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(Hypertension. 1995;25:443-448.)
© 1995 American Heart Association, Inc.

Articles

Locally Generated Angiotensin II in the Adrenal Gland Regulates Basal, Corticotropin-, and Potassium-Stimulated Aldosterone Secretion

Prem Gupta; Roberto Franco-Saenz; Patrick J. Mulrow

From the Department of Medicine, Medical College of Ohio, Toledo.

Correspondence to Roberto Franco-Saenz, MD, Division of Endocrinology, Medical College of Ohio, PO Box 10008, Toledo, OH 43699-0008.

	Abstract

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Abstract The zona glomerulosa cells of the adrenal gland have an intrinsic renin-angiotensin system that appears to modulate the aldosterone response to potassium and corticotropin. The actions of circulating angiotensin II (Ang II) are mediated by the activation of the Ang II type 1 (AT₁) receptor on the adrenal cortex. In this study we examined the effects of the AT₁ receptor antagonist DuP 753 and other antagonists on aldosterone secretion in cultured bovine zona glomerulosa cells. Zona glomerulosa cells were cultured in PFMR-4 medium containing 10% fetal calf serum for 72 hours, and the medium was replaced with serum-free medium for the next 24-hour experimental period. DuP 753 (10 µmol/L) inhibited basal aldosterone secretion (from 88.6±7.1 to 54.8±9.6 pg/10⁶ cells per hour; 38% inhibition). EXP 3174, an active metabolite of DuP 753, also inhibited aldosterone dose dependently (from 88.6±7.1 to 55.9±8.4 at 1 µmol/L and 88.6±7.1 to 21.7±3.3 at 100 µmol/L; 37% and 75% inhibition, respectively). Another and more potent AT₁ receptor antagonist, L158,809, showed significant inhibition at 100 nmol/L, and at 10 µmol/L it inhibited basal aldosterone secretion (from 144.7±18.2 to 83.4±17.1 pg/10⁶ cells per hour; 42% inhibition). DuP 753 inhibited Ang II (100 nmol/L)–stimulated aldosterone production in a dose-dependent fashion, with a 30% reduction at 100 nmol/L and complete inhibition at 100 µmol/L. DuP 753 also inhibited potassium (12 nmol/L) and corticotropin (1 nmol/L) stimulation of aldosterone in a dose-dependent fashion. There was no evidence of cell toxicity as judged by gross and microscopic appearance of the cell culture, trypan blue exclusion, and the ability of cells to synthesize the protein renin. Furthermore, the AT₂ receptor antagonist PD 123319 did not inhibit basal, Ang II–, corticotropin-, or potassium-stimulated aldosterone. In conclusion, the AT₁ receptor antagonists inhibit basal, corticotropin-, and potassium-stimulated aldosterone. These data suggest that the adrenal renin-angiotensin system plays an important role in the regulation of aldosterone secretion.

Key Words: adrenal glands • aldosterone • cells, cultured • angiotensin II • potassium • corticotropin • renin

	Introduction

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Adrenal steroidogenesis in cultured rat and bovine adrenal zona glomerulosa cells is regulated by corticotropin (ACTH), K⁺, and angiotensin II (Ang II).^{1 2 3} The actions of Ang II are mediated by specific receptors that are located on the adrenal cell membrane. Ang II receptors are classified into two major subtypes: AT₁ and AT₂. These receptors have been located on the adrenal gland, brain, uterus, vascular smooth muscle cells, and liver.^{4 5} The AT₁ receptor has been cloned from cultured bovine adrenal zona glomerulosa cells.⁶ The biological actions of Ang II appear to occur through the AT₁ receptor.^{7 8 9 10}

We recently demonstrated that bovine zona glomerulosa cells can synthesize renin,³ and these cells have been shown to synthesize and secrete Ang II.¹¹ A number of experiments both in vivo and in vitro with cultured rat adrenal zona glomerulosa cells show a correlation between renin and aldosterone levels.^{1 12} Angiotensin-converting enzyme inhibitors can reduce aldosterone production in vitro.^{1 13 14 15} Since the zona glomerulosa is the site of aldosterone production, it is reasonable to infer that a local renin-angiotensin system may play a role in aldosterone regulation. In this study we examined the effects of AT₁ and AT₂ receptor antagonists on basal, ACTH-, potassium-, and Ang II–stimulated aldosterone production in cultured bovine zona glomerulosa cells.

