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Endocrinology Vol. 141, No. 1 169-173
Copyright © 2000 by The Endocrine Society

ARTICLES

Actions of Neuropeptide Y on the Rat Adrenal Cortex1

D. Renshaw, L. M. Thomson, M. Carroll, S. Kapas and J. P. Hinson

Molecular and Cellular Biology Section, Division of Biomedical Sciences, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, London, United Kingdom E1 4NS; and the Clinical Sciences Research Centre, St. Bartholomew’s and the Royal London School of Medicine and Dentistry (S.K.), London, United Kingdom E1 2AT

Address all correspondence and requests for reprints to: Dr. J. P. Hinson, Molecular and Cellular Biology Section, Division of Biomedical Sciences, St. Bartholomew’s and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, Mile End Road, London, United Kingdom E1 4NS. E-mail: j.hinson{at}qmw.ac.uk


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Although several studies have demonstrated the presence of neuropeptide Y (NPY) in nerves supplying the mammalian adrenal cortex, its function in this tissue remains unclear, with reports of both stimulatory and inhibitory effects on aldosterone secretion apparently depending on the tissue preparation used. In the present study the effects of NPY on rat adrenal capsular tissue were investigated. NPY significantly stimulated aldosterone secretion in a dose-dependent manner, and this effect was abolished by atenolol, a ß1-adrenergic antagonist. NPY also stimulated the release of catecholamines from intact rat adrenal capsular tissue with the same dose-dependent relationship as the stimulation of aldosterone release. These observations suggest that the actions of NPY may be mediated by the local release of catecholamines from chromaffin cells within adrenal capsular tissue, as we have previously described for vasoactive intestinal peptide.

The second part of this study concerned the NPY receptor subtype mediating the actions of NPY on the adrenal cortex. It was found that peptide YY stimulated aldosterone release with a comparable potency to NPY, whereas pancreatic polypeptide (PP) was without effect. The Y1 selective NPY analog Leu31Pro34NPY had a greater effect on aldosterone release than the Y2 selective analog NPY18–36. Studies using the specific Y1 receptor antagonist BIBP 3226 showed significant attenuation of the aldosterone response to NPY, but no effect on the response to added norepinephrine. Binding studies carried out using [125I]NPY revealed the presence of a single population of NPY-binding sites with a Kd of 12.25 nmol/liter and a binding capacity of 623 fmol/mg protein. Competition studies revealed displacement of [125I]NPY specific binding by NPY, peptide YY, and Leu31Pro34NPY, but not by other peptides. Messenger RNA analysis revealed the presence of messenger RNA coding for both the Y1 receptor and the Y4 receptor, but not the other subtypes. Taken together these data suggest that the effects of NPY on the rat adrenal cortex are mediated by the Y1 receptor subtype.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
SEVERAL STUDIES have demonstrated the presence of neuropeptide Y (NPY) in nerves supplying the adrenal cortex of the rat as well as in other mammalian species. The actions of NPY on steroid release and adrenal growth have also been investigated (for review, see Ref. 1). It has been found that, when infused in vivo, NPY acts to increase the circulating concentration of aldosterone (2, 3). NPY also stimulates aldosterone release from the intact perfused rat adrenal preparation (4). Other studies have shown that NPY can modulate adrenocortical responsiveness to stimulation by ACTH, for example (5). Studies on the effects of NPY on cells, however, have produced variable results, with reports of both stimulation and inhibition of aldosterone secretion (6, 7). As noted by Nussdorfer and Gottardo, however, these effects were only observed at high concentrations of NPY and are therefore unlikely to be physiologically relevant (1). There remains, therefore, some discrepancy between the responsiveness of different tissue preparations to NPY stimulation.

Similar data obtained with vasoactive intestinal peptide (VIP) led us to investigate mechanisms that might account for these discrepancies. We found that VIP stimulates the release of catecholamines from rat adrenal capsular tissue, presumably from the chromaffin cells, which may be found in the outer part of the adrenal cortex (for review, see Refs. 8, 9). As it was shown that a ß1-adrenergic antagonist inhibited the response to VIP, we hypothesized that the catecholamines then stimulate aldosterone secretion via ß1-adrenoceptors (10, 11). Studies using analogs of NPY have suggested that NPY may act by a similar mechanism as VIP (12). However, to date there have been no studies investigating catecholamine release in response to NPY stimulation of adrenal capsular tissue, nor has it been determined whether adrenoceptor blockers inhibit the aldosterone response to NPY. The present study was therefore designed to elucidate the mechanisms involved in the adrenocortical response to NPY stimulation.

