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Hypertension. 1995;26:624-627

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(Hypertension. 1995;26:624-627.)
© 1995 American Heart Association, Inc.

Articles

Reduced Renal Extraction of Atrial Natriuretic Peptide in Primary Aldosteronism

Terry J. Tunny; Richard D. Gordon; Shelley A. Klemm; Michael Stowasser

From the Hypertension Unit, Greenslopes Hospital, Brisbane, Queensland, Australia.


*    Abstract
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 *Abstract
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Abstract We investigated renal and peripheral forearm extraction of atrial natriuretic peptide in patients with primary aldosteronism to determine whether alterations in extraction may contribute to the elevated levels of circulating atrial natriuretic peptide observed in primary aldosteronism. We obtained simultaneous venous blood samples from the left renal vein and a peripheral vein and from the radial artery in 28 patients with primary aldosteronism and 10 patients with essential hypertension. Renal extraction of atrial natriuretic peptide was significantly (P<.001) reduced (40±2%) in primary aldosteronism compared with essential hypertensive patients (62±3%). Peripheral forearm extraction was also reduced (P<.01) in primary aldosteronism compared with essential hypertensive patients (24±3% versus 38±4%). These findings are consistent with widespread downregulation of atrial natriuretic peptide receptors in primary aldosteronism. Consistent with reports that marked reduction in glomerular filtration rate is required before the renal extraction of atrial natriuretic peptide is reduced, no significant relationship between renal extraction of atrial natriuretic peptide and plasma creatinine was seen in primary aldosteronism or essential hypertension. Although the major regulators of atrial natriuretic peptide secretion in primary aldosteronism are presumably alterations in arterial blood pressure and plasma volume, reduced renal and peripheral extraction of atrial natriuretic peptide in primary aldosteronism may also contribute significantly to the elevated circulating levels observed.


Key Words: hyperaldosteronism • atrial natriuretic factor • human


*    Introduction
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 *Introduction
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Primary aldosteronism (PA) is an important, potentially curable form of mineralocorticoid hypertension, now diagnosed more frequently because of the implementation of more sensitive screening tests that can be applied to all hypertensive patients.1 2 The true incidence of PA3 4 is therefore much higher than previously accepted.

As atrial natriuretic peptide (ANP) and aldosterone have counterregulatory effects on blood volume and arterial pressure and as ANP is an effective inhibitor of aldosterone secretion,5 an understanding of the role of ANP in the pathophysiology of PA is of great interest. ANP levels are elevated in PA,6 7 presumably largely because of increased atrial stretch and increased arterial pressure levels, which are the major regulators of ANP secretion.8 9

Although aldosterone is autonomously secreted in PA, levels are not fixed and respond to a number of humoral factors, such as corticotropin, angiotensin II, potassium, and ANP.3 10 In PA, ANP levels are also responsive to short-term stimuli such as saline load and angiotensin II infusion.11 12 ANP has been implicated in the natriuresis observed during mineralocorticoid escape13 14 and during short-term sodium load in PA.10

The kidney is a major target and also a major clearance organ for circulating ANP, and 60% to 70% of ANP presented to the kidney is cleared in a single passage.15 Total renal ANP clearance contributes approximately 25% to 30% to the overall metabolic clearance rate of ANP.16 Neutral endopeptidase 3.4.24.11 contributes significantly to the renal clearance as well as the total body clearance of ANP.17 Monoclonal antibody studies have localized large concentrations of this enzyme in the terminal segment of the renal proximal tubule. Neutral endopeptidase inhibition can reduce ANP clearance rate by approximately one third.18 High-affinity clearance receptors constitute 90% to 95% of all ANP receptors not coupled to particulate guanylyl cyclase19 and up to 95% of all natriuretic peptide receptors in the renal cortex. Rapid internalization of ANP by these receptors is an efficient clearance mechanism. ANP clearance receptor blockade can decrease ANP metabolic clearance by up to 76%.20 Binding of ANP to the remaining 5% to 10% of biologically active natriuretic peptide receptors in the kidney, which occur in high concentrations in the glomeruli, proximal tubule, and inner medullary collecting duct, would presumably have only a minor role in overall renal clearance of ANP.

Glomerular filtration rate appears not to alter the renal extraction of ANP except when glomerular filtration rate is markedly impaired, as is sometimes seen in patients with severe unilateral renal artery stenosis.21 22

In this study we examined the renal and peripheral forearm extraction of ANP in PA to determine whether the elevated circulating levels of ANP seen in PA were solely caused by increased secretion due to plasma volume expansion and increased arterial blood pressure or in part caused by an alteration in ANP extraction.


