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Enhanced antinatriuresis in response to angiotensin II in essential hypertension
AJH
2000;13:986 –993
Enhanced Antinatriuresis in Response to Angiotensin II in Essential Hypertension Arnfried U. Klingbeil, Johannes Jacobi, Matthias R.W. Langenfeld, Stefan John, Karl F. Hilgers, and Roland E. Schmieder
Angiotensin II regulates sodium homeostasis by modulating aldosterone secretion, renal vascular response, and tubular sodium reabsorption. We hypothesized that the antinatriuretic response to angiotensin II is enhanced in human essential hypertension. We therefore studied 48 white men with essential hypertension (defined by ambulatory blood pressure measurement) and 72 normotensive white control persons, and measured mean arterial pressure, sodium excretion, renal plasma flow, glomerular filtration rate, and aldosterone secretion in response to angiotensin II infusion (0.5 and 3.0 ng/kg/min). Hypertensive subjects exhibited a greater increase of mean arterial pressure (16.7 ⴞ 8.2 mm Hg v 13.4 ⴞ 7.1 mm Hg in normotensives, P < .05) and a greater decrease of renal plasma flow (ⴚ151.5 ⴞ 73.9 mL/ min v ⴚ112.6 ⴞ 68.0 mL/min in controls, P < .01) when 3.0 ng/kg/min angiotensin II was infused. The increase of glomerular filtration rate and serum aldosterone concentration was similar in
S
both groups. Sodium excretion in response to 3.0 ng/kg/min angiotensin II was diminished in both groups (P < .01). However, the decrease in sodium excretion was more pronounced in hypertensives than in normotensives (ⴚ0.18 ⴞ 0.2 mmol/min v ⴚ0.09 ⴞ 0.2 mmol/min, P < .05), even if baseline mean arterial pressure and body mass index were taken into account (P < .05). We conclude that increased sodium retention in response to angiotensin II exists in subjects with essential hypertension, which is unrelated to changes in glomerular filtration rate and aldosterone concentration. Our data suggest a hyperresponsiveness to angiotensin II in essential hypertension that could lead to increased sodium retention. Am J Hypertens 2000;13:986 –993 © 2000 American Journal of Hypertension, Ltd. KEY WORDS:
Angiotensin II, essential hypertension, sodium excretion, glomerular filtration, renal plasma flow.
odium balance and its interaction with the renin-angiotensin-aldosterone system is among the most important long-term regulators of the cardiovascular system.1,2 The effects of angiotensin II on renal hemodynamics and sodium handling are well known.3–5 Angiotensin II infusion in moderate doses, which does not induce massive elevations of
blood pressure, causes a strong renal vasoconstriction, leading to a marked decrease in effective renal plasma flow. Because of the pronounced contraction of the efferent glomerular vessels, the filtration fraction increases.6 –12 Infusion of such moderate doses of angiotensin II decreases renal sodium excretion in animals and in humans, even in the presence of an increase of blood pres-
Received August 23, 1999. Accepted February 29, 2000. From the Department of Medicine IV/Nephrology, University of Erlangen-Nu¨rnberg, Nu¨rnberg, Germany. This study was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG Schm 638/8-1 and 638/8-2).
Address correspondence and reprint requests to Prof. Dr. Roland E. Schmieder, Medizinische Klinik IV/Nephrologie, Universita¨t Erlangen-Nu¨rnberg, Breslauer Str. 201, D-90471 Nu¨rnberg, Germany; e-mail: [email protected]
© 2000 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
0895-7061/00/$20.00 PII S0895-7061(00)01191-2
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sure.6 – 8,13 Micropuncture and in vivo microperfusion experiments, as well as measurements of the lithium clearance, have shown that angiotensin II increases sodium reabsorption in the proximal tubules in a dosedependent manner.8,14 –20 With higher doses of the peptide, this effect is offset by the concomitant increase of blood pressure.8 Very high doses of angiotensin II are natriuretic (“pressure natriuresis”).3 Under these conditions, the hemodynamic effects of angiotensin II3,5 oppose the direct effect of angiotensin II on proximal tubular cells,19 ultimately leading to increased sodium excretion. In many patients with essential hypertension blood pressure is susceptible to changes in dietary sodium.21 In a subset of patients with essential hypertension, Hollenberg and coworkers demonstrated an increased sodium sensitivity of blood pressure that was associated with a blunted renal vascular response.22–24 These same investigators reported an enhanced renovascular response to infused angiotensin II in a subgroup of patients with essential hypertension.25,26 Previous results of our group demonstrated that the heart also shows an increased sensitivity to angiotensin II in at least some hypertensive subjects with hypertensive heart disease.27 In addition, van Paassen et al28 suggested an inadequate downregulation or hyperresponsiveness of the intrarenal renin-angiotensin system in salt-sensitive patients with essential hypertension. Little is known about the intrarenal effects of angiotensin II on sodium reabsorption in patients with essential hypertension. We hypothesized that the antinatriuretic response to angiotensin II infusion is exaggerated in patients with essential hypertension. METHODS Study Cohort By announcement we screened young white male students at the campus of the University of Erlangen-Nu¨rnberg for high blood pressure. Blood pressure values were considered to be increased, if the average of all casual blood pressure readings taken four times on two different occasions in our outpatient clinic (at least 2 weeks apart) was ⱖ140 mm Hg systolic or ⱖ90 mm Hg diastolic according to the World Health Organization recommendations. Normotensive participants (systolic blood pressure ⬍140 mm Hg and diastolic blood pressure ⬍90 mm Hg) without a family history of arterial hypertension were matched to the hypertensive individuals by age, body weight, and height. The cuff size of the sphygmomanometer was adjusted according to the person’s arm circumference and blood pressure was measured with the participant seated after 5 min of rest. Sixty normotensive and sixty hypertensive subjects—according to casual blood pressure—who satisfied the inclusion criteria (age between 20 and 40
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years, male gender, no current or previous treatment for arterial hypertension, no cardiovascular disease, no secondary hypertension or World Health Organization stage III of hypertensive disease) were enrolled in the study. Exclusion criteria were advanced hypertensive funduscopic changes, myocardial infarction, or any other evidence of coronary artery disease, congestive heart failure (New York Heart Association classes II through IV), previous cerebrovascular event, hepatic or renal insufficiency. Of the 60 hypertensive subjects, 48 subjects were hypertensive according to 24-h ambulatory blood pressure with blood pressure values ⱖ130 mm Hg systolic or ⱖ80 mm Hg diastolic (thereby excluding white coat hypertension). Each participant underwent a routine clinical workup. In particular, a 12-lead electrocardiography at rest was performed, as well as a funduscopic evaluation, sonography of the kidneys and adrenal glands, duplex sonography of renal arteries, and routine laboratory tests. Detailed evaluation of hormones and endocrine metabolites was conducted if indicated. The study protocol was approved by our Clinical Investigation Committee and written informed consent was obtained from each participant. Clinical Measurements At baseline 24-h urinary sodium excretion was measured. Dietary salt intake was estimated twice with participants on their usual diet by measurement