Although binding sites for NPY have been identified in the bovine and rat zona glomerulosa (13, 14), it remains to be established which NPY receptor subtype is present. To date four NPY receptors have been cloned, although there is pharmacological evidence for the existence of two more (15). There is conflicting evidence regarding the receptor subtype present in the rat adrenal gland, suggesting the presence of several different NPY receptors in this tissue, including one of the putative receptors (1). This study therefore addressed the question of which subtype of NPY receptor mediates the effects of this peptide on the rat adrenal cortex.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
NPY, peptide YY (PYY), pancreatic polypeptide (PP), and the NPY receptor agonists Leu31Pro34NPY (Y1 selective) (16) and NPY18–36 (Y2 selective) were obtained from Bachem (UK) Ltd. (Saffron Walden, UK); ICI 118 551 (ß2-adrenoceptor antagonist) was obtained from Semat Technical (UK) Ltd. (St. Albans, UK); BIBP 3226, the Y1 receptor antagonist, was purchased from Peninsula Laboratories, Inc. (St. Helen’s, UK). All radiolabels were obtained from Amersham International (Aylesbury, UK). All other chemicals were of analytical grade obtained from Sigma-Aldrich Corp. or Merck-BDH, (Poole, UK).

Male and female Wistar rats (250–400 g BW) were obtained either from A. Tuck and Sons (Battlesbridge, UK) or from the colony maintained at Queen Mary and Westfield College. The rats were stunned and then killed by cervical dislocation in accordance with Home Office regulations. Adrenals were rapidly removed and cleaned of adhering fat. Capsule fractions (with mainly zona glomerulosa cells attached) were separated from inner adrenocortical tissue by pressure between glass plates. Capsules were preincubated in Krebs-Ringer bicarbonate containing glucose (2 mg/ml; KRBG) for 1 h at 37 C under an atmosphere of 95% O2-5% CO2. After preincubation, capsules were incubated in fresh KRBG for 1h under an atmosphere of 95% O2-5% CO2 in the absence or presence of stimulants or inhibitors.

Effects of NPY and other agonists/inhibitors on steroidogenesis
All peptides and inhibitors were dissolved in KRBG to the required concentrations. A range of concentrations of NPY, PYY, and the NPY receptor agonists, from 10-10–10-6 mol/liter, was used. Epinephrine was diluted in acidic medium and diluted in KRBG (with pH correction) immediately before addition to the incubation medium to minimize oxidative loss. In other experiments, to test the effects of antagonists on NPY-stimulated aldosterone secretion, capsules were incubated with various concentrations of NPY in the presence of 10-7 mol/liter adrenoceptor antagonist or 10-6 mol/liter BIBP 3226 for 1 h. After incubation, the capsules were discarded, half the incubation medium was placed into clean microfuge tubes, and the tubes were stored at -20 C until the media were assayed for aldosterone. Aldosterone was measured in an aliquot of unextracted incubation medium by direct RIA (17). A small volume of acetic acid was added to the remaining incubation media (final concentration, 10%, vol/vol), and the media were assayed for catecholamines.

Catecholamine assay
The assay of epinephrine and norepinephrine is based on the trihydroxyindole fluorescence method of Brocklehurst and Pollard (18). The technique involves the oxidation of catecholamines by K2Fe(CN)6, and the subsequent generation of the trihydroxyindole fluorophore product by NaOH and ascorbic acid. The oxidation reactions were performed under both acidic and neutral pH conditions to allow measurement of epinephrine and norepinephrine. Briefly, assays were carried out as follows. To one set of 50-µl samples 500 µl 0.5 mol/liter sodium phosphate buffer (pH 7.0) were added. To another (identical) set of samples 500 µl 10% (vol/vol) acetic acid were added. All samples received 50 µl K2Fe(CN)6 and were incubated on ice for 20 min. The reactions were terminated with 1 ml 9 mol/liter NaOH containing 0.4% ascorbic acid (wt/vol), followed by vigorous vortexing. After the addition of 2 ml water, the trihydroxyindole fluorescence product was measured in a spectrofluorometer (luminescent fluorometer LS-50B, Perkin-Elmer Corp., Warrington, UK) with an excitation wavelength of 412 nm and an emission wavelength of 523 nm.

