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(Hypertension. 1999;33:1185-1189.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Proadrenomedullin N-Terminal 20 Peptide (PAMP), Acting Through PAMP(12–20)-Sensitive Receptors, Inhibits Ca²⁺-Dependent, Agonist-Stimulated Secretion of Human Adrenal Glands

Anna S. Belloni; Gian Paolo Rossi; Paola G. Andreis; Francesco Aragona; Hunter C. Champion; Philip J. Kadowitz; William A. Murphy; David H. Coy; Gastone G. Nussdorfer

From the Departments of Anatomy (A.S.B., P.G.A., G.G.N.), Clinical and Experimental Medicine (G.P.R.), and Urology (F.A.), School of Medicine, University of Padua, Padua, Italy; and the Departments of Pharmacology (H.C.C., P.J.K.) and Medicine (W.A.M., D.H.C.), School of Medicine, Tulane University, New Orleans, La.

Correspondence to Professor Gastone G. Nussdorfer, Department of Anatomy, Via Gabelli 65, I-35121 Padova, Italy. E-mail ggnanat{at}ipdunidx.unipd.it

	Abstract

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Abstract—Proadrenomedullin N-terminal 20 peptide (PAMP) is a 20–amino acid hypotensive peptide expressed in the adrenal medulla. We investigated the localization and function of PAMP receptors in the human adrenal gland. Autoradiography showed the presence of [¹²⁵I]PAMP-binding sites in both zona glomerulosa and adrenal medulla that were displaced by cold PAMP and PAMP(12–20) but not by other preproadrenomedullin-derived peptides. PAMP, but not PAMP(12–20), counteracted, in a concentration dependent manner, both aldosterone response of zona glomerulosa cells and catecholamine response of adrenal medulla cells to BAYK-8644, the selective agonist of voltage-activated Ca²⁺ channels, as well as to K⁺ and angiotensin II. PAMP(12–20) partially reversed this antisecretagogue effect of PAMP. Collectively, these findings suggest (1) that PAMP inhibits Ca²⁺-dependent, agonist-stimulated aldosterone and catecholamine secretion, acting via specific receptors and through a mechanism involving the impairment of Ca²⁺ influx; and (2) that PAMP(12–20) acts as a weak antagonist of PAMP receptors, thereby suggesting that both C- and N-terminal sequences of the PAMP molecule are required for this peptide to exert its antisecretagogue action on the human adrenal gland.

Key Words: PAMP • adrenal glands • aldosterone • catecholamines

	Introduction

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Adrenomedullin (ADM) and proadrenomedullin N-terminal 20 peptide (PAMP) are 2 hypotensive peptides produced by the posttranslational processing of prepro-ADM, a 185–amino acid prohormone.^{1 2 3} Both peptides are highly expressed in the mammalian adrenal medulla (AM),^{2 4 5} and the presence of specific binding sites for ADM and PAMP has been demonstrated in both the adrenal cortex and AM of rats^{5 6 7 8} and humans.^{9 10}

Like ADM,⁴ PAMP was found to inhibit angiotensin (Ang) II–stimulated and K⁺-stimulated aldosterone production by dispersed rat^{11 12} and human zona glomerulosa (ZG) cells^{9 10} without affecting either basal or adrenocorticotropic hormone (ACTH)–stimulated secretion. There is also indirect evidence that PAMP exerts its antisecretagogue action on human ZG cells by impairing agonist-enhanced Ca²⁺ influx, inasmuch as a Ca²⁺ ionophore is able to counteract its effect.⁹ Several experimental studies also showed that PAMP, in contrast to ADM,^{4 13 14} can hamper catecholamine release by bovine and rat AM chromaffin cells,^{15 16 17} and compelling evidence suggests that the mechanism underlying this effect may involve impairment of Ca²⁺ influx.

Because these findings have been mainly obtained in experimental animals, it seemed worthwhile to investigate the distribution and specificity of [¹²⁵I]PAMP-binding sites in the human adrenal gland and to verify whether PAMP exerts its antisecretagogue action by exclusively impairing agonist-stimulated Ca²⁺ influx. To this end, we studied the effect of PAMP on the secretory response of the human adrenal gland to BAYK-8644, a well known agonist of voltage-activated Ca²⁺ channels,¹⁸ and to the Ca²⁺-dependent agonists K⁺ and Ang II. Moreover, we investigated whether PAMP,^{12 13 14 15 16 17 18 19 20} the C-terminal nonapeptide sequence of PAMP, is able to mimic or counteract the effect of PAMP on the adrenal gland.