of sodium excretion in the urine collected over a 24-h period, which represents a rough but valuable estimate of daily sodium intake.29 To ensure complete collection of urine, all samples containing less than 600 mL or the expected creatinine per kilogram body weight were excluded.30,31 Clearances were calculated according to standard formulas. According to the study protocol, ambulatory blood pressure monitoring took place in parallel to 24-h urinary collection, whereas endocrine investigations were done directly thereafter. None of the participants followed any specific dietary guidelines before the hemodynamic evaluation and measurement of 24-h sodium excretion. Twenty-four-hour ambulatory blood pressure was assessed as the most valid, noninvasive tool of the hemodynamic afterload imposed on the left ventricle, as it has been shown to be more closely related to left ventricular hypertrophy than casual blood pressure measurements.32–34 Ambulatory blood pressure monitoring was performed by the use of an automatic portable device (model 90207, SpaceLabs Medical, Redmond, WA).35 Measurement intervals were every 15 min during daytime (defined from 06:00 to 22:00) and every 30 min during nighttime. Average 24-h ambulatory blood pressure readings were considered to be hypertensive if blood pressure was ⱖ130 mm Hg systolic or ⱖ80 mm Hg diastolic. Blood samples for the determination of plasma re-
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nin activity, plasma angiotensin II concentration, and serum aldosterone concentration were collected with the participant in the supine position for 1 h. Measurements were done in duplicate and the averages are reported (for details, see reference 27). Angiotensin II was measured by collecting 10 mL of blood into prechilled syringes prepared with 125 mmol of EDTA and 26 mmol of phenanthroline (Merck, Darmstadt, Germany) to inhibit the angiotensin converting enzyme and angiotensinases. The samples were centrifuged for 10 min at 4°C immediately after collection, and plasma was stored rapidly after centrifugation at ⫺21°C and analyzed within 3 months by radioimmunoassay with antiserum Celine III (kindly provided by Prof. D. Ganten, Max Delbru¨ck Zentrum, Berlin, Germany) and labeled angiotensin II (NEX 105, DuPont, Mechelen, Belgium). All determinations of immunoreactive angiotensin II were made in duplicate, and the mean value is given. The coefficient of variation was 8.8%. Blood samples for determination of plasma renin activity (125 mmol EDTA added) and serum aldosterone were also collected in prechilled 10-mL syringes and centrifuged for 10 min at 4°C. Plasma was frozen immediately and stored at ⫺21°C until incubation and subsequent radioimmunoassay for angiotensin I (antibody K 18 kindly provided by Prof. Hackenthal, Heidelberg, Germany) in a similar manner as it was done for angiotensin II radioimmunoassay.36 Serum aldosterone was measured by a commercially available radioimmunoassay kit (Aldosterone Maia 12254, Serono Diagnostics, Freiburg, Germany). Measurements were done in duplicate, the mean value is given. The coefficient of variance was less than 10%. Response to Angiotensin II Infusion One week (days 1 to 7) before the hemodynamic evaluation participants were advised to increase their oral dietary intake to about 13 g of salt per day (which equals a sodium excretion of ⬎200 mmol/24 h) by increasing their salt intake with salt tablets. The rational for a high salt intake was to achieve low levels of endogenous angiotensin II and, therefore, to maximize the response to exogenous angiotensin II. After achieving steady-state conditions,29,37 on day 8 at 10:00 am blood pressure (mean of 10 automatic measurements over a period of 10 min; Dinamap, Criticon, Tampa, FL), urinary sodium excretion, plasma renin activity, angiotensin II, and aldosterone were measured after 1 h of rest in supine position as described above and renal hemodynamics were checked at baseline. To avoid bladder catheterization we applied the constant infusion technique to determine renal perfusion (p-aminohippurate clearance) and glomerular filtration rate
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(inulin clearance) as previously described in detail.38,39 This method may overestimate renal plasma flow by 20%, but changes from baseline in each subject are not affected by this potential bias. Filtration fraction was calculated by dividing glomerular filtration rate by renal plasma flow. After emptying their bladder participants started with a resting period in the supine position. To enhance urinary output an intravenous water load of 10 mL/kg body weight of 0.9% sodium chloride was given as a bolus. Subsequently, participants received intravenously 0.9% sodium chloride in a volume equivalent to their volume loss. After 2 h of rest blood pressure, urine volume (total amount of the 2-h period), and urinary sodium concentration, serum aldosterone, and renal hemodynamics were measured. A constant infusion of angiotensin II (Hypertensin, Ciba Geigy, Basel, Switzerland) at a dose of 0.5 ng/kg/min was then administered for 30 min. Thereafter the aforementioned parameters were measured again. Subsequently, the dose of angiotensin II was increased to 3.0 ng/kg/min for another 30 min. At the end of this period, the same measurements were done again. The doses of angiotensin II were chosen according to the literature.40 – 42 Statistics All statistical analyses were carried out using SPSS software (SPSS Inc., Chicago, IL).43 The paired Student’s t test was used for comparison of baseline parameters, the unpaired Student’s t test for comparison between the two groups, defined according to 24-h ambulatory blood pressure values. In addition, MANOVA was applied for detection of any difference between the two groups in response to increasing doses of angiotensin II. Linear correlation analysis (Pearson) and partial correlation analysis were applied to identify determinants of urinary sodium excretion. Unless otherwise stated, values are given as mean ⫾ 1 standard deviation. Two-tailed P values are given throughout the text. Two-tailed P values less than .05 were considered to be significant. RESULTS Baseline Characteristics Clinical characteristics of 72 normotensive and 48 hypertensive subjects—according to the 24-h ambulatory blood pressure—are given in Table 1. By study design, 24-h ambulatory blood pressure differed between the two groups. Accordingly, resting and casual systolic and diastolic blood pressures were higher in the hypertensive than in the normotensive group (P ⬍ .001). At baseline no significant difference was found between the normotensive and hypertensive group with respect to 24-h sodium excretion, plasma renin activity, plasma angiotensin II, serum aldosterone, and the renal hemodynamic parameters
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TABLE 1. BASELINE CHARACTERISTICS OF 48 HYPERTENSIVE AND 72 NORMOTENSIVE PARTICIPANTS Characteristics Age (y) Body mass index (kg/m2) Casual blood pressure (mm Hg) Systolic Diastolic 24-h Ambulatory blood pressure (mm Hg) Systolic Diastolic Urinary sodium excretion (mmol/24 h) Angiotensin II (pg/mL) Aldosterone (pg/mL) Renal plasma flow (mL/min) Glomerular filtration rate (mL/min) Filtration fraction (%)
Hypertensive (N)* (n ⴝ 48)
Normotensive (H)* (n ⴝ 72)
P HvN
26 ⫾ 3 24.2 ⫾ 2.9
25 ⫾ 2 23.7 ⫾ 2.6
NS NS
152 ⫾ 13 96 ⫾ 10
131 ⫾ 13 83 ⫾ 10
⬍.001 ⬍.001
138 ⫾ 7 82 ⫾ 7 205 ⫾ 84 8.6 ⫾ 3.7 135 ⫾ 42 661 ⫾ 100 123 ⫾ 14 18.9 ⫾ 2.5
121 ⫾ 5 71 ⫾ 4 185 ⫾ 60 8.8 ⫾ 4.1 130 ⫾ 34 632 ⫾ 95 114 ⫾ 14 18.4 ⫾ 2.9
⬍.001 ⬍.001 NS NS NS NS .03 NS
NS ⫽ not significant. * defined according to ambulatory blood pressure monitoring criteria (24-h ambulatory blood pressure ⬎130 or ⬎80 mm Hg).