*    Methods
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 *Methods
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Ethical approval and signed patient consent were obtained for these studies. All studies were performed in accordance with the guidelines of the National Health and Medical Research Council of Australia.

Patients
Twenty-eight patients with elevated ratios of plasma aldosterone to plasma renin activity had PA confirmed by the failure of aldosterone to suppress to less than 6 ng% after 5 days of fludrocortisone acetate (0.1 mg administered at 6 hourly intervals) and dietary salt supplements (20 mmol NaCl, three times daily). Bilateral adrenal venous sampling with simultaneous ratios of aldosterone to cortisol was performed3 successfully in all patients, with bilateral adrenal production of aldosterone evident in 18 and unilateral aldosterone-producing adenoma in 10 patients. Mean plasma creatinine was normal (0.09±0.01 mmol/L, n=28).

Ten essential hypertensive (EHT) control patients had secondary causes for hypertension excluded, including normal aldosterone-renin ratio to exclude PA, normal urinary epinephrine and norepinephrine levels to exclude pheochromocytoma, and nonlateralizing simultaneous renal venous renin ratio estimations23 to exclude renovascular hypertension. Mean plasma creatinine was 0.09±0.01 mmol/L (n=10).

Because cessation of antihypertensive drug therapy increases risk, antihypertensive medications were continued. No patient in this study was on diuretic therapy.

Study Design
All patients were admitted to the Hypertension Unit and continued on a restricted sodium diet (24-hour urinary sodium, 50±4 mmol/d; n=38). On the morning of day 4 patients were transferred recumbent to the Radiology Unit where, under local anesthesia, catheters were inserted into the femoral and left renal veins under fluoroscopic control. Simultaneous blood samples were then collected from the left renal vein, a peripheral forearm vein, and the radial artery. EHT patients underwent renal ANP extraction studies identical to those of the PA group, except that in this group blood was collected from both the left and right renal veins, allowing renal ANP extraction to be calculated across both left and right kidneys.

Plasma ANP was measured by double-antibody radioimmunoassay after prior extraction on Sep-Pak C18 cartridges (Waters Chromatography Division, Millipore Corp) as previously described.6 Plasma aldosterone was measured by radioimmunoassay. Results are expressed as mean±SEM and analyzed by Student's paired t test and paired and unpaired Mann-Whitney U tests. Renal extraction of ANP was calculated as E=A-V/Ax100%, where A is the ANP concentration in the radial artery and V is the ANP concentration in the left renal vein. Peripheral forearm extraction of ANP was also calculated with the same formula and simultaneously collected ANP samples from a forearm vein in the antecubital fossa.


*    Results
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In each PA patient arterial ANP levels were significantly (P<.001) higher (121±10 pg/mL) than peripheral levels (89±7 pg/mL), which were in turn higher (P<.001) than left renal vein ANP levels (74±11 pg/mL) (Fig 1). This pattern was also observed for the EHT group (55±8, 35±6, and 22±4 pg/mL, respectively) (Fig 2).



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  		Figure 1. Line graph shows simultaneously collected plasma atrial natriuretic peptide (ANP) levels in each patient with primary aldosteronism. Arterial ANP levels were significantly (P<.001) higher than peripheral levels (forearm vein), which were in turn higher (P<.001) than levels in the left renal vein in each patient.



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  		Figure 2. Line graph shows simultaneously collected plasma atrial natriuretic peptide (ANP) levels in each patient with essential hypertension. Arterial ANP levels were significantly (P<.001) higher than peripheral levels (forearm vein), which were in turn higher (P<.001) than levels in the left renal vein in each patient.

Mean ANP levels from each site were significantly (P<.001) greater in PA patients than in the EHT group (peripheral: 89±7 versus 35±6 pg/mL, respectively; left renal vein: 74±9 versus 22±4 pg/mL; and radial artery: 121±10 versus 55±8 pg/mL). Mean peripheral ANP levels in PA patients were significantly (P<.001) greater than in healthy subjects (reference range: 28±2 pg/mL, n=262). No significant difference in peripheral ANP levels between EHT patients and healthy subjects was seen in this study (35±6 versus 28±2 pg/mL).

Renal extraction of ANP across both kidneys could be compared in EHT patients and was similar for each kidney. Renal extraction of ANP was significantly (P<.001) lower in PA than EHT (40±2% versus 62±3%) patients (Fig 3). No difference in renal ANP extraction between the kidneys in EHT patients was observed. No significant correlation between renal ANP extraction in PA patients and peripheral plasma aldosterone levels or plasma creatinine levels was observed. Peripheral forearm extraction of ANP was also significantly (P<.01) lower in PA than in EHT (24±3% versus 38±4%) patients.