	Methods

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Reagents
Human PAMP(1–20), hereafter called PAMP, human ADM(1–52), human calcitonin gene-related peptide (CGRP), Ang II, ACTH, and [¹²⁵I]PAMP (specific activity, 2000 Ci/mmol) were purchased from Peninsula Laboratories. PAMP(12–20) and ADM(22–52) were synthesized in the Peptide Research Laboratories of the Department of Medicine, Tulane University. BAYK-8644 was obtained from Biomol, and medium 199 was obtained from Difco Laboratories. HSA and other laboratory reagents were obtained from Sigma Chemical Co.

Adrenal Glands
Fragments of adrenal glands were obtained from 6 adult patients (35 to 50 years old) undergoing unilateral nephrectomy and ipsilateral adrenalectomy for kidney cancer who did not require medications to alter adrenal function. Each gave written informed consent. Starting 2 weeks before surgery, patients were kept on a normal diet. Portions of the head and tails of each adrenal gland, which, respectively, contain and do not contain medullary chromaffin tissue,¹⁴ were placed in Krebs-Ringer bicarbonate buffer with 0.2% glucose at 4°C and immediately brought to our laboratory. The study protocol followed institutional guidelines for human studies.

Autoradiographic Studies
Adrenal head fragments were immediately frozen and used to prepare 10- to 15-µm-thick sections for autoradiography. PAMP-binding sites were labeled in vitro by incubation for 120 minutes at 37°C with 10^-9 mol/L of [¹²⁵I]PAMP.¹⁰ The ability of cold PAMP, PAMP(12–20), ADM(1–52), ADM(22–52), and CGRP to displace [¹²⁵I]PAMP binding in a concentration-dependent manner was checked by adding 10^-10 to 10^-7 mol/L of each peptide. The processing of sections for autoradiography was previously described in detail.¹⁹ Three autoradiograms obtained from 4 adrenal glands were analyzed by computer-assisted densitometry.²⁰ For each autoradiogram, 10 areas of ZG and AM (36 000 pixels) were analyzed. The [¹²⁵I]PAMP-binding value of the adrenal connective capsule was assumed to be the background value.

Secretion Studies
Head fragments were decapsulated and halved, and the AM was removed under the dissecting microscope. Capsular strips (containing adherent ZG) from both head and tail fragments were used to obtain dispersed ZG cell preparations by collagenase digestion and mechanical disaggregation.¹⁴ AM fragments and dispersed ZG cells were placed in medium 199 and Krebs-Ringer bicarbonate buffer with 0.2% glucose containing 5 mg/mL of HSA and incubated (4 to 5 mg/mL or 5x10⁴ cells/mL) as follows: (1) PAMP or PAMP(12–20) (10^-10 to 10^-7 mol/L) in the presence or absence of 5x10^-6 mol/L of BAYK-8644, 10^-2 mol/L of K⁺, 10^-9 mol/L of Ang II, and 10^-9 mol/L of ACTH; and (2) PAMP (10^-8 mol/L) plus BAYK-8644 (5x10^-6 mol/L), K⁺ (10^-2 mol/L), or Ang II (10^-9 mol/L) in the presence or absence of 10^-7 mol/L PAMP(12–20). Cells were incubated for 90 minutes in a shaking bath at 37°C in an atmosphere of 95% air and 5% CO₂. The medium was collected and stored at -80°C until hormonal assays were performed.

Hormonal Assays
After extraction from the incubation medium and purification by high-performance liquid chromatography (HPLC),¹⁴ aldosterone was measured by radioimmunoassay using the ALDO-CTK2 kit (sensitivity, 14 fmol/mL; cross-reactivity of aldosterone, 100%; cross-reactivity of 17-iso-aldosterone and other steroids, <0.1%; and intra- and interassay coefficients of variation, 7.5% and 8.6%, respectively). The concentrations of epinephrine and norepinephrine in the supernatants were measured by HPLC as described earlier.¹⁴ The sensitivity of the assay was 3 fmol/mL, and intra- and interassay coefficients of variation were 5.9% and 6.8%, respectively.

Statistics
Data from each adrenal gland were averaged and expressed as the mean±SEM of 3 experiments (3 adrenal glands from 3 patients). Statistical comparisons were made with ANOVA, followed by Duncan's multiple range test.

	Results

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Autoradiography
[¹²⁵I]PAMP binding was intense in the outer portion of the adrenal cortex (including subcapsular ZG) and AM (Figure 1A). Binding was displaced by the addition of both cold PAMP and PAMP(12–20) (Figure 1B and 1C), whereas ADM(1–52), ADM(22–52), and CGRP were ineffective (Figure 1D through 1F). Quantitative densitometry confirmed these qualitative descriptions (Figure 2). It also showed that PAMP is more potent than PAMP(12–20) in displacing [¹²⁵I]PAMP binding. In fact, although EC₅₀ values did not differ significantly (ZG, 1.1±0.3x10^-9 versus 0.8±0.2x10^-9 mol/L; AM, 0.7±0.2x10^-9 versus 0.9±0.3x10^-9 mol/L), at their maximal effective concentration (10^-8 mol/L), PAMP and PAMP(12–20) elicited 96% to 98% and 71% to 72% displacement, respectively.