with the exception of a slightly, yet significantly, higher glomerular filtration rate in hypertensive subjects (P ⫽ .03) (Table 1). Response to Angiotensin II in the Normotensive and Hypertensive Groups Both doses of angiotensin II increased mean blood pressure in normotensive and hypertensive subjects in a dose-dependent manner (Table 2). The higher dose of angiotensin II caused a significantly greater increase of blood pressure in hypertensive subjects, if compared to normotensive volunteers (Table 2). Sodium excretion was decreased significantly by the low dose of angiotensin II (0.5 ng/kg/min) in hypertensive subjects, whereas only a nonsignificant trend toward decreased sodium excretion was observed in normotensives (Table 3). In response to the higher dose of angiotensin II (3.0 ng/kg/min), sodium excretion decreased in both hypertensives and normotensives (P ⬍ .001), but the decrease was significantly higher in hypertensive subjects (⫺0.18 ⫾ 0.2 mmol/ min for hypertensives v ⫺0.09 ⫾ 0.2 mmol/min for normotensives, P ⬍ .05) (Table 3). When the effect of angiotensin II on sodium excretion was analyzed by analysis of variance for repeated measurements, hypertensives showed a greater sodium retention than normotensive subjects (normotensives v hypertensives: P ⬍ .05; baseline v angiotensin II administration: P ⬍ .01). Urine flow rate in response to 0.5 ng/kg/min angiotensin II increased by 1.37 ⫾ 3.7 mL/min in hypertensives and 2.68 ⫾ 4.7 mL/min in normotensives (P ⬍ .001 for both groups), but was similar to that under resting conditions in response to 3.0 ng/kg/ min angiotensin II. The difference between the urine
flow rate in response to 0.5 ng/kg/min angiotensin II and the one in response to 3.0 ng/kg/min angiotensin II was significant (2.55 ⫾ 3.6 mL/min in hypertensives and 2.31 ⫾ 5.9 mL/min in normotensives, P ⬍ .001 for both groups) with no difference between hypertensives and normotensives (Table 3). Renal plasma flow was decreased by the infusion of angiotensin II in a dose-dependent manner in both normotensive and hypertensive subjects (P ⬍ .001), but the effect was exaggerated in hypertensives (renal plasma flow: ⫺151.5 ⫾ 73.9 mL/min for hypertensives v ⫺112.6 ⫾ 68.0 mL/min for normotensives, P ⬍ .01, at 3.0 ng/kg/min angiotensin II). The glomerular filtration rate increased (P ⬍ .001) with either dose of angiotensin II in both groups to a similar extent. Consequently, the filtration fraction increased in both groups with either dose of angiotensin II (P ⬍ .001), with the increase being more pronounced in hypertensive than in normotensive subjects (P ⬍ .01) (Table 2). For the dose-dependent increase of aldosterone secretion (P ⬍ .01) in response to the infusion of angiotensin II (in either dosage), no significant difference was found between normotensive and hypertensive individuals (Table 2). No significant correlation was found between the decrease of urinary sodium excretion on the one hand and changes in mean arterial pressure, renal plasma flow, glomerular filtration rate, and aldosterone secretion on the other in normotensive and hypertensive subjects in response to angiotensin II (data not shown). In summary, angiotensin II caused the expected increase in mean arterial pressure, glomerular filtration rate, and aldosterone secretion, and the expected
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TABLE 2. CHANGE OF MEAN ARTERIAL PRESSURE, RENAL HEMODYNAMICS, AND PLASMA ALDOSTERONE IN RESPONSE TO INFUSION WITH ANGIOTENSIN II 0.5 NG/KG/MIN AND 3.0 NG/KG/MIN IN 48 HYPERTENSIVE AND 72 NORMOTENSIVE PARTICIPANTS Characteristics Mean arterial pressure (mm Hg) Preinfusion Change to AII 0.5 ng/kg/min Change to AII 3.0 ng/kg/min Renal plasma flow (mL/min) Preinfusion Change to AII 0.5 ng/kg/min Change to AII 3.0 ng/kg/min Glomerular filtration rate (mL/min) Preinfusion Change to AII 0.5 ng/kg/min Change to AII 3.0 ng/kg/min Filtration fraction (%) Preinfusion Change to AII 0.5 ng/kg/min Change to AII 3.0 ng/kg/min Plasma aldosterone (pg/mL) Preinfusion Change to AII 0.5 ng/kg/min Change to AII 3.0 ng/kg/min
Hypertensive (H)* (n ⴝ 48) 103 ⫾ 10 5.7 ⫾ 5.7‡ 16.7 ⫾ 8.2‡ 661 ⫾ 100 ⫺51.1 ⫾ 64.7‡ ⫺151.5 ⫾ 73.9‡
Normotensive (N)* (n ⴝ 72) 91 ⫾ 10 4.5 ⫾ 4.6‡ 13.4 ⫾ 7.1‡ 632 ⫾ 95 ⫺42.0 ⫾ 57.2‡ ⫺112.6 ⫾ 68.0‡
P HvN ⬍.001 NS .022 NS NS .004
123 ⫾ 14 4.3 ⫾ 59‡ 4.9 ⫾ 8.4‡
114 ⫾ 14 4.7 ⫾ 4.7‡ 6.9 ⫾ 5.5‡
.03 NS NS
18.9 ⫾ 2.5 2.3 ⫾ 1.8‡ 6.6 ⫾ 2.6‡
18.4 ⫾ 2.9 2.1 ⫾ 1.7‡ 5.2 ⫾ 2.6‡
NS NS ⬍.006
93 ⫾ 25 25 ⫾ 54† 97 ⫾ 70‡
101 ⫾ 37 18 ⫾ 37† 92 ⫾ 66‡
NS NS NS
Abbreviation as in Table 1; AII ⫽ angiotensin II. * defined according to ambulatory blood pressure monitoring criteria (24-h ambulatory blood pressure ⬎130 or ⬎80 mm Hg). † P ⬍ .01 and ‡ P ⬍ .001 for the difference between preinfusion and after angiotensin II infusion.