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  		Figure 3. Graph shows that renal extraction of atrial natriuretic peptide (ANP) was significantly lower (P<.001) in patients with primary aldosteronism (n=28) than in patients with essential hypertension (n=10).

Renal extraction of ANP was lower (P<.03) in patients with PA caused by an adenoma compared with patients with bilateral adrenal hyperplasia (35±3% versus 43±2%). Mean forearm extraction of ANP was slightly lower in the adenoma group compared with the bilateral hyperplasia group, but this did not reach significance (21±5% versus 26±3%, P=NS). Basal peripheral plasma aldosterone levels were higher (P<.01) in the adenoma group than in the bilateral hyperplasia group (1193±166 versus 743±83 pmol/L).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
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 up arrowResults
 *Discussion
down arrowReferences
 
This study suggests that ANP extraction may be important in the determination of circulating levels in PA. Circulating ANP levels result from a balance between active secretion and clearance24 and are elevated in PA6 7 and responsive to short-term volume changes.10 The physiological effects of ANP of natriuresis, diuresis, and vasodilatation are insufficient to control hypertension and hypervolemia in PA. A more complete knowledge of ANP metabolism may be important, with the possible introduction of neutral endopeptidase inhibitors, with or without the concurrent administration of angiotensin-converting enzyme inhibitors,25 26 27 as a possible drug therapy in PA.

The renal ANP extraction observed in EHT patients was similar to renal ANP extraction levels reported by other researchers in healthy subjects.15 A number of mechanisms may have influenced the observed reduction in renal ANP extraction in PA. Michel and coworkers28 reported a 35% reduction in glomerular ANP clearance receptors in rats on a long-term high salt diet, and as volume expansion is a feature of PA, a reduction in ANP clearance receptor numbers is possible.

Because peripheral forearm extraction of ANP was also reduced in PA, a more generalized downregulation of ANP receptors is suggested. A more widespread reduction in ANP receptor numbers would result in a greater reduction in total body extraction of ANP and hence body clearance, and downregulation of ANP receptor-A density may limit the biological effectiveness of ANP in PA. This overall reduction would contribute to increased endogenous circulating ANP levels and have a greater effect than a reduction in renal ANP extraction alone. Further studies are required for measurement of the effect of this reduction on endogenous plasma ANP levels in PA.

Greater reduced renal extraction of ANP in patients with aldosterone-producing adenoma compared with bilateral adrenal hyperplasia may have reflected the biochemical severity of the disease, with higher circulating plasma aldosterone levels in the adenoma group, which presumably would have resulted in greater volume expansion in this subtype.

Outer renal cortical blood flow, which is usually three times greater than mean medullary flow,29 has been reported to be reduced in volume-expanded, saltretaining states.30 The resultant redistribution in renal blood flow, with an increase in juxtamedullary cortical and outer medullary flows, would also tend to direct blood away from cortical ANP clearance receptors and reduce renal ANP extraction.

Changes in renal sympathetic nerve activity produce significant changes in renal blood flow, glomerular filtration rate, reabsorption of water and sodium, and release of renin and prostaglandins.31 Sympathetic nervous system stimulation attenuates the natriuretic response to ANP infusion.32 However, reduced levels of norepinephrine, epinephrine, and dopamine have been noted in adrenal venous blood in PA compared with patients with EHT or renovascular hypertension, consistent with reduced sympathetic nervous system activity in PA.33 As reduced renal sympathetic activity upregulates ANP receptors and clearance,34 it is not an explanation for reduced renal ANP extraction in PA.

Since neutral endopeptidase 3.4.24.11 levels are reduced in volume-expanded states, low neutral endopeptidase levels may also contribute to reduced renal extraction of ANP in PA.

The lack of a relationship between renal ANP extraction and plasma creatinine in PA is not surprising, as reduced renal ANP extraction has been reported only in the presence of gross renal impairment.22

In summary, renal and peripheral forearm extraction of ANP is significantly reduced in PA compared with EHT patients. This reduction in ANP extraction may result in a significant reduction in overall ANP clearance. Although the greatest contribution to increased circulating ANP levels in PA is presumably due to increased atrial stretch and arterial pressure levels, reduced ANP extraction in PA will contribute to the elevated circulating ANP levels observed.


*    Acknowledgments
 
This study was supported by the National Heart Foundation of Australia, the National Health and Medical Research Council of Australia, and The Department of Veterans' Affairs.


*    Footnotes
 
Reprint requests to Terry Tunny, Hypertension Unit, Greenslopes Hospital, Brisbane, Queensland 4120, Australia.

Received November 21, 1994; first decision April 7, 1995; accepted June 14, 1995.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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