View larger version (172K): [in this window] [in a new window]   Figure 1. Autoradiographs of hematoxylin and eosin–stained frozen sections of human adrenal gland incubated with 10-9 mol/L of [125I]PAMP(1–20). A, Binding is intense in the ZG and AM. B and C, 10-7 mol/L of cold PAMP(1–20) (B) and PAMP(12–20) (C) almost completely displace [125I]PAMP(1–20) binding. D through F, 10-7 mol/L of ADM(1–52) (D), ADM(22–52) (E), and CGRP (F) are ineffective. c indicates gland capsule; ZF/R, zona fasciculata–reticularis; v, medullary blood vessels; at, adipose tissue; and *, connective tissue trabeculae. Magnification, x55.

View larger version (26K): [in this window] [in a new window]   Figure 2. Evaluation by quantitative densitometry of 10-9 mol/L of [125I]PAMP(1–20) binding (total binding) in ZG (top) and AM (bottom) and its displacement by unlabeled peptides. Values are mean±SEM (n=3). +P<0.05 and *P<0.01 vs control value (C). aP<0.05 and AP<0.01 vs background value.

Hormone Secretion
The Ca²⁺ channel agonist BAYK-8644 induced 4.4- and 5.5-fold increases in aldosterone and catecholamine release by ZG and AM, respectively (Figure 3). PAMP, but not PAMP(12–20), decreased, in a concentration-dependent manner, BAYK-8644–stimulated production of both aldosterone (Figure 3, top) and catecholamines (Figure 3, bottom). IC₅₀ values were 3.1±0.8x10^-10 and 0.9±0.2x10^-10 mol/L for aldosterone and catecholamines, respectively, and 10^-9 to 10^-8 mol/L PAMP completely suppressed the secretory response to BAYK-8644. Basal hormonal secretions were not affected by either peptide (Figure 3). ACTH-stimulated (10^-9 mol/L) secretion of aldosterone was not affected by PAMP (baseline, 30.8±4.1 pmol/10⁶ cells per hour; 10^-9 mol/L ACTH, 242.1±28.2 pmol/10⁶ cells per hour; and ACTH plus 10^-8 mol/L PAMP, 218.7±25.7 pmol/10⁶ cells per hour). PAMP (10^-8 mol/L), but not PAMP(12–20), annulled the responses of aldosterone and catecholamine to K⁺ and partially reversed (by 50% to 85%) that to Ang II (Figure 4).

View larger version (25K): [in this window] [in a new window]   Figure 3. Effects of PAMP(1–20) and PAMP (12–20) on basal and 5x10-6 mol/L BAYK-8644 (BAY)–stimulated aldosterone secretion of dispersed ZG cells (top) and catecholamine release by AM tissue (bottom). Values are mean±SEM (n=3). *P<0.01 vs respective control value (C). aP<0.05 and AP<0.01 vs respective baseline value.

View larger version (38K): [in this window] [in a new window]   Figure 4. Effects of PAMP(1–20) and PAMP(12–20) on K+-stimulated (10 mmol/L) and Ang II–stimulated (10-9 mol/L) aldosterone and catecholamine secretion of dispersed ZG cells and AM tissue, respectively. Values are mean±SEM (n=3). *P<0.01 vs respective control value (C). aP<0.05 and AP<0.01 vs respective baseline value shown on ordinate.

PAMP(12–20) (10^-7 mol/L) partially counteracted (by 40% to 60%) the inhibitory effect of the maximal effective concentration of PAMP on the responses of both aldosterone and catecholamine to BAYK-8644 and K⁺ and completely reversed that to Ang II (Figure 5).

View larger version (31K): [in this window] [in a new window]   Figure 5. Effects of 10-7 mol/L of PAMP(12–20) on PAMP(1–20)-induced inhibition of aldosterone (left) and catecholamine response (right) of dispersed ZG cells and AM tissue, respectively, to BAYK-8644 (BAY, 5x10-6 mol/L) (top), K+ (10 mmol/L) (middle), and Ang II (10-9 mol/L) (bottom). Values are mean±SEM (n=3). *P<0.01 vs respective no-PAMP(1–20) value (N). AP<0.01 vs respective control value. bP<0.05 and BP<0.01 vs respective baseline value shown on ordinate.