decrease in renal plasma flow and urinary sodium excretion in both study groups. However, the increase in mean arterial pressure, the decrease in renal plasma flow and the decrease in urinary sodium excretion were significantly enhanced in hypertensive subjects. DISCUSSION Our most striking result was that sodium retention in response to infusion of angiotensin II was significantly higher in hypertensive than in normotensive individuals. This difference was clearly present with the higher dose of angiotensin II, but a trend was already found for the lower dose of angiotensin II. An antinatriuretic effect of angiotensin II can be demonstrated in normotensive individuals at doses as low as 1.0 ng/kg/min,20 whereas the effect peaks at doses between 4.0 and 8.0 nmol/kg/min angiotensin II. The latter dose results in an 80% decrease of urinary sodium excretion, a 25 mm Hg increase in systolic blood pressure, a decrease in renal plasma flow by approximately 55%, a slight decrease of glomerular filtration rate, and a marked increase of filtration fraction by about 50%.44 These data agree with results of Olsen et al,8 who found that during angiotensin II infusion in captopril-treated dogs the transition from an antinatriuretic to a natriuretic effect occurs at a dose of 15 ng/kg/min. At this dose, blood pressure
in the renal artery increased by approximately 30 mm Hg. Our observation of a borderline change of urinary sodium excretion in response to a low dose infusion of angiotensin II (0.5 ng/kg/min) and a significant decrease in urinary sodium excretion in response to a higher dose of angiotensin II (3.0 ng/kg/min) is in agreement with previous reports.8,22,40 In contrast to the normotensive individuals, the antinatriuretic effect of angiotensin II was found in hypertensive subjects already at the lower dose of 0.5 ng/kg/min of angiotensin II. At the higher dose of 3.0 ng/kg/min of angiotensin II, antinatriuresis was significantly more pronounced in hypertensive compared to normotensive individuals. Pressure natriuresis as a possible confounding phenomenon could not explain this finding because the increase of arterial pressure was too modest to induce it.8 In general, urinary sodium excretion is influenced by glomerular filtration rate and tubular reabsorption. The glomerular filtration rate was slightly higher at baseline in hypertensive participants, which was somewhat unexpected.45 Previously, we observed an increased glomerular filtration rate during exposure to mental stress, which was more marked in hypertensives than in normotensives.46 In response to angiotensin II we noted a similar increase in the glomerular
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TABLE 3. CHANGE OF URINARY SODIUM EXCRETION IN RESPONSE TO INFUSION WITH ANGIOTENSIN II 0.5 NG/KG/MIN AND 3.0 NG/KG/MIN IN 48 HYPERTENSIVE AND 72 NORMOTENSIVE PARTICIPANTS Characteristics Urinary sodium excretion (mmol/min) Preinfusion After AII 0.5 ng/kg/min Change to AII 0.5 ng/kg/min After AII 3.0 ng/kg/min Change to AII 3.0 ng/kg/min Urine flow rate (mL/min) Preinfusion After AII 0.5 ng/kg/min Change to AII 0.5 ng/kg/min After AII 3.0 ng/kg/min Change from AII 0.5 ng/kg/min to AII 3.0 ng/kg/min
Hypertensive (H)* (n ⴝ 48)
Normotensive (N)* (n ⴝ 72)
P HvN
0.40 ⫾ 0.2 0.32 ⫾ 0.2† ⫺0.06 ⫾ 0.2 0.19 ⫾ 0.1§ ⫺0.18 ⫾ 0.2
0.36 ⫾ 0.2 0.34 ⫾ 0.2 ⫺0.02 ⫾ 0.2 0.26 ⫾ 0.2‡ ⫺0.09 ⫾ 0.3
NS NS NS .07 ⬍.05
4.79 ⫾ 2.7 6.16 ⫾ 3.9§ 1.37 ⫾ 3.7 3.61 ⫾ 3.8㛳
3.99 ⫾ 2.6 6.67 ⫾ 4.9§ 2.68 ⫾ 4.7 4.37 ⫾ 5.7㛳
⫺2.55 ⫾ 3.6
⫺2.31 ⫾ 5.9
NS NS NS NS NS
Abbreviations as in Table 2. * defined according to ambulatory blood pressure monitoring criteria (24-h ambulatory blood pressure ⬎130 or ⬎80 mm Hg). † P ⬍ .05, ‡ P ⬍ .01, and § P ⬍ .001 for the difference between preinfusion and after angiotensin II infusion; 㛳 P ⬍ .001 for the difference between angiotensin 0.5 ng/kg/min and 3.0 ng/kg/min.
filtration rate in both hypertensives and normotensives. Thus, the effects of angiotensin II on the filtered sodium load do not appear to account for a different sodium excretion between hypertensives and normotensives. The higher increase of the filtration fraction in response to angiotensin II in hypertensives is explained by the more pronounced reduction of renal plasma flow. The increase of urine flow rate despite a low dose of angiotensin II is explained by the high volume input rate during the infusion period; the lower urine flow rate with the higher dose of angiotensin II reflects the known decreasing effect of angiotensin II on urine output. The plasma aldosterone concentration at baseline and its change in response to angiotensin II was similar in normotensives and hypertensives, which is in agreement with the data of London et al,47 who showed similar correlations between sodium clearance and plasma aldosterone in hypertensives compared to normotensives. Therefore, the observed different sodium excretion rate in response to angiotensin II cannot be due to a different regulation of the aldosterone-controlled sodium handling at the distal tubule. Renal plasma flow at baseline was similar in our young hypertensive and normotensive study participants, as reported previously by other researchers.48 Of note, this finding does not prove similar renal vascular resistance, because renal plasma flow is determined by renal vascular resistance and cardiac output, which was not determined in our study. London et al49 demonstrated that, despite an elevated renal
vascular resistance, subjects with essential hypertension showed a “normal” renal plasma flow because of an elevated cardiac output. Which mechanism may finally account for the higher sodium retention of hypertensives in response to angiotensin II? Tubular sodium reabsorption occurs mainly in proximal tubular cells, which are a target of angiotensin II action.6 – 8 Because there was no indication of alterations of either the filtered sodium load or distal aldosterone effects, the observed exaggerated sodium retention in hypertensive subjects is most likely due to an increased tubular reabsorption triggered by angiotensin II. The peptide could act directly on proximal tubular cells, or indirectly by altering peritubular perfusion. The increased sodium retention in response to angiotensin II infusion fits well to the concept of an hyperresponsiveness to angiotensin II in essential hypertension.25–28,50 In this context it is of some interest that—in contrast to data from Italy and France—in another northern European community, Sweden, an enhanced renal vascular response to angiotensin II has been described. A geographic heterogeneity, to either genes or culture, might be responsible for this discrepancy. To the best of our knowledge, this study is the first report of an increased sodium retention in response to angiotensin II in a suitably large group of young patients with essential hypertension. The increased antinatriuresis may facilitate sodium retention, which could contribute to further increases of blood pressure as well as to target organ damage.
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Siersbaek-Nielsen K, Hansen JH, Kampmann J, Kristensen M: Rapid evaluation of creatinine clearance. Lancet 1971;1:1133–1134.
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Cockroft DW, Goult H: Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31– 41.
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Perloff D, Sokolow M, Cowan R: The prognostic value of ambulatory blood pressure. JAMA 1983;249:2792– 2798.
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Parati G, Pomidossi G, Albini F, Malaspina D, Mancia G: Relationship of 24-hour blood pressure mean and variability to severity of target organ damage in hypertension. J Hypertens 1987;5:93–98.
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Rahman AR, Motwani JG, Lang CC, Struthers AD: Circulating angiotensin II and renal sodium handling in man: a dose-response study. Clin Sci 1993;85:147– 156.
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Harris PJ, Young JA. Dose-dependent stimulation and inhibition of proximal tubular sodium reabsorption by angiotensin II in the rat kidney. Pflu¨gers Arch 1977;367: 295–297.
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Liu F-Y, Cogan M: Angiotensin II: a potent regulator of acidification in the rat early proximal convoluted tubule. J Clin Invest 1987;80:272–275.
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Devereux RB, Pickering TG: Relation between ambulatory blood and exercise blood pressure and cardiac structure. Am Heart J 1988;116:1124 –1133.
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Geenen DL, Malkotva A, Scheuer J: Angiotensin II increases cardiac protein synthesis in adult rat heart. Am J Physiol 1993;265:H238 –H243.