Receptor binding assay
The binding assay was carried out as previously described (19). Rat adrenal capsules were prepared as described above. After incubation, capsules were homogenized in 150 mmol/liter Tris-HCl buffer (pH 7.6) containing 1 µg/ml each of aprotinin and soybean trypsin inhibitor. Homogenates were centrifuged at 800 x g for 10 min, and the supernatant was recentrifuged at 100,000 x g for 1 h. The particulate (membrane) fraction was then resuspended in Tris-HCl buffer containing 100 mmol/liter NaCl, 6 mmol/liter MgCl2, 0.1% (wt/vol) BSA, and protease inhibitors (1 µg/ml each of soybean trypsin inhibitor and aprotinin).

Aliquots of membrane suspension (100 µg protein/tube) were incubated with 3-[125I-iodotyrosyl10]NPY (2000 Ci/mmol; final concentration, 0.15 nmol/liter) with increasing concentrations of unlabeled NPY, NPY agonists, atenolol, ICI 118551, angiotensin II, and ACTH (0.39–50 nmol/liter). Nonspecific binding was determined by incubating labeled cells with a 100-fold excess of unlabeled NPY. Incubations were carried out in triplicate at 22 C for 45 min and terminated by the addition of 800 µl ice-cold buffer followed by centrifugation at 10,000 x g for 5 min at 4 C. Supernatants were discarded, and the pellets were washed twice. After washing, radioactivity bound to the membrane was estimated using a 1272 Clinigamma counter (LKB Wallac, Inc., St. Albans, UK). Binding studies were repeated at least three times.

Messenger RNA (mRNA) analysis
Total RNA was isolated using RNAzol solution (Biogenesis, Poole, UK) following the manufacturer’s instructions. The purity of RNA was estimated by measuring OD at 260/280. Five micrograms of total RNA were subjected to first strand complementary DNA (cDNA) synthesis in a 10-µl reaction containing 250 mmol/liter Tris-HCl (pH 8.3; 20 C), 375 mmol/liter KCl, 15 mmol/liter MgCl2, 1 mmol/liter dithiothreitol, 1 mmol/liter deoxy-NTP, and 20 U ribonuclease inhibitor in the presence of 1.5 µg oligo(deoxythymidine)(12, 13, 14, 15, 16, 17, 18) primer and 200 U Superscriptase (all from Life Technologies, Inc., Paisley, Scotland, UK). After completion of first strand cDNA synthesis, the reaction was stopped by heat inactivation (5 min at 95 C) and diluted with water to 50 ng/µl RNA equivalents. cDNA amounts equivalent to 100 ng total RNA were subjected to PCR in a 50-µl reaction volume containing 10 mmol/liter Tris-HCl (pH 9; 25 C), 50 mmol/liter KCl, 1.5 mmol/liter MgCl2, 0.01% (wt/vol) gelatin, 0.1% (vol/vol) Triton X-100, 2 mmol/liter DTT, 200 µmol/liter deoxy-NTP, 1 µmol/liter of each primer, and 0.2 U Taq DNA polymerase (Flowgen, Cambridge, UK) under the following conditions: denaturation at 94 C for 5 min, followed by 35 cycles of denaturation, 30 sec at 94 C, primer annealing for 1 min at 64 C, and primer extension for 1 min at 72 C, with a final extension period for 10 min at 72 C. Ten microliters of PCR products were electrophoresed through 1% agarose gels and viewed by UV illumination. Oligonucleotide primers used were as described by Goumain et al. (20).

Statistical analysis
Arithmetic means and SEM values were calculated. One-way ANOVA was used to test whether NPY had a significant effect on basal (control) levels of aldosterone or catecholamine release as appropriate. Student’s t tests were used to test whether the above-mentioned responses were affected by the presence of antagonists. Saturation data were analyzed by LIGAND (21).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
NPY caused a dose-dependent increase in aldosterone secretion by intact rat adrenal capsular tissue incubated in vitro (Fig. 1Go). A similar effect was seen with PYY, but not with PP. The minimum concentration of NPY or PYY required for significant stimulation of aldosterone was 10 nmol/liter, and a maximal effect was seen at 1 µmol/liter for both peptides. The effects of NPY were mimicked by both NPY receptor agonists tested, with the specific Y1 receptor agonist Leu31Pro34NPY having a significantly greater effect than the Y2 agonist NPY18–36 (Fig. 2Go).



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  		Figure 1. Effects of increasing concentrations of NPY, PYY, and PP on aldosterone secretion by intact rat adrenal capsular tissue. Data are the mean ± SEM from several different experiments and are expressed as a percentage of the appropriate control value for each experiment to allow for the variation in basal aldosterone between different experiments. *, P < 0.05, **, P < 0.01; ***, P < 0.001 (compared with basal secretion, by ANOVA).

