(Hypertension. 1996;27:1254-1258.)
© 1996 American Heart Association, Inc.
Articles |
Renal Extraction of Atrial Natriuretic Peptide in Hypertensive Patients With or Without Renal Artery Stenosis
From the Department of Internal Medicine, University Hospital, and Department of Pharmacology, State University Limburg (P.M.H.S.), Maastricht, Netherlands.
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Abstract |
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Abstract The renin-angiotensin-aldosterone system plays a major role in renovascular hypertension, but the relationship between renin release and the renal fractional extraction of atrial natriuretic peptide (ANP) in this condition is not well defined. We measured ANP levels in the renal veins and aortas of 49 untreated hypertensive patients studied under standardized conditions immediately before renal angiography. Twenty-one patients had renal artery stenosis, 13 of which were unilateral and 8 bilateral. Five of the 13 patients with unilateral renal artery stenosis had an elevated renin ratio (
1.5). Patients with renal artery
stenosis were older (P<.01) and had higher
systolic pressures (P<.05) than patients with
essential hypertension. Arterial levels of ANP were
significantly higher in patients with unilateral or bilateral renal
artery stenosis than in patients with essential hypertension
(P<.05). Patients with hypertension and left
ventricular hypertrophy had significantly
higher arterial ANP levels than those with no
hypertrophy (40 versus 26 pmol/L, P<.05), but
in patients with renal artery stenosis, arterial
ANP levels were similar in those with or without
hypertrophy. Renal venous ANP levels were significantly
higher in stenotic than in normal kidneys. Moreover, in
unilateral renal artery stenosis, stenotic kidneys of
patients with an elevated renin ratio (stenotic
kidney/contralateral kidney 1.5) had a significantly higher renal
venous ANP level than stenotic kidneys of patients with a
normal renin ratio (30 versus 17 pmol/L, P<.05). However,
the median fractional extraction of ANP was similar, around 0.50
(range, 0 to 0.83), in normal kidneys of hypertensive patients and in
stenotic and contralateral kidneys of patients with renal
artery stenosis. A significant inverse correlation between
arterial ANP and renal venous active plasma renin
concentration was found for normal kidneys (r=-.62,
P<.01) of hypertensive patients without
hypertrophy. However, for stenotic kidneys, no such
relationship was apparent. A significant correlation between
arterial ANP and the arteriovenous difference of ANP
(r=+.92, P<.001) was found. This relationship
was similar for normal and stenotic kidneys. In conclusion, an
inverse relationship between arterial ANP and renal venous
active plasma renin concentration exists in normal kidneys of essential
hypertensive patients without left ventricular
hypertrophy. Furthermore, data of ANP extraction through
normal and stenotic kidneys suggest that saturation of ANP
extraction does not occur. Increased levels of ANP in renal artery
stenosis are likely caused by enhanced cardiac secretion of
this peptide.
Key Words: atrial natriuretic peptide • hypertension, essential • renal artery stenosis • renin
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Introduction |
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The cardiac hormone ANP has multiple actions.1 For instance, ANP interacts at several levels with the renin-angiotensin-aldosterone system: It inhibits renal renin secretion, suppresses aldosterone release, and attenuates the vasoconstrictor effects of Ang II.2 3 Therefore, it has been suggested that ANP may act as an endogenous antagonist to the renin-angiotensin-aldosterone system.2 4
In normal human volunteers, plasma levels of ANP are inversely related to plasma renin,5 and similar data have been found in patients with EH.6 7 However, in some studies, dealing predominantly with patients with low-renin EH, no such association could be detected.8 In patients with renovascular hypertension, a relationship between renin and ANP levels is also absent.9 10 11
In both healthy individuals12 13 14 and patients with EH or renovascular hypertension, the renal fractional extraction of ANP has been found to be approximately 0.50.9 11 15 However, Sudir and coworkers16 found renal extraction of around 0.60 to 0.70 in normal subjects. On the other hand, Pedersen and coworkers10 reported much lower ANP extraction ratios in renovascular hypertension, there being no difference between the affected and unaffected kidneys (median values, 0.25 and 0.29). Since in the latter study patients were extensively treated with antihypertensive drugs, including diuretics, at the time of sampling, the possibility cannot be excluded that antihypertensive medication reduces renal extraction of ANP. In the study of Bruun and coworkers,15 patients were on unrestricted sodium intake, and antihypertensive medication was continued when necessary. In two other studies, patients with RAS had been selected on the basis of a renal vein renin ratio greater than 1.59 11 or excluded if they had evidence of secondary organ damage such as LVH.11
Since the renin-angiotensin-aldosterone system plays a major role in renovascular hypertension, we were interested in the relationship between the renal fractional extraction of ANP and renin release in untreated patients who were studied under standardized conditions. Therefore, we measured arterial and renal venous levels of ANP, renin, and Ang II immediately before renal angiography in patients suspected of having RAS.
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Methods |
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Forty-nine patients who had been referred to the Hypertension Clinic for evaluation were included in this study. All of them had a diastolic pressure higher than 100 mm Hg on at least three occasions. They were selected for renal angiography because a diagnosis of renovascular hypertension was suspected on clinical grounds or on the basis of MAG-3 renography. Antihypertensive medication, if any, was gradually withdrawn before the study so that none of the patients had used antihypertensive drugs for at least 2 weeks before the angiographic procedure. Sodium intake was standardized at 55 mmol/d. Selective renal catheterization was performed via the transfemoral route, and blood samples for the determination of renin, Ang II, aldosterone, and ANP were drawn simultaneously from the aorta and renal veins before any contrast material had been administered. The renal angiogram was considered positive for RAS when the arterial lumen was reduced by 50% or more.17 Patients with no RAS were considered to have EH, since other causes of hypertension had already been excluded. In all patients, global renal function was assessed by plasma creatinine.
Biochemical Measurements
APRC was measured by the immunoradiometric assay (IRMA) method
(Pasteur Diagnostics).18 The
performance characteristics of this assay in our laboratory are
as follows: sensitivity, 2.5 mU/L; intra-assay variability, 2.9%;
and interassay variability, 7.6%. Ang II was determined by
radioimmunoassay after Ph Phenyl column extraction (Amersham
International).19 In our hands, this assay is
characterized by a sensitivity of 2.2 pmol/L, an intra-assay
variability of 4.6%, and an interassay variability of 7.7%.
Aldosterone was assayed by means of a solid-phase
protein-binding radioimmunoassay (antibody-coated tubes)
(Diagnostic Products Corp)20 with a
sensitivity of 0.02 nmol/L, intra-assay variability of 4.3%, and
interassay variability of 6.7%. ANP was measured by a competitive
protein-binding radioimmunoassay (Nichols Institute
Diagnostics) following extraction of plasma over Sep-Pak
C18 columns.21 The performance characteristics of
the ANP assay in our laboratory are as follows: sensitivity, 4.5
pmol/L; intra-assay variability, 7.0%; and interassay variability,
12.9%. The fractional extraction of ANP was calculated from the
formula (A-V)/A, where A and V are arterial and
venous concentrations, respectively. Since our measurements did not
reveal any significant differences in hematocrit between
arterial and venous blood, hormonal data were not corrected
for hematocrit.
Statistics
Since sample sizes were relatively small and data showed
significant curtosis and skewness (even after logarithmic
transformation), the data are expressed as medians with ranges, and
nonparametric statistics (Mann-Whitney U test)
were applied for comparison of data from groups of patients and groups
of kidneys. Correlations between variables were obtained by
Spearman's correlation coefficient. A value of P<.05 was
considered statistically significant.
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Results |
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On renal angiography, 27 patients (17 men) had normal renal arteries, and they were diagnosed as having EH. Twenty-one patients (9 men) had RAS, 13 of which were unilateral and 8 bilateral. The clinical characteristics of both patient groups are given in Table 1
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Five of the 13 patients with unilateral RAS had an elevated renin ratio
(stenotic kidney/contralateral kidney 1.5). Renin ratios in
these patients ranged from 1.6 to 3.2, compared with 0.6 to 1.4 in the
others. The number of kidneys was 54 for normal kidneys, 29 for kidneys
with RAS (13 from the unilateral RAS patients and 16 from the bilateral
RAS patients), and 13 for kidneys contralateral to a
stenosis.
Patients with EH were significantly younger than patients with RAS. No significant differences between patients with EH and RAS were found in renal function and diastolic pressure. Systolic pressure was significantly higher in patients with RAS (P<.05). There was no significant difference between groups with respect to the duration of hypertension, number of antihypertensive drugs used, or number of patients with LVH.
In patients with unilateral RAS, age, blood pressure, and renal function did not differ between those with an elevated and those with a normal renin ratio.
Arterial Hormone Levels
No significant differences were found in arterial
APRC, Ang II, and aldosterone levels between patients with
EH and those with RAS (both for patients with unilateral and for those
with bilateral disease).
Arterial ANP levels were significantly higher in patients with RAS (median, 40 pmol/L; range, 18 to 201) than in patients with EH (median, 28 pmol/L; range, 7.6 to 93) (P<.05). This was true both for patients with unilateral (43 pmol/L) and for those with bilateral (39 pmol/L) RAS.
In patients with unilateral RAS, a significant difference in arterial ANP levels was apparent between those with an elevated and those with a normal renin ratio (70 versus 37 pmol/L, P<.05). Arterial aldosterone and Ang II levels in these two groups were similar.
When patients with RAS were matched for arterial APRC with patients with EH, patients with RAS still had significantly higher arterial ANP levels (P<.01).
Patients with EH and electrocardiographic evidence of LVH (n=6) had significantly higher arterial ANP levels than those without LVH (40 pmol/L [range, 34 to 93] versus 26 pmol/L [range, 7.6 to 49]; P<.05). However, in patients with RAS, arterial ANP levels were similar between those with (n=5) or without LVH (49 pmol/L [range, 26 to 201] versus 39 pmol/L [range, 18 to 107]). In both groups of hypertensive patients, arterial Ang II and aldosterone levels were similar in those with or without LVH.
Renal Venous Hormone Levels and ANP Extraction
Renal venous levels of APRC were significantly higher in
unilateral and bilateral stenotic kidneys than in normal ones
(both P<.05), but renal venous levels of
aldosterone and Ang II were similar in the different kidney
groups.
Renal venous ANP levels and fractional extraction of ANP in the
different kidney groups are given in Table 2.
Differences in renal venous ANP levels mirrored those in
arterial blood and were significantly higher in the venous
effluent of kidneys with a stenotic artery than in effluent of
normal kidneys, with similar levels for unilateral and bilateral RAS
kidneys. Kidneys contralateral to stenotic kidneys also tended
to have higher venous ANP levels than normal kidneys. Likewise, in
unilateral RAS, stenotic kidneys of patients with an elevated
renin ratio (1.5) had a significantly higher renal venous ANP level
than stenotic kidneys of patients with a normal renin ratio
(median, 30 pmol/L [range, 8.3 to 40] versus 17 pmol/L [range, 13 to
23]; P<.05).
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Renal venous levels of ANP in EH patients were significantly higher for those with LVH than for those without LVH (median, 19 pmol/L [range, 12 to 34] versus 13 pmol/L [range, 7.3 to 41]; P<.01).
The median arteriovenous differences of ANP levels were 15 (range, 0.4 to 66), 17 (range, 1.3 to 120), and 24 (range, 0 to 87) pmol/L for normal, stenotic, and contralateral kidneys, respectively. Gradients were not different between these kidney groups.
The median fractional extraction of ANP was 0.53 (range, 0.04 to 0.75),
0.50 (range, 0.06 to 0.79), and 0.56 (range, 0 to 0.83) in normal,
stenotic, and contralateral kidneys, respectively. All kidneys
but one extracted ANP from the circulation regardless of the presence
of a stenotic artery. In patients with unilateral RAS,
fractional extraction of ANP was similar for those with an elevated
renin ratio (1.5) and those with a low renin ratio (<1.5) (both
0.53).
As shown in Fig 1, a significant correlation between
arterial ANP and the arteriovenous difference of ANP was
found (r=+.92, P<.001;
y=-15+0.58x). This relationship was similar
for normal (r=+.90, P<.001;
y=-7+0.60x) and stenotic
(r=+.94, P<.001;
y=-18+0.57x) kidneys. A significant inverse
correlation between arterial ANP and renal venous APRC was
found in normal kidneys (r=-.62, P<.01;
y=72-0.84x) in EH patients without LVH.
However, for stenotic kidneys, no such relationship was
apparent (Fig 2).
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indicates normal kidney; x, stenotic kidney;
and hourglass symbol, kidney contralateral to stenosis.
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No correlations were found between blood pressure, creatinine, or Ang II on the one hand and arterial or venous levels of ANP on the other. Also, no correlation was found between age, blood pressure, creatinine, and arterial or venous hormone levels on the one hand and the arteriovenous difference of ANP or fractional extraction of ANP on the other.
Results of Intervention in Relation to ANP Levels
Of the 21 patients with RAS, 7 had a favorable
response22 to intervention (all angioplasty) and 9 (7
angioplasty, 2 surgery) had no response. In 5 patients, no intervention
was performed for various reasons. Arterial or venous ANP
levels and extraction of ANP were similar in the patients who had a
favorable response after intervention and those with no response.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The results of the present study demonstrate that regardless of their condition, the fractional extraction of ANP is similar in all kidneys (approximately 0.50), albeit with a wide range (0 to 0.83). These data are in line with those of other researchers who also found fractional extraction of ANP through the kidneys to be around 0.50.9 12 15 16 The constant relationship between arterial ANP levels and the arteriovenous difference of ANP (in both normal and stenotic kidneys) suggests that saturation of ANP extraction by the kidney does not occur and that the extraction efficiency probably is independent of renal blood flow. Therefore, it appears that differences in ANP levels between patients with EH and those with RAS are unlikely to be caused by decreased ANP clearance by the kidneys.
Our data further indicate that circulating ANP levels are significantly higher in patients with RAS (both unilateral and bilateral) than in patients with EH. It is improbable, however, that the elevated ANP levels in RAS are caused by enhanced activity of the renin-angiotensin system. First, when matched for arterial renin, patients with RAS still had significantly higher arterial ANP levels than patients with EH. Moreover, we failed to find a relationship between ANP and Ang II levels. Thus, the renin-angiotensin-aldosterone system is probably not dominantly involved in the elevation of ANP levels.
However, in patients with unilateral RAS and an elevated renin ratio (indicating hemodynamic significance of the stenosis), arterial ANP levels were significantly higher than in patients with a normal renin ratio. So it may be that another humoral factor is responsible for the elevation of ANP levels, but it would be speculative to suggest that this factor is secreted by the ischemic kidney. Since decreased extraction of ANP across the kidneys is unlikely to be the cause of elevated ANP levels in RAS, other mechanisms, such as decreased peripheral clearance or increased ANP secretion by the heart, must be present.
Major mechanisms for ANP clearance are uptake by clearance receptors and degradation by an endoprotease (EC 3.4.24.11.).22 The contribution of various organs to total body ANP clearance differs considerably because of marked differences in organ blood flow. Recently, Tunny and coworkers23 found renal and peripheral forearm extractions of ANP to be significantly reduced in patients with primary aldosteronism compared with EH patients. These findings were thought to be consistent with widespread downregulation of ANP receptors in primary aldosteronism. Although downregulation of clearance receptors would explain increased ANP levels in RAS, our data show that at least in the kidney, ANP extraction is normal. To the best of our knowledge, no studies concerning peripheral forearm ANP extraction in RAS have been performed. On the basis of our results, therefore, we consider reduced clearance of ANP a less likely mechanism to explain elevated peripheral levels of this peptide. Thus, in our view, cardiac secretion of ANP must be enhanced in RAS. The increased cardiac secretion of ANP, with its effects on natriuresis, diuresis, and vasodilatation, would then seem to act as a counterregulatory mechanism to the renin-angiotensin-aldosterone system.
Although raised circulating levels of ANP have been reported also in EH,8 in particular in patients with signs of LVH,7 this is not a uniform finding.24 25 In our study, patients with EH and LVH had significantly higher arterial ANP levels than those without LVH, but in patients with RAS, levels were similar between those with and without LVH. It is known that in animals with LVH the ventricle secretes substantial amounts of ANP26 and that patients with hypertrophic cardiomyopathy but without apparent congestive symptoms express ANP immunohistochemically in their left and right ventricles.27 However, the mechanism underlying the association between enhanced ANP release and LVH in patients with EH remains uncertain. Conceivably, an elevation of ANP levels in hypertension may reflect impaired ventricular compliance, but apparently this association is lost in patients with RAS.
From experimental renal artery occlusion in animals it is known that during the period of ischemia not only the renin-angiotensin-aldosterone system is activated but there is also a sustained increase in plasma ANP levels.28 Ang II has been shown to promote ANP release in animals29 and humans.30 Although this effect of Ang II has been ascribed to its hemodynamic action leading to increased atrial wall stretch,30 other mechanisms may be involved as well.1 30 Since ANP possesses an antihypertrophic action on vascular smooth muscle cells31 and since Ang II stimulates the growth of vascular smooth muscle cells,32 ANP may be elevated in RAS as a counterregulatory mechanism independent of the presence of LVH. However, the absence of a relationship between arterial or renal venous ANP levels on the one hand and renal arterial and venous levels of Ang II on the other in our study does not support this hypothesis. We also found an inverse relationship between arterial ANP and renal venous renin in patients with EH. In patients with RAS this relationship was disturbed. These data, therefore, suggest that ANP may suppress renin release only under conditions of normal flow. In ischemic kidneys, on the other hand, another stimulus for renin release apparently is able to overcome the suppressing effect of ANP.
In conclusion, our data demonstrate that arterial and renal venous ANP levels are elevated in untreated patients with unilateral or bilateral RAS and that EH patients with LVH have significantly higher plasma ANP levels than those without LVH. Renal ANP extraction is comparable in EH and hypertension associated with RAS. Furthermore, a constant relationship between arterial ANP levels and the arteriovenous difference of ANP was observed for all kidneys, suggesting no saturation of ANP extraction by the kidneys and an extraction efficiency that is independent of renal blood flow. Moreover, in patients with renovascular hypertension, arterial and venous ANP levels and extraction of ANP do not show a relationship with the response after intervention.
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Selected Abbreviations and Acronyms |
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Footnotes |
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Reprint requests to P.W. de Leeuw, MD, PhD, Department of Internal Medicine, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, Netherlands.
Received September 14, 1995; first decision October 16, 1995; accepted February 15, 1996.
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