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Cole RB, Giangiacomo J, Ingelfinger JR, Robsa A: Measurement of renal function without urine collection. A critical evaluation of the constant-infusion-technique for determination of inulin and para-aminohippurate. N Engl J Med 1972;287:1109 –1114.
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Schmieder RE, Gatzka CD, Schobel HP, Scha¨chinger H, Weihprecht H: Renal hemodynamic response to stress is influenced by ACE-inhibitors. Clin Nephrol 1994;6: 381–388.
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Shoback DM, Moore TJ, Dluky RG, Hollenberg NK, Williams GH: Defect in the sodium modulated tissue responsiveness to angiotensin II in essential hypertension. J Clin Invest 1983;72:2115–2124.
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43.
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Vos PF, Koomans HA, Boer P, Dorhout Mees EJ: Effects of angiotensin II on renal sodium handling and diluting capacitiy in man pretreated with high-salt diet and enalapril. Nephrol Dial Transplant 1992;7:991–996.
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Guyton AC, Coleman TG, Cowley AW Jr, Scheel KW, Manning RD, Norman RA: Arterial pressure regulation: Overriding dominance of the kidneys in longterm regulation and in hypertension. Am J Med 1972; 52:584 –594.
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London GM, Levenson JA, London AM, Simon AC, Safar ME: Systemic compliance, renal hemodynamics and sodium excretion in hypertension. Kidney Int 1984; 26:342–350.
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2000;13:986 –993
Enhanced Antinatriuresis in Response to Angiotensin II in Essential Hypertension Arnfried U. Klingbeil, Johannes Jacobi, Matthias R.W. Langenfeld, Stefan John, Karl F. Hilgers, and Roland E. Schmieder
Angiotensin II regulates sodium homeostasis by modulating aldosterone secretion, renal vascular response, and tubular sodium reabsorption. We hypothesized that the antinatriuretic response to angiotensin II is enhanced in human essential hypertension. We therefore studied 48 white men with essential hypertension (defined by ambulatory blood pressure measurement) and 72 normotensive white control persons, and measured mean arterial pressure, sodium excretion, renal plasma flow, glomerular filtration rate, and aldosterone secretion in response to angiotensin II infusion (0.5 and 3.0 ng/kg/min). Hypertensive subjects exhibited a greater increase of mean arterial pressure (16.7 ⴞ 8.2 mm Hg v 13.4 ⴞ 7.1 mm Hg in normotensives, P < .05) and a greater decrease of renal plasma flow (ⴚ151.5 ⴞ 73.9 mL/ min v ⴚ112.6 ⴞ 68.0 mL/min in controls, P < .01) when 3.0 ng/kg/min angiotensin II was infused. The increase of glomerular filtration rate and serum aldosterone concentration was similar in
S
both groups. Sodium excretion in response to 3.0 ng/kg/min angiotensin II was diminished in both groups (P < .01). However, the decrease in sodium excretion was more pronounced in hypertensives than in normotensives (ⴚ0.18 ⴞ 0.2 mmol/min v ⴚ0.09 ⴞ 0.2 mmol/min, P < .05), even if baseline mean arterial pressure and body mass index were taken into account (P < .05). We conclude that increased sodium retention in response to angiotensin II exists in subjects with essential hypertension, which is unrelated to changes in glomerular filtration rate and aldosterone concentration. Our data suggest a hyperresponsiveness to angiotensin II in essential hypertension that could lead to increased sodium retention. Am J Hypertens 2000;13:986 –993 © 2000 American Journal of Hypertension, Ltd. KEY WORDS:
Angiotensin II, essential hypertension, sodium excretion, glomerular filtration, renal plasma flow.
odium balance and its interaction with the renin-angiotensin-aldosterone system is among the most important long-term regulators of the cardiovascular system.1,2 The effects of angiotensin II on renal hemodynamics and sodium handling are well known.3–5 Angiotensin II infusion in moderate doses, which does not induce massive elevations of
blood pressure, causes a strong renal vasoconstriction, leading to a marked decrease in effective renal plasma flow. Because of the pronounced contraction of the efferent glomerular vessels, the filtration fraction increases.6 –12 Infusion of such moderate doses of angiotensin II decreases renal sodium excretion in animals and in humans, even in the presence of an increase of blood pres-
Received August 23, 1999. Accepted February 29, 2000. From the Department of Medicine IV/Nephrology, University of Erlangen-Nu¨rnberg, Nu¨rnberg, Germany. This study was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG Schm 638/8-1 and 638/8-2).
Address correspondence and reprint requests to Prof. Dr. Roland E. Schmieder, Medizinische Klinik IV/Nephrologie, Universita¨t Erlangen-Nu¨rnberg, Breslauer Str. 201, D-90471 Nu¨rnberg, Germany; e-mail: [email protected]
© 2000 by the American Journal of Hypertension, Ltd. Published by Elsevier Science, Inc.
0895-7061/00/$20.00 PII S0895-7061(00)01191-2
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sure.6 – 8,13 Micropuncture and in vivo microperfusion experiments, as well as measurements of the lithium clearance, have shown that angiotensin II increases sodium reabsorption in the proximal tubules in a dosedependent manner.8,14 –20 With higher doses of the peptide, this effect is offset by the concomitant increase of blood pressure.8 Very high doses of angiotensin II are natriuretic (“pressure natriuresis”).3 Under these conditions, the hemodynamic effects of angiotensin II3,5 oppose the direct effect of angiotensin II on proximal tubular cells,19 ultimately leading to increased sodium excretion. In many patients with essential hypertension blood pressure is susceptible to changes in dietary sodium.21 In a subset of patients with essential hypertension, Hollenberg and coworkers demonstrated an increased sodium sensitivity of blood pressure that was associated with a blunted renal vascular response.22–24 These same investigators reported an enhanced renovascular response to infused angiotensin II in a subgroup of patients with essential hypertension.25,26 Previous results of our group demonstrated that the heart also shows an increased sensitivity to angiotensin II in at least some hypertensive subjects with hypertensive heart disease.27 In addition, van Paassen et al28 suggested an inadequate downregulation or hyperresponsiveness of the intrarenal renin-angiotensin system in salt-sensitive patients with essential hypertension. Little is known about the intrarenal effects of angiotensin II on sodium reabsorption in patients with essential hypertension. We hypothesized that the antinatriuretic response to angiotensin II infusion is exaggerated in patients with essential hypertension. METHODS Study Cohort By announcement we screened young white male students at the campus of the University of Erlangen-Nu¨rnberg for high blood pressure. Blood pressure values were considered to be increased, if the average of all casual blood pressure readings taken four times on two different occasions in our outpatient clinic (at least 2 weeks apart) was ⱖ140 mm Hg systolic or ⱖ90 mm Hg diastolic according to the World Health Organization recommendations. Normotensive participants (systolic blood pressure ⬍140 mm Hg and diastolic blood pressure ⬍90 mm Hg) without a family history of arterial hypertension were matched to the hypertensive individuals by age, body weight, and height. The cuff size of the sphygmomanometer was adjusted according to the person’s arm circumference and blood pressure was measured with the participant seated after 5 min of rest. Sixty normotensive and sixty hypertensive subjects—according to casual blood pressure—who satisfied the inclusion criteria (age between 20 and 40