 


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  		Figure 2. Effects of increasing concentrations of NPY and the NPY receptor agonists Leu31Pro34NPY and NPY(18–36) on aldosterone secretion by intact rat adrenal capsular tissue. Data are expressed as the mean ± SEM (n = 6).

 
NPY was also found to cause an increase in catecholamine release from intact capsular tissue (Fig. 3Go). Both epinephrine and norepinephrine levels were increased by NPY, with a dose dependency comparable to that seen for aldosterone release. The effects of NPY on aldosterone secretion were abolished by the ß1-adrenoceptor antagonist atenolol, but were not significantly affected by the presence of the ß2-antagonist ICI 118551 (Fig. 4Go). Norepinephrine significantly stimulated aldosterone release by adrenal capsular tissue (Fig. 5Go). The effects of NPY were significantly attenuated by the Y1 receptor antagonist BIBP 3226, but this agent did not affect either basal aldosterone release or the aldosterone response to norepinephrine (Fig. 5Go).



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  		Figure 3. Effects of increasing concentrations of NPY on epinephrine (open bars) and norepinephrine (hatched bars) release by intact rat adrenal capsular tissue. Data are expressed as the mean ± SEM (n = 6). **, P < 0.01; ***, P < 0.001 (compared with basal, by ANOVA).

 


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  		Figure 4. Effects of the ß1-adrenoceptor antagonist atenolol (100 nmol/liter; closed squares) and the ß2-antagonist ICI-118551 (100 nmol/liter; open squares) on the aldosterone response to increasing concentrations of NPY. Data are expressed as the mean ± SEM (n = 6). 2+++, P < 0.001 (compared with NPY alone, by ANOVA).

 


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  		Figure 5. Effects of the NPY Y1 receptor antagonist, BIBP3226 (1 µmol/liter; hatched bars), on basal, NPY-stimulated (100 pmol/liter), and norepinephrine-stimulated (5 µmol/liter) aldosterone release. Data are expressed as the mean ± SEM (n = 6). ***, P < 0.001 (compared with basal); +, P < 0.05 (compared with NPY alone, by ANOVA).

 
Receptor binding studies revealed a single population of NPY binding sites with a Kd of 12.25 nmol/liter and a density of 623 fmol/mg protein (Fig. 6Go). The Hill coefficient was 0.811 (P < 0.05). Specific [125I]NPY binding was significantly displaced only by cold NPY, PYY, and Leu31Pro34NPY. No displacement of binding was seen with the adrenoceptor antagonists, pancreatic polypeptide, ACTH, or angiotensin II (Table 1Go).



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  		Figure 6. Scatchard analysis of [125I]NPY binding to rat adrenal capsular homogenates (Kd, 12.25 nmol/liter; binding capacity, 623 fmol/mg protein; Hill coefficient, 0.811; P < 0.05).

 

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  		Table 1. Effects of various peptides and other competitors (50 µmol/liter) on specific [125I]NPY binding to rat adrenal capsular homogenates

 
Molecular studies revealed the presence of Y1 and Y4 receptor mRNA in both the capsule and inner zones/medulla. There was no evidence for the expression of the other NPY receptor subtypes in the rat adrenal gland (Fig. 7Go).



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  		Figure 7. Detection of mRNA encoding NPY receptors in rat adrenal capsules. Total RNA extracted was subjected to RT and amplification using specific primers for the different subtypes of NPY receptors. To assess the integrity of the RNA, glyceraldehyde-3-phosphate dehydrogenase primers were used to amplify DNA products from the same preparation. PCR products were visualized in 1% agarose gels stained with ethidium bromide. The fragment sizes are indicated.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of this study, showing a dose-dependent stimulatory effect of NPY on aldosterone secretion, are consistent with those of other studies investigating the effects of NPY on intact adrenal tissue either in vitro or in vivo, where stimulatory effects have been reported (2, 3, 4, 12, 22). These findings contrast with data obtained using dispersed zona glomerulosa cells, where either no effect or inhibition of steroidogenesis by NPY has been reported (5, 6, 23). PYY has also been reported to stimulate aldosterone release in rats in vivo, but not by dispersed rat zona glomerulosa cells in vitro (24). The finding that NPY stimulation of aldosterone secretion had a threshold of 10 nmol/liter suggests that this may be a physiologically relevant action of NPY, as this concentration is likely to reflect intraadrenal concentrations of NPY (8). Previous studies of the actions of NPY in this tissue have reported effects of significantly higher concentrations of peptide (5, 6), which may not be physiologically relevant, although calculating local concentrations of peptide released from intraadrenal neurons is extremely difficult.