	Methods

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Primary Cell Culture
The procedure for primary bovine zona glomerulosa monolayer culture was based on that described by Gospodarowicz et al¹⁶ and previously published by our laboratory.³ In brief, adrenal glands were collected from freshly slaughtered animals and transported in L-15 medium. The glands were trimmed of fat and cut into several blocks. All subsequent steps for cell disruption were carried out in serum-free medium. Slices 500 µm in thickness, including the capsule, were cut from the blocks with a Stadie Riggs microtome (Thomas Scientific) and chopped into small fragments with scissors. A cell suspension was prepared from the fragments by incubating them for 2 hours with 2.5 mg/mL collagenase and 0.1 mg/mL deoxyribonuclease. The cells were dispersed by repeated pipetting and filtered through two-layer nylon gauze (pore size, 70 µmol/L). The cell pellet was washed three times by resuspension in M-199 medium. The dispersed cells were further purified to remove the contamination of fasciculata cells and red blood cells using a Percoll gradient (0% to 75%). Pure zona glomerulosa cells from band III were removed with the use of a Pasteur pipette and washed three times by resuspension in PFMR-4 medium with recentrifugation at 1000g for 5 minutes at 4°C. The PFMR-4 medium (Pasadena Foundation for Medical Research Medium No. 4) was supplemented with insulin (1 µg/mL), vitamin A (ß retinyl acetate, 0.1 µg/mL), ascorbic acid (100 µmol/L), -tocopherol (1 µmol/L), penicillin G (100 U/mL), gentamicin (25 µg/mL), and amphotericin B (Fungizone) (1 µg/mL). Approximately 1x10⁶ cells per dish were resuspended in PFMR-4 medium (4.2 mmol/L K⁺) containing 10% fetal calf serum, seeded in 35x10-mm plastic fibronectin-coated culture dishes, and incubated in an atmosphere of 95% air and 5% CO₂ at 37°C. After 72 hours of incubation to allow cell attachment, cells were washed twice with serum-free PFMR-4 medium containing 0.1% bovine serum albumin and incubated for 24 hours of the experimental period in this serum-free medium as described previously.³ Each treatment was given in two to four Petri plates. Culture medium was collected at the end of the treatments and stored at -70°C for measurement of aldosterone by radioimmunoassay.

Cell Culture and Viability
Cell number and viability in serum-free medium were determined at the beginning and end of the experimental period. For determination of cell number, medium was removed, and cells were detached by incubation with 1 mL HEPES buffer containing 0.2% trypsin, 0.04% EGTA, and 2% polyvinylpyrrolidone for 10 minutes at 37°C. The cells were examined for viability by the trypan blue exclusion method.

Materials
The following chemicals were obtained from Sigma Chemical Co: ACTH (1-24 fragment), N⁶-2'-O-dibutyryl-cAMP sodium salt, M-199 (K⁺-free), Ang II, fetal calf serum (molecular weight cutoff, 1000), penicillin G, gentamicin, amphotericin B, and collagenase type V. The other chemicals used were obtained from the following sources: deoxyribonuclease-I from Worthington Biochemical Corp, PFMR-4 medium and vitamin A from Biofluids, Inc, -tocopherol from Kodak Laboratory and Research Products, and fibronectin from Calbiochem Corp. DuP 753 (losartan), EXP 3174, L158,809, and PD 123319 were generous gifts from the DuPont Merck Pharmaceutical Co and Parke-Davis.

Radioimmunoassay and Statistical Analysis
Aldosterone in the medium was measured by direct assay using a radioimmunoassay kit (Coat-A-Count, Diagnostic Products), and results were normalized to picograms per 10⁶ cells per hour of secretion. Renin activity in the cells and medium was measured as described previously.³ cAMP was measured in cells as previously described.¹⁷ Data were converted to percentage of control value (control as 100%) and analyzed statistically with the use of nonparametric one-way ANOVA by rank and the Kruskal-Wallis test. If significance was shown, the Mann-Whitney test was used to determine which differences were significant. We lowered the levels of significance to P<.01 in the multiple comparisons to guard against type 1 error. The control values of aldosterone production varied considerably between experiments; however, each experiment had its own control cultures, and the treated cultures were compared with control and the results expressed as percentage of control.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Effects of DuP 753, EXP 3174, and L158,809 on Basal Aldosterone Secretion
The dose-dependent effects of DuP 753, EXP 3174, and L158,809 are shown in Fig 1. The results are expressed as a percentage of the control value. DuP 753, EXP 3174, and L158,809 inhibited aldosterone secretion from these cells dose dependently, but the inhibition potency varied. DuP 753 inhibited basal aldosterone secretion from 88.6±7.1 to 54.8±9.6 and 30.0±6.3 pg/10⁶ cells per hour at a concentration of 10 and 100 µmol/L, respectively (38% and 65% inhibition). EXP 3174, an active metabolite of DuP 753, also inhibited aldosterone from 88.6±7.1 to 55.9±8.4 and to 21.7±3.3 pg/10⁶ cells per hour at 1 and 100 µmol/L, respectively (37% and 75% inhibition). Another AT₁ receptor antagonist, L158,809, inhibited in a dose-dependent fashion from 100 nmol/L and at 10 µmol/L inhibited basal aldosterone secretion from 144.7±18.2 to 83.4±17.1 pg/10⁶ cells per hour (42% inhibition).

