided with a greater renal vasodilation. This indeed suggests that an inappropriately suppressed RAS may have prevented renal vasodilation during high sodium intake. A number of investigators have studied the RAS in relation to salt sensitivity of blood pressure in essential hypertension.16 44 45 46 47 Systemic renin is assumed to be low and the response to sodium restriction blunted in salt-sensitive patients. This corroborates our findings, but we also show that the blunted renin response correlates with diminished renal vasodilation. Furthermore, a significant correlation between renin decrease and renal vasodilation also existed in a subgroup of our hypertensive patients, with renin levels that were similar to those in the normotensive control group (n=9, P=.01). In addition, multivariate analysis in normotensive subjects demonstrated a correlation between the sodium-induced renin decrease and renal vasodilation when age was added to the model. The observed variation in renin response could not be explained by differences in adherence to both sodium diets. It seems likely that the responsiveness of the RAS is individually determined. Indeed, we found that in both normotensive and hypertensive subjects, the renin response to sodium corresponded strikingly with the reactive rise in renin induced by remikiren.
It is of note that whereas some authors state that the blunted renin response to sodium suggests a relatively minor contribution of the RAS to sodium sensitivity, we argue that it just as well could mirror a less pronounced renin decrease within the kidney, with considerable impact on renal hemodynamics.16 45 46 We then used the renin inhibitor as a specific tool to explore whether an increase in renal blood flow during the high sodium diet still could be established. A more effective blockade by renin inhibition in those patients whose RAS had been less completely suppressed by sodium could be anticipated. Data from the literature indicate that the remikiren dose of 600 mg is at the top of the dose-response curve, at least with respect to the blood pressure–lowering effect.48 Remikiren indeed induced an increase in renal blood flow predominantly in these patients, indicating reversible and therefore functional rather than structural changes in the renal vascular bed but also a higher state of activation of the RAS within the kidney. Our data support a mechanism that was also proposed by Redgrave et al49 and Dluhy et al.50 They showed that 3 days of treatment with the angiotensin-converting enzyme inhibitor enalapril could partly correct the impaired renal hemodynamic response to sodium that was characteristic for their nonmodulating subjects. Furthermore, renovascular responsiveness to infused angiotensin II was also significantly enhanced in the nonmodulators, which prompted the authors to suggest that the enalapril-induced increase in renal blood flow reflected a fall in intrarenal angiotensin II and not an increase in prostaglandins or kinins. Taken together, these findings strongly suggest that an abnormal interaction between dietary sodium and the RAS is a cause for impaired renal hemodynamic response, although it is still unknown at exactly which level this disturbance takes place. Our data primarily suggest dysfunctional regulation within the renal tissue. Differences in responsiveness of the renal vasculature to prevailing angiotensin II levels could also have contributed to our findings.51 Further studies that could measure the exact local state of activation of the RAS are needed to clarify this issue.
Could we have overlooked other neurohumoral regulatory systems to explain our findings? There is evidence that salt-sensitive hypertension may be dependent on increased activity of the sympathetic nervous system, although not all investigators could confirm this.45 52 Campese et al8 in their aforementioned study found indirect support that abnormalities in autonomic nerve function exist in salt-sensitive patients since they observed a relatively more pronounced decrease in heart rate in response to high sodium intake in the sodium-resistant subjects. However, we did not find a relationship between sodium-induced changes in heart rate and ERPF or blood pressure. An increase in the ratio of norepinephrine to dopamine secretion, a reduced secretion or action of atrial natriuretic factor, and many other factors have all been proposed as possible mediators in the pathophysiology of hypertension and salt sensitivity.40 53 54 Although not studied by us, it is unlikely that these factors could explain the observed renal and systemic responses after renin inhibition in the present study. Moreover, most of these studies did not take into account the sodium-induced changes in renal hemodynamics.
The renal hemodynamic response to sodium and to remikiren in normotensive control subjects deserves short attention. The less pronounced rise in ERPF during high sodium intake in a minority of the subjects did not, in contrast to the situation in hypertensive subjects, result in a rise in MAP. Remikiren induced a significant, further increase in ERPF, despite the high sodium intake and the clearly suppressed systemic renin. This ERPF response is rather unusual and was not found with other RAS blockers.55 56 57 Thus, the response to remikiren could be drug specific. Animal experiments indeed show that the renin inhibitor remikiren has a strong affinity for renal tissue compared with other RAS blockers.58 However, an alternative explanation can be found in the data of Uneda et al,59 who showed a renal vasodilator response to captopril during a normal diet in normotensive adolescents genetically predisposed to hypertension. Regretfully, we have no verified information on the family history of our study groups and do not know whether the same phenomenon is in play.
In conclusion, adaptation of the normal kidney to a higher sodium intake is characterized by a rise in GFR and ERPF, with unchanged blood pressure. The RAS is an important modulator of these hemodynamic changes. In essential hypertension, a rise in blood pressure in response to high sodium intake appears to partially be the result of insufficient renal vasodilation. This seems to be the result of an inadequate (possibly intrarenal) response of the RAS.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We acknowledge the support and assistance of P. van Brummelen and G. Verwey (both of Hoffmann–La Roche Ltd). Furthermore, we acknowledge the technical assistance of P.T. Hesling-Kuiper, A. Drent-Bremer, and M. van Kammen.
Received April 27, 1995; first decision September 5, 1995; accepted September 5, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
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1. Dahl LK. Possible role of salt intake in the development of essential hypertension. In: Cottier P, Bock KD, eds. Essential Hypertension: An International Symposium. Berlin, Germany: Springer-Verlag; 1960;53-65.
2. Elliott P. Observational studies on salt and blood pressure. Hypertension. 1991;17(suppl I):I-3-I-8.
3. Stamler J, Rose G, Elliott P, Dyer A, Marmot M, Kesteloot H, Stamler R. Findings of the international cooperative INTERSALT study. Hypertension. 1991;17(suppl I):I-9-I-15.
4. Muntzel M, Drucke T. A comprehensive review of the salt and blood pressure relationship. Am J Hypertens. 1992;5:1S-42S. [Medline] [Order article via Infotrieve]
5. Williams GH, Tuck ML, Sullivan JM, Dluhy RG, Hollenberg NK. Parallel adrenal and renal abnormalities in the young patient with essential hypertension. Am J Med. 1982;72:907-914. [Medline] [Order article via Infotrieve]
6. Hollenberg NK. `Sodium-sensitive' essential hypertension: emerging insights into pathogenesis and therapeutic implications. Contemp Nephrol. 1985;3:303-331.
7. Hollenberg NK, Moore T, Shoback D, Redgrave J, Rabinowe S, Williams GH. Abnormal renal sodium handling in essential hypertension. Am J Med. 1986;81:412-418. [Medline] [Order article via Infotrieve]
8.
Campese VM, Parise M, Karubian F, Bigazzi R.
Abnormal renal hemodynamics in black salt-sensitive
patients with hypertension. Hypertension. 1991;18:805-812.
9. Mimran A, Guiod L, Hollenberg NK. The role of angiotensin in the cardiovascular and renal response to sodium restriction. Kidney Int. 1974;5:348-355. [Medline] [Order article via Infotrieve]
10. Navis GJ, de Jong PE, Donker AJM, van der Hem GK, de Zeeuw D. Enalapril and the kidney: renal vasodilation and natriuresis due to inhibition of angiotensin II formation. J Cardiovasc Pharmacol. 1985;8(suppl 1):S30-S34.
11. Navis G, de Jong PE, Donker AJM, van der Hem GK, de Zeeuw D. Moderate sodium restriction in hypertensive subjects: renal effects of ACE-inhibition. Kidney Int. 1987;37:815-819.
12. Rabinowe SL, Redgrave JE, Shoback DM, Podolsky S, Hollenberg NK, Williams GW. Angiotensin and the renal circulation in hypertension. Circulation. 1988;77:159-163.
13. Menard J, Guyene TT, Corvol P, Pau B, Simon D, Ronucci R. Direct immunometric assay of active renin in human plasma. J Hypertens. 1985;3(suppl 3):275-278.
14. Donker AJM, van der Hem GK, Sluiter WJ, Beekhuis H. A radio-isotope method for simultaneous determination of the glomerular filtration rate and the effective renal plasma flow. Neth J Med. 1977;20:97-103. [Medline] [Order article via Infotrieve]
15. Weinberger MH, Miller JZ, Luft FC, Grim CE, Fineberg NS. Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension. 1986;8(suppl II):II-127-II-134.
16.
Sullivan JM, Prewitt RL, Ratts TE, Josephs JA, Connor
MJ. Hemodynamic characteristics of
sodium-sensitive subjects. Hypertension. 1987;9:398-406.
17.
Weinberger MH, Fineberg NS. Sodium and volume
sensitivity of blood pressure: age and pressure change over
time. Hypertension. 1991;12:67-71.
18. Frohlich ED. The heart in hypertension: a 1991 overview. Hypertension. 1991;18(5 suppl):III-62-III-68.
19.
Bigazzi R, Bianchi S, Baldari D, Sgherri G, Baldari G,
Campese VM. Microalbuminuria in
salt-sensitive patients: a marker for renal and
cardiovascular risk factors.
Hypertension. 1994;23:195-199.
20. Bigazzi R, Bianchi S, Baldari G, Sgherri G, Campese VM. Diurnal variations of blood pressure and microalbuminuria in essential hypertension. Am J Hypertens. 1994;7:23-29. [Medline] [Order article via Infotrieve]
21.
Luft FC, Rankin LI, Block R, Weyman AE, Willis LR,
Murray RH, Grim CE, Weinberger LH.
Cardiovascular and humoral responses to extremes of
sodium intake in normal black and white man.
Circulation. 1979;60:697-706.
22.
Chrysant SG, Danisa K, Kem DC, Dillard BL, Smith WJ,
Frohlich ED. Racial differences in pressure, volume and renin
interrelationships in essential hypertension.
Hypertension. 1979;1:136-141.
23.
Sowers JR, Zemel MB, Zemel P, Beck FWJ, Walsh MF,
Zawada ET. Salt sensitivity in blacks.
Hypertension. 1988;12:485-490.
24. Luft FC, Miller JZ, Grim CE, Fineberg NS, Christian JC, Daugherty SA, Weinberger MH. Salt-sensitivity and resistance of blood pressure: age and race as factors in physiological responses. Hypertension. 1991;17(suppl I):I-187-I-197.
25. Fujita T, Henry WL, Bartter FC, Lake CR, Delea CS. Factors influencing blood pressure in salt-sensitive patients with hypertension. Am J Med. 1980;69:334-344. [Medline] [Order article via Infotrieve]
26. Sims EA. Mechanisms of hypertension in the syndromes of obesity. Int J Obes. 1981;(suppl I):9-18.
27. Gillum RF, Prineas RJ, Jeffery RW, Jacobs DR, Elmer PJ, Gomez O, Blackburn H. Nonpharmacologic therapy of hypertension: the independent effects of weight reduction and sodium restriction in overweight borderline hypertensive patients. Am Heart J. 1983;105:128-133. [Medline] [Order article via Infotrieve]
28. Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Katch V, Martin M. The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med. 1989;321:580-585. [Abstract]
29. Mimran A, Ribstein J, Jover B. Aging and sodium homeostasis. Kidney Int. 1992;41(suppl 37):S107-S113.
30. Guyton AC, Langston JB, Navar G. Theory for renal autoregulation by feedback at the juxtaglomerular apparatus. Circ Res. 1964;14/15(suppl I):I-187-I-197.
31. Guyton AC, Coleman TG, Cowley AW Jr, Scheel KW, Manning RD, Norman RA. Arterial pressure regulation: overriding dominance of the kidneys in long term regulation in hypertension. Am J Med. 1972;52:584-594.[Medline] [Order article via Infotrieve]
32. de Wardener HE. The primary role of the kidney and salt intake in the etiology of essential hypertension: part I. Clin Sci. 1990;79:193-200. [Medline] [Order article via Infotrieve]
33. de Wardener HE. The primary role of the kidney and salt intake in the etiology of essential hypertension: part II. Clin Sci. 1990;79:289-297. [Medline] [Order article via Infotrieve]
34. Sealy JE, Blumenfeld JD, Bell GM, Pecker MS, Sommers SC, Laragh JH. On the renal basis for essential hypertension: nephron heterogeneity with discordant renin secretion and sodium excretion causing a hypertensive vasoconstriction-volume relationship. J Hypertens. 1988;6:763-777. [Medline] [Order article via Infotrieve]
35. Kawasaki T, Delea CS, Bartter FC, Smith H. The effect of high sodium and low sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am J Med. 1978;64:193-198.[Medline] [Order article via Infotrieve]
36. Dustan HP, Valdes G, Bravo E, Tarazi RC. Excessive sodium retention as a characteristic of salt-sensitive hypertension. Am J Med Sci. 1986;292:67-74. [Medline] [Order article via Infotrieve]
37.
Dustan HP, Kirk KA. Corcoran lecture: the case
for and against salt in hypertension.
Hypertension. 1989;13:696-705.
38. Hollenberg NK, Adams DF. The renal circulation in hypertensive disease. Am J Med. 1976;60:773-784. [Medline] [Order article via Infotrieve]
39. Shoback DM, Williams GH, Moore TJ, Dluhy RG, Podolsky S, Hollenberg NK. Defect in the sodium-modulated tissue responsiveness to angiotensin II in essential hypertension. J Clin Invest. 1983;72:2115-2124.
40.
Gill JR Jr, Gullner HG, Lake CR, Lakatua DJ, Lan
G. Plasma and urinary catecholamines in
salt-sensitive idiopathic hypertension.
Hypertension. 1988;11:312-319.
41. Van Hooft IMS, Grobbee DE, Derkx FHM, de Leeuw P, Schalekamp MADH, Hofman A. Renal hemodynamics and the renin-angiotensin-aldosterone-system in normotensive subjects with hypertensive and normotensive parents. N Engl J Med. 1991;324:1305-1311. [Abstract]
42. Woods JE. Renal function in essential hypertension. Semin Nephrol. 1983;30:30-39.
43.
Schmieder RE, Schachinger H, Messerli FH.
Accelerated decline in renal perfusion with aging in essential
hypertension. Hypertension. 1994;23:351-357.
44. Hall JE, Guyton AC, Smith MJ Jr, Coleman TG. Blood pressure and renal function during chronic changes in sodium intake: role of angiotensin. Am J Physiol. 1980;239:F271-F280.
45.
Sullivan JM, Ratts TE. Sodium-sensitivity in
human subjects. Hypertension. 1988;11:717-723.
46. Campese VM, Romoff MS, Levitan D, Saglikes Y, Friedler RM, Massry SG. Abnormal relationship between sodium intake and sympathetic nervous system activity in salt-sensitive patients with essential hypertension. Kidney Int. 1982;21:371-378. [Medline] [Order article via Infotrieve]
47.
Hollenberg NK, Williams GH. Renin suppression by
saline is blunted in nonmodulating essential hypertension.
Hypertension. 1987;10:404-408.
48. Kobrin I, Viskoper RJ, Laszt A, Boch J, Weber C, Charlon V. Effects of an orally active renin-inhibitor Ro 42-5892 in patients with essential hypertension. Am J Hypertens. 1993;6:349-356. [Medline] [Order article via Infotrieve]
49. Redgrave JE, Rabinowe SL, Hollenberg NK, Williams GH. Correction of abnormal renal blood flow response to angiotensin II by converting-enzyme inhibition in essential hypertensives. J Clin Invest. 1985;75:1285-1290.
50.
Dluhy RG, Smith K, Taylor T, Hollenberg NK, Williams
GH. Prolonged converting enzyme inhibition in non-modulating
hypertension. Hypertension. 1989;13:371-377.
51.
Ljungman S, Aurell M, Hartford M, Wikstrand J, Berglund
G. Effects of subpressor doses of angiotensin II on
renal hemodynamics in relation to blood
pressure. Hypertension. 1983;5:368-374.
52.
Koolen MI, van Brummelen P. Adrenergic activity
and peripheral hemodynamics in relation to
sodium-sensitivity in patients with essential hypertension.
Hypertension. 1984;6:820-825.
53. Kohno M, Yasunari K, Murakawa K, Kanayama Y, Matsuura T, Takeda T. Effects of high sodium and low sodium intake on circulating atrial natriuretic peptides in salt-sensitive patients with systemic hypertension. Am J Cardiol. 1987;59:1212-1213. [Medline] [Order article via Infotrieve]
54.
Campese VM. Salt sensitivity in hypertension:
renal and cardiovascular implications.
Hypertension. 1994;23:531-550.
55. Hollenberg NK, Williams GH, Taub KJ, Ishikawa I, Brown C, Adams DF. Renal vascular response to interruption of the renin-angiotensin system in normal man. Kidney Int. 1977;12:285-293. [Medline] [Order article via Infotrieve]
56. Hollenberg NK, Meggs LG, Williams GH, Katz J, Garnic JD, Harrington DP. Sodium intake and renal response to captopril in normal man and essential hypertension. Kidney Int. 1981;20:240-245. [Medline] [Order article via Infotrieve]
57. Vos PF, Boer P, Koomans HA. Effects of enalapril on renal sodium handling in healthy subjects on low, intermediate and high sodium intake. J Cardiovasc Pharmacol. 1993;22:27-32. [Medline] [Order article via Infotrieve]
58. El Amrani AIK, Menard J, Gonzales MF, Michel JB. Effects of blocking the angiotensin II receptor, converting enzyme, and renin activity on the renal hemodynamics of normotensive guinea pigs. J Cardiovasc Pharmacol. 1993;22:231-239. [Medline] [Order article via Infotrieve]
59. Uneda S, Fujishima S, Fujiki Y, Tochikubo O, Oda H, Asahina S, Kaneko Y. Renal hemodynamics and the renin-angiotensin system in adolescents genetically predisposed to essential hypertension. J Hypertens. 1984;2:S3:437-439.
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