In view of the obvious differences in responsiveness to NPY seen with different tissue preparations, we hypothesized that a mechanism similar to that used by VIP in the adrenal may account for these observations (10). The results presented in this study clearly show that NPY stimulated the release of catecholamines from intact capsular tissue. Presumably, these are released by the islets of chromaffin cells located in the outer part of the rat adrenal cortex, adjacent to the connective tissue capsule (9, 25), although the possibility that they may derive from neurons in the capsular tissue cannot be discounted. Bernet’s group has previously shown release of catecholamines from rat adrenal capsules in response to a single concentration of NPY analogs, although not to NPY itself (12). The present study is therefore the first demonstration of a dose-related effect of NPY on catecholamine release, parallel with the dose response for aldosterone. Previous studies have shown that the aldosterone response to NPY is attenuated in the presence of a ß1-adrenergic antagonist (12). However, it has been suggested that NPY may interact with adrenoceptors (26). The binding data obtained in the present studies suggested that atenolol, the ß1-adrenergic antagonist, did not affect NPY binding to its receptor. Taken together, the finding of increased catecholamine release in response to NPY with attenuated aldosterone response in the presence of a ß-adrenergic antagonist strongly suggest that the effects of NPY on aldosterone secretion in rat adrenal capsular tissue are mediated by the local release of catecholamines. This is supported by the observation that norepinephrine significantly stimulated aldosterone secretion, consistent with other reports of the actions of catecholamines on aldosterone release (27; for reviews, see Refs. 8, 9).

These data demonstrating comparable potencies of NPY and PYY, with PP having no effect on aldosterone secretion, suggest that the effects of NPY on the adrenal cortex are mediated by the Y1 receptor subtype. This conclusion is supported by the binding data and the mRNA analysis and are further strengthened by the observation that the actions of NPY were significantly attenuated in the presence of BIBP 3226, a highly specific Y1 receptor antagonist (28). The degree of inhibition seen was consistent with the antagonist profile of this inhibitor (28). Previous studies on adrenal NPY receptors have reported that PYY has no effect on aldosterone secretion and concluded that the receptor subtype present is Y3 (29). Other studies, using receptor antagonists not employed in the present study, have suggested the presence of both Y1 and Y2 receptors in the rat adrenal cortex (1). The finding of a small, but significant, stimulatory effect of the Y2 agonist NPY(18–36), in the present study may suggest the presence of Y2 receptors, but there was only a small, albeit significant, displacement seen in the binding studies, and mRNA analysis did not reveal the presence of mRNA encoding this receptor subtype. The Y3 receptor remains a putative receptor and is classified on the basis of a response to NPY but not PYY (15). The results of the present study, in which PYY clearly both increased aldosterone release and displaced specific [125I]NPY binding, do not support the suggestion of a Y3 receptor in the rat adrenal cortex.

It has been suggested that PP may regulate rat adrenocortical function, specifically zona fasciculata/reticularis secretion of corticosterone (30), and there is evidence for the presence of PP receptors, now classified as Y4 receptors, in the inner cortical zones of the rat adrenal gland (14). These data are consistent with the present finding of PP having no effect on aldosterone secretion. The present study did not investigate NPY peptide family effects on inner zone function. It is likely that the mRNA coding for the Y4 receptor subtype may reflect zona fasciculata contamination of the zona glomerulosa preparation, which is typically around 5–8% with the decapsulation method for separating zona glomerulosa from inner zone cells (personal observation). Binding studies did not reveal any displacement of NPY binding with PP, but this is expected, as NPY is only a weak agonist at the Y4 receptor (15).

Taken together these data suggest that 1) NPY and PYY have a stimulatory effect on aldosterone secretion; 2) the effects of NPY on aldosterone secretion are mediated by local release of catecholamines; and 3) the Y1 receptor is the subtype responsible for mediating the effects of NPY on the rat adrenal zona glomerulosa.


   Footnotes
 
1 This work was supported by the Wellcome Trust. Back

Received June 16, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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G. Mazzocchi, L. K. Malendowicz, F. Aragona, R. Spinazzi, and G. G. Nussdorfer
Cholecystokinin (CCK) Stimulates Aldosterone Secretion from Human Adrenocortical Cells via CCK2 Receptors Coupled to the Adenylate Cyclase/Protein Kinase A Signaling Cascade
J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1277 - 1284.
[Abstract] [Full Text] [PDF]

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