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years, male gender, no current or previous treatment for arterial hypertension, no cardiovascular disease, no secondary hypertension or World Health Organization stage III of hypertensive disease) were enrolled in the study. Exclusion criteria were advanced hypertensive funduscopic changes, myocardial infarction, or any other evidence of coronary artery disease, congestive heart failure (New York Heart Association classes II through IV), previous cerebrovascular event, hepatic or renal insufficiency. Of the 60 hypertensive subjects, 48 subjects were hypertensive according to 24-h ambulatory blood pressure with blood pressure values ⱖ130 mm Hg systolic or ⱖ80 mm Hg diastolic (thereby excluding white coat hypertension). Each participant underwent a routine clinical workup. In particular, a 12-lead electrocardiography at rest was performed, as well as a funduscopic evaluation, sonography of the kidneys and adrenal glands, duplex sonography of renal arteries, and routine laboratory tests. Detailed evaluation of hormones and endocrine metabolites was conducted if indicated. The study protocol was approved by our Clinical Investigation Committee and written informed consent was obtained from each participant. Clinical Measurements At baseline 24-h urinary sodium excretion was measured. Dietary salt intake was estimated twice with participants on their usual diet by measurement of sodium excretion in the urine collected over a 24-h period, which represents a rough but valuable estimate of daily sodium intake.29 To ensure complete collection of urine, all samples containing less than 600 mL or the expected creatinine per kilogram body weight were excluded.30,31 Clearances were calculated according to standard formulas. According to the study protocol, ambulatory blood pressure monitoring took place in parallel to 24-h urinary collection, whereas endocrine investigations were done directly thereafter. None of the participants followed any specific dietary guidelines before the hemodynamic evaluation and measurement of 24-h sodium excretion. Twenty-four-hour ambulatory blood pressure was assessed as the most valid, noninvasive tool of the hemodynamic afterload imposed on the left ventricle, as it has been shown to be more closely related to left ventricular hypertrophy than casual blood pressure measurements.32–34 Ambulatory blood pressure monitoring was performed by the use of an automatic portable device (model 90207, SpaceLabs Medical, Redmond, WA).35 Measurement intervals were every 15 min during daytime (defined from 06:00 to 22:00) and every 30 min during nighttime. Average 24-h ambulatory blood pressure readings were considered to be hypertensive if blood pressure was ⱖ130 mm Hg systolic or ⱖ80 mm Hg diastolic. Blood samples for the determination of plasma re-
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nin activity, plasma angiotensin II concentration, and serum aldosterone concentration were collected with the participant in the supine position for 1 h. Measurements were done in duplicate and the averages are reported (for details, see reference 27). Angiotensin II was measured by collecting 10 mL of blood into prechilled syringes prepared with 125 mmol of EDTA and 26 mmol of phenanthroline (Merck, Darmstadt, Germany) to inhibit the angiotensin converting enzyme and angiotensinases. The samples were centrifuged for 10 min at 4°C immediately after collection, and plasma was stored rapidly after centrifugation at ⫺21°C and analyzed within 3 months by radioimmunoassay with antiserum Celine III (kindly provided by Prof. D. Ganten, Max Delbru¨ck Zentrum, Berlin, Germany) and labeled angiotensin II (NEX 105, DuPont, Mechelen, Belgium). All determinations of immunoreactive angiotensin II were made in duplicate, and the mean value is given. The coefficient of variation was 8.8%. Blood samples for determination of plasma renin activity (125 mmol EDTA added) and serum aldosterone were also collected in prechilled 10-mL syringes and centrifuged for 10 min at 4°C. Plasma was frozen immediately and stored at ⫺21°C until incubation and subsequent radioimmunoassay for angiotensin I (antibody K 18 kindly provided by Prof. Hackenthal, Heidelberg, Germany) in a similar manner as it was done for angiotensin II radioimmunoassay.36 Serum aldosterone was measured by a commercially available radioimmunoassay kit (Aldosterone Maia 12254, Serono Diagnostics, Freiburg, Germany). Measurements were done in duplicate, the mean value is given. The coefficient of variance was less than 10%. Response to Angiotensin II Infusion One week (days 1 to 7) before the hemodynamic evaluation participants were advised to increase their oral dietary intake to about 13 g of salt per day (which equals a sodium excretion of ⬎200 mmol/24 h) by increasing their salt intake with salt tablets. The rational for a high salt intake was to achieve low levels of endogenous angiotensin II and, therefore, to maximize the response to exogenous angiotensin II. After achieving steady-state conditions,29,37 on day 8 at 10:00 am blood pressure (mean of 10 automatic measurements over a period of 10 min; Dinamap, Criticon, Tampa, FL), urinary sodium excretion, plasma renin activity, angiotensin II, and aldosterone were measured after 1 h of rest in supine position as described above and renal hemodynamics were checked at baseline. To avoid bladder catheterization we applied the constant infusion technique to determine renal perfusion (p-aminohippurate clearance) and glomerular filtration rate
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(inulin clearance) as previously described in detail.38,39 This method may overestimate renal plasma flow by 20%, but changes from baseline in each subject are not affected by this potential bias. Filtration fraction was calculated by dividing glomerular filtration rate by renal plasma flow. After emptying their bladder participants started with a resting period in the supine position. To enhance urinary output an intravenous water load of 10 mL/kg body weight of 0.9% sodium chloride was given as a bolus. Subsequently, participants received intravenously 0.9% sodium chloride in a volume equivalent to their volume loss. After 2 h of rest blood pressure, urine volume (total amount of the 2-h period), and urinary sodium concentration, serum aldosterone, and renal hemodynamics were measured. A constant infusion of angiotensin II (Hypertensin, Ciba Geigy, Basel, Switzerland) at a dose of 0.5 ng/kg/min was then administered for 30 min. Thereafter the aforementioned parameters were measured again. Subsequently, the dose of angiotensin II was increased to 3.0 ng/kg/min for another 30 min. At the end of this period, the same measurements were done again. The doses of angiotensin II were chosen according to the literature.40 – 42 Statistics All statistical analyses were carried out using SPSS software (SPSS Inc., Chicago, IL).43 The paired Student’s t test was used for comparison of baseline parameters, the unpaired Student’s t test for comparison between the two groups, defined according to 24-h ambulatory blood pressure values. In addition, MANOVA was applied for detection of any difference between the two groups in response to increasing doses of angiotensin II. Linear correlation analysis (Pearson) and partial correlation analysis were applied to identify determinants of urinary sodium excretion. Unless otherwise stated, values are given as mean ⫾ 1 standard deviation. Two-tailed P values are given throughout the text. Two-tailed P values less than .05 were considered to be significant. RESULTS Baseline Characteristics Clinical characteristics of 72 normotensive and 48 hypertensive subjects—according to the 24-h ambulatory blood pressure—are given in Table 1. By study design, 24-h ambulatory blood pressure differed between the two groups. Accordingly, resting and casual systolic and diastolic blood pressures were higher in the hypertensive than in the normotensive group (P ⬍ .001). At baseline no significant difference was found between the normotensive and hypertensive group with respect to 24-h sodium excretion, plasma renin activity, plasma angiotensin II, serum aldosterone, and the renal hemodynamic parameters
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TABLE 1. BASELINE CHARACTERISTICS OF 48 HYPERTENSIVE AND 72 NORMOTENSIVE PARTICIPANTS Characteristics Age (y) Body mass index (kg/m2) Casual blood pressure (mm Hg) Systolic Diastolic 24-h Ambulatory blood pressure (mm Hg) Systolic Diastolic Urinary sodium excretion (mmol/24 h) Angiotensin II (pg/mL) Aldosterone (pg/mL) Renal plasma flow (mL/min) Glomerular filtration rate (mL/min) Filtration fraction (%)
Hypertensive (N)* (n ⴝ 48)
Normotensive (H)* (n ⴝ 72)
P HvN
26 ⫾ 3 24.2 ⫾ 2.9
25 ⫾ 2 23.7 ⫾ 2.6
NS NS
152 ⫾ 13 96 ⫾ 10
131 ⫾ 13 83 ⫾ 10
⬍.001 ⬍.001
138 ⫾ 7 82 ⫾ 7 205 ⫾ 84 8.6 ⫾ 3.7 135 ⫾ 42 661 ⫾ 100 123 ⫾ 14 18.9 ⫾ 2.5
121 ⫾ 5 71 ⫾ 4 185 ⫾ 60 8.8 ⫾ 4.1 130 ⫾ 34 632 ⫾ 95 114 ⫾ 14 18.4 ⫾ 2.9
⬍.001 ⬍.001 NS NS NS NS .03 NS
NS ⫽ not significant. * defined according to ambulatory blood pressure monitoring criteria (24-h ambulatory blood pressure ⬎130 or ⬎80 mm Hg).
with the exception of a slightly, yet significantly, higher glomerular filtration rate in hypertensive subjects (P ⫽ .03) (Table 1). Response to Angiotensin II in the Normotensive and Hypertensive Groups Both doses of angiotensin II increased mean blood pressure in normotensive and hypertensive subjects in a dose-dependent manner (Table 2). The higher dose of angiotensin II caused a significantly greater increase of blood pressure in hypertensive subjects, if compared to normotensive volunteers (Table 2). Sodium excretion was decreased significantly by the low dose of angiotensin II (0.5 ng/kg/min) in hypertensive subjects, whereas only a nonsignificant trend toward decreased sodium excretion was observed in normotensives (Table 3). In response to the higher dose of angiotensin II (3.0 ng/kg/min), sodium excretion decreased in both hypertensives and normotensives (P ⬍ .001), but the decrease was significantly higher in hypertensive subjects (⫺0.18 ⫾ 0.2 mmol/ min for hypertensives v ⫺0.09 ⫾ 0.2 mmol/min for normotensives, P ⬍ .05) (Table 3). When the effect of angiotensin II on sodium excretion was analyzed by analysis of variance for repeated measurements, hypertensives showed a greater sodium retention than normotensive subjects (normotensives v hypertensives: P ⬍ .05; baseline v angiotensin II administration: P ⬍ .01). Urine flow rate in response to 0.5 ng/kg/min angiotensin II increased by 1.37 ⫾ 3.7 mL/min in hypertensives and 2.68 ⫾ 4.7 mL/min in normotensives (P ⬍ .001 for both groups), but was similar to that under resting conditions in response to 3.0 ng/kg/ min angiotensin II. The difference between the urine
flow rate in response to 0.5 ng/kg/min angiotensin II and the one in response to 3.0 ng/kg/min angiotensin II was significant (2.55 ⫾ 3.6 mL/min in hypertensives and 2.31 ⫾ 5.9 mL/min in normotensives, P ⬍ .001 for both groups) with no difference between hypertensives and normotensives (Table 3). Renal plasma flow was decreased by the infusion of angiotensin II in a dose-dependent manner in both normotensive and hypertensive subjects (P ⬍ .001), but the effect was exaggerated in hypertensives (renal plasma flow: ⫺151.5 ⫾ 73.9 mL/min for hypertensives v ⫺112.6 ⫾ 68.0 mL/min for normotensives, P ⬍ .01, at 3.0 ng/kg/min angiotensin II). The glomerular filtration rate increased (P ⬍ .001) with either dose of angiotensin II in both groups to a similar extent. Consequently, the filtration fraction increased in both groups with either dose of angiotensin II (P ⬍ .001), with the increase being more pronounced in hypertensive than in normotensive subjects (P ⬍ .01) (Table 2). For the dose-dependent increase of aldosterone secretion (P ⬍ .01) in response to the infusion of angiotensin II (in either dosage), no significant difference was found between normotensive and hypertensive individuals (Table 2). No significant correlation was found between the decrease of urinary sodium excretion on the one hand and changes in mean arterial pressure, renal plasma flow, glomerular filtration rate, and aldosterone secretion on the other in normotensive and hypertensive subjects in response to angiotensin II (data not shown). In summary, angiotensin II caused the expected increase in mean arterial pressure, glomerular filtration rate, and aldosterone secretion, and the expected
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TABLE 2. CHANGE OF MEAN ARTERIAL PRESSURE, RENAL HEMODYNAMICS, AND PLASMA ALDOSTERONE IN RESPONSE TO INFUSION WITH ANGIOTENSIN II 0.5 NG/KG/MIN AND 3.0 NG/KG/MIN IN 48 HYPERTENSIVE AND 72 NORMOTENSIVE PARTICIPANTS Characteristics Mean arterial pressure (mm Hg) Preinfusion Change to AII 0.5 ng/kg/min Change to AII 3.0 ng/kg/min Renal plasma flow (mL/min) Preinfusion Change to AII 0.5 ng/kg/min Change to AII 3.0 ng/kg/min Glomerular filtration rate (mL/min) Preinfusion Change to AII 0.5 ng/kg/min Change to AII 3.0 ng/kg/min Filtration fraction (%) Preinfusion Change to AII 0.5 ng/kg/min Change to AII 3.0 ng/kg/min Plasma aldosterone (pg/mL) Preinfusion Change to AII 0.5 ng/kg/min Change to AII 3.0 ng/kg/min
Hypertensive (H)* (n ⴝ 48) 103 ⫾ 10 5.7 ⫾ 5.7‡ 16.7 ⫾ 8.2‡ 661 ⫾ 100 ⫺51.1 ⫾ 64.7‡ ⫺151.5 ⫾ 73.9‡
Normotensive (N)* (n ⴝ 72) 91 ⫾ 10 4.5 ⫾ 4.6‡ 13.4 ⫾ 7.1‡ 632 ⫾ 95 ⫺42.0 ⫾ 57.2‡ ⫺112.6 ⫾ 68.0‡
P HvN ⬍.001 NS .022 NS NS .004
123 ⫾ 14 4.3 ⫾ 59‡ 4.9 ⫾ 8.4‡
114 ⫾ 14 4.7 ⫾ 4.7‡ 6.9 ⫾ 5.5‡
.03 NS NS
18.9 ⫾ 2.5 2.3 ⫾ 1.8‡ 6.6 ⫾ 2.6‡
18.4 ⫾ 2.9 2.1 ⫾ 1.7‡ 5.2 ⫾ 2.6‡
NS NS ⬍.006
93 ⫾ 25 25 ⫾ 54† 97 ⫾ 70‡
101 ⫾ 37 18 ⫾ 37† 92 ⫾ 66‡
NS NS NS
Abbreviation as in Table 1; AII ⫽ angiotensin II. * defined according to ambulatory blood pressure monitoring criteria (24-h ambulatory blood pressure ⬎130 or ⬎80 mm Hg). † P ⬍ .01 and ‡ P ⬍ .001 for the difference between preinfusion and after angiotensin II infusion.
decrease in renal plasma flow and urinary sodium excretion in both study groups. However, the increase in mean arterial pressure, the decrease in renal plasma flow and the decrease in urinary sodium excretion were significantly enhanced in hypertensive subjects. DISCUSSION Our most striking result was that sodium retention in response to infusion of angiotensin II was significantly higher in hypertensive than in normotensive individuals. This difference was clearly present with the higher dose of angiotensin II, but a trend was already found for the lower dose of angiotensin II. An antinatriuretic effect of angiotensin II can be demonstrated in normotensive individuals at doses as low as 1.0 ng/kg/min,20 whereas the effect peaks at doses between 4.0 and 8.0 nmol/kg/min angiotensin II. The latter dose results in an 80% decrease of urinary sodium excretion, a 25 mm Hg increase in systolic blood pressure, a decrease in renal plasma flow by approximately 55%, a slight decrease of glomerular filtration rate, and a marked increase of filtration fraction by about 50%.44 These data agree with results of Olsen et al,8 who found that during angiotensin II infusion in captopril-treated dogs the transition from an antinatriuretic to a natriuretic effect occurs at a dose of 15 ng/kg/min. At this dose, blood pressure
in the renal artery increased by approximately 30 mm Hg. Our observation of a borderline change of urinary sodium excretion in response to a low dose infusion of angiotensin II (0.5 ng/kg/min) and a significant decrease in urinary sodium excretion in response to a higher dose of angiotensin II (3.0 ng/kg/min) is in agreement with previous reports.8,22,40 In contrast to the normotensive individuals, the antinatriuretic effect of angiotensin II was found in hypertensive subjects already at the lower dose of 0.5 ng/kg/min of angiotensin II. At the higher dose of 3.0 ng/kg/min of angiotensin II, antinatriuresis was significantly more pronounced in hypertensive compared to normotensive individuals. Pressure natriuresis as a possible confounding phenomenon could not explain this finding because the increase of arterial pressure was too modest to induce it.8 In general, urinary sodium excretion is influenced by glomerular filtration rate and tubular reabsorption. The glomerular filtration rate was slightly higher at baseline in hypertensive participants, which was somewhat unexpected.45 Previously, we observed an increased glomerular filtration rate during exposure to mental stress, which was more marked in hypertensives than in normotensives.46 In response to angiotensin II we noted a similar increase in the glomerular
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TABLE 3. CHANGE OF URINARY SODIUM EXCRETION IN RESPONSE TO INFUSION WITH ANGIOTENSIN II 0.5 NG/KG/MIN AND 3.0 NG/KG/MIN IN 48 HYPERTENSIVE AND 72 NORMOTENSIVE PARTICIPANTS Characteristics Urinary sodium excretion (mmol/min) Preinfusion After AII 0.5 ng/kg/min Change to AII 0.5 ng/kg/min After AII 3.0 ng/kg/min Change to AII 3.0 ng/kg/min Urine flow rate (mL/min) Preinfusion After AII 0.5 ng/kg/min Change to AII 0.5 ng/kg/min After AII 3.0 ng/kg/min Change from AII 0.5 ng/kg/min to AII 3.0 ng/kg/min
Hypertensive (H)* (n ⴝ 48)
Normotensive (N)* (n ⴝ 72)
P HvN
0.40 ⫾ 0.2 0.32 ⫾ 0.2† ⫺0.06 ⫾ 0.2 0.19 ⫾ 0.1§ ⫺0.18 ⫾ 0.2
0.36 ⫾ 0.2 0.34 ⫾ 0.2 ⫺0.02 ⫾ 0.2 0.26 ⫾ 0.2‡ ⫺0.09 ⫾ 0.3
NS NS NS .07 ⬍.05
4.79 ⫾ 2.7 6.16 ⫾ 3.9§ 1.37 ⫾ 3.7 3.61 ⫾ 3.8㛳
3.99 ⫾ 2.6 6.67 ⫾ 4.9§ 2.68 ⫾ 4.7 4.37 ⫾ 5.7㛳
⫺2.55 ⫾ 3.6
⫺2.31 ⫾ 5.9
NS NS NS NS NS
Abbreviations as in Table 2. * defined according to ambulatory blood pressure monitoring criteria (24-h ambulatory blood pressure ⬎130 or ⬎80 mm Hg). † P ⬍ .05, ‡ P ⬍ .01, and § P ⬍ .001 for the difference between preinfusion and after angiotensin II infusion; 㛳 P ⬍ .001 for the difference between angiotensin 0.5 ng/kg/min and 3.0 ng/kg/min.
filtration rate in both hypertensives and normotensives. Thus, the effects of angiotensin II on the filtered sodium load do not appear to account for a different sodium excretion between hypertensives and normotensives. The higher increase of the filtration fraction in response to angiotensin II in hypertensives is explained by the more pronounced reduction of renal plasma flow. The increase of urine flow rate despite a low dose of angiotensin II is explained by the high volume input rate during the infusion period; the lower urine flow rate with the higher dose of angiotensin II reflects the known decreasing effect of angiotensin II on urine output. The plasma aldosterone concentration at baseline and its change in response to angiotensin II was similar in normotensives and hypertensives, which is in agreement with the data of London et al,47 who showed similar correlations between sodium clearance and plasma aldosterone in hypertensives compared to normotensives. Therefore, the observed different sodium excretion rate in response to angiotensin II cannot be due to a different regulation of the aldosterone-controlled sodium handling at the distal tubule. Renal plasma flow at baseline was similar in our young hypertensive and normotensive study participants, as reported previously by other researchers.48 Of note, this finding does not prove similar renal vascular resistance, because renal plasma flow is determined by renal vascular resistance and cardiac output, which was not determined in our study. London et al49 demonstrated that, despite an elevated renal
vascular resistance, subjects with essential hypertension showed a “normal” renal plasma flow because of an elevated cardiac output. Which mechanism may finally account for the higher sodium retention of hypertensives in response to angiotensin II? Tubular sodium reabsorption occurs mainly in proximal tubular cells, which are a target of angiotensin II action.6 – 8 Because there was no indication of alterations of either the filtered sodium load or distal aldosterone effects, the observed exaggerated sodium retention in hypertensive subjects is most likely due to an increased tubular reabsorption triggered by angiotensin II. The peptide could act directly on proximal tubular cells, or indirectly by altering peritubular perfusion. The increased sodium retention in response to angiotensin II infusion fits well to the concept of an hyperresponsiveness to angiotensin II in essential hypertension.25–28,50 In this context it is of some interest that—in contrast to data from Italy and France—in another northern European community, Sweden, an enhanced renal vascular response to angiotensin II has been described. A geographic heterogeneity, to either genes or culture, might be responsible for this discrepancy. To the best of our knowledge, this study is the first report of an increased sodium retention in response to angiotensin II in a suitably large group of young patients with essential hypertension. The increased antinatriuresis may facilitate sodium retention, which could contribute to further increases of blood pressure as well as to target organ damage.
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