	Discussion

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Our autoradiographic findings showed the presence of specific binding sites for PAMP in the ZG and AM of the human adrenal gland. The specificity of [¹²⁵I]PAMP binding was demonstrated by its displacement by PAMP and PAMP(12–20) but not by other pro-ADM–derived peptides, such as ADM(1–52) and ADM(22–52). ADM inhibits aldosterone response of ZG cells to Ang II by activating the CGRP1 receptor subtype in both rats^{13 21} and humans,¹⁴ and ADM(22–52) is a powerful ligand antagonist of this receptor.²² Our results showed that neither CGRP nor ADM(22–52) displaced PAMP binding to ZG and AM, thereby ruling out the possibility that PAMP-binding sites belong to this class of receptors. These findings, in contrast to the recent demonstration in rat adrenal ZG, but not AM, that [¹²⁵I]PAMP binds 2 classes of receptors, 1 of which is displaced by ADM,⁷ suggested relevant interspecific differences.

The results of the present study confirm the pivotal role played by Ca²⁺ channels in the secretory activity of adrenal cells,²³ inasmuch as BAYK-8644, an agonist of the high-voltage-activated L-type Ca²⁺ channels,²⁴ evoked a clear-cut secretory response of both human ZG and AM cells. They also clearly demonstrate that PAMP completely reversed the secretory response of both cell types to BAYK-8644 and K⁺, thereby strongly suggesting that PAMP acts on the human adrenal glands exclusively by inhibiting agonist-elicited Ca²⁺ influx. This contention is in keeping with the observation that PAMP abolished the secretory response to K⁺ but only partially reversed that to Ang II and left unaffected that to ACTH. In fact, in contrast to K⁺, Ang II stimulates ZG cells through signaling mechanisms involving the rise in Ca²⁺ influx, and ACTH acts largely via Ca²⁺-independent mechanisms.²³

PAMP(12–20), although displacing [¹²⁵I]PAMP binding to human ZG and AM, was unable to mimic the antisecretagogue effect of PAMP. This finding suggests that even though the C-terminal domain is sufficient for PAMP to bind its receptors, both the C- and N-terminal domains are required for receptor activation and the ensuing inhibitory effect of PAMP on aldosterone secretion. This observation makes PAMP(12–20) a good candidate as a PAMP receptor-selective antagonist, a contention supported by the present finding that PAMP(12–20), although ineffective per se, partially suppressed the PAMP inhibitory action on the secretory response of ZG and AM to Ca²⁺-dependent agonists. Because the PAMP(9–20) fragment is the major endogenous PAMP peptide in porcine AM,²⁵ we hypothesized that posttranslational processing of the prepro-ADM molecule gives rise not only to PAMP but also its fragments. Along with our present findings concerning PAMP(12–20), this raises the interesting possibility that adrenal PAMP receptors may be agonistically and antagonistically modulated by endogenous ligands.

The present results are the first, to the best of our knowledge, to demonstrate (1) the presence of PAMP-specific receptors in human ZG and AM and (2) a potent PAMP-induced antisecretagogue effect on aldosterone and catecholamines that is possibly related to impairment of Ca²⁺ influx. However, the physiological relevance of our findings remains to be firmly demonstrated. In fact, although prepro-ADM peptides are almost ubiquitously expressed in human tissues,^{2 3} the blood concentration of PAMP under both basal and pathological conditions does not exceed 0.5 to 4.0x10^-12 mol/L,⁴ well below its minimal effective concentration exerting a sizable antisecretagogue effect on human adrenal glands. Thus, it is unlikely that PAMP acts on adrenal glands as a circulating hormone. However, compelling evidence indicates the physiological relevance of the paracrine interactions between cortex and medulla in the adrenal glands.²⁶ PAMP is highly expressed in AM, and on stimulation it could reach an intraadrenal concentration of 6x10^-8 mol/L, ie, well above its maximal effective concentration in vitro.⁴ Hence, PAMP could regulate adrenal secretion, acting in a paracrine/autocrine manner. In this connection, it must be recalled that catecholamines released by AM can enhance aldosterone secretion by ZG cells.²⁶ Thus, the inhibitory effect of PAMP on catecholamine release may help to potentiate its direct aldosterone antisecretagogue action.

The role of prepro-ADM–derived peptides in the control of water and electrolyte excretion has recently been emphasized.^{2 27} Because of the involvement of aldosterone in these mechanisms, it is not unreasonable to conceive that PAMP, which is 10 to 15 times more effective than ADM in inhibiting aldosterone secretion,^{10 11} may play a major role in pathophysiological conditions in situations where a resetting of fluid and electrolyte balance is needed.

Received November 4, 1998; first decision November 23, 1998; accepted January 11, 1999.

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