View larger version (47K): [in this window] [in a new window]   Figure 1. Bar graphs show effects of DuP 753, EXP 3174, and L158,809 on aldosterone secretion. Percentage of control value ±SEM (control as 100%) of three separate experiments is shown; each treatment was carried out in two Petri plates. *P<.01 compared with aldosterone control values. Cells were treated with different doses of DuP 753, EXP 3174, and L158,809 for 24 hours in serum-free medium.

Effect of DuP 753 on Ang II–, K⁺-, and ACTH-Stimulated Aldosterone
Fig 2 shows the effects of Ang II on aldosterone secretion and of DuP 753 on Ang II–stimulated aldosterone. Ang II stimulated aldosterone secretion dose dependently from 10 pmol/L to 100 nmol/L. Maximal stimulation was found at 100 nmol/L; at this concentration, Ang II stimulated aldosterone secretion by 210% over control values (from 279.9±40.2 to 624.5±145.16 pg/10⁶ cells per hour). DuP 753 inhibited Ang II–stimulated aldosterone dose dependently at doses from 100 nmol/L to 100 µmol/L.

View larger version (49K): [in this window] [in a new window]   Figure 2. Bar graphs show dose-dependent effect of angiotensin II (Ang II and AII in figure) on aldosterone (top) and effect of DuP 753 on Ang II–stimulated aldosterone (bottom). Percentage of the control value ±SEM (control as 100%) of four separate experiments is shown; each treatment was carried out in two separate Petri plates. Top, Cells were treated with 10 pmol/L to 100 nmol/L Ang II for 24 hours in serum-free medium. *P<.001 compared with control values. Bottom, Effects of different doses of DuP 753 (DuP) on aldosterone stimulated by 100 nmol/L Ang II. +P<.01, control vs 100 nmol/L Ang II; *P<.01, Ang II alone vs 100 nmol/L Ang II plus different doses of DuP 753.

Fig 3 shows the dose-dependent effect of DuP 753 on potassium (12 mmol/L)-stimulated aldosterone. DuP 753 inhibited potassium-stimulated aldosterone production dose dependently.

View larger version (51K): [in this window] [in a new window]   Figure 3. Bar graph shows dose-dependent effect of DuP 753 (DUP) on potassium-stimulated aldosterone production. Percentage of control value ±SEM (control as 100%) of three separate experiments is shown; each treatment was given in three Petri plates. Cells were incubated with 12 mmol/L potassium alone or in combination with different doses of DuP 753 from 10-8 to 100 µmol/L for 24 hours in serum-free medium.

Fig 4 shows the dose-dependent effect of DuP 753 on ACTH (1 nmol/L)-stimulated aldosterone. Again, DuP 753 (100 nmol/L to 100 µmol/L) inhibited ACTH-stimulated aldosterone in a dose-dependent manner. Furthermore, DuP 753 had no effect on basal cAMP production but partially inhibited ACTH stimulation of cAMP (Fig 5).

View larger version (45K): [in this window] [in a new window]   Figure 4. Bar graph shows dose-dependent effect of DuP 753 (DUP) on corticotropin (ACTH and AC)-stimulated aldosterone. Percentage of the control value ±SEM (control as 100%) of four separate experiments is shown; each treatment was given in triplicate plates. Cells were incubated for 24 hours with 1 nmol/L ACTH alone or in combination with DuP 753 from 1 nmol/L to 100 µmol/L in serum-free medium.

View larger version (27K): [in this window] [in a new window]   Figure 5. Bar graph shows effects of DuP 753 (DuP) on corticotropin (ACTH) stimulation of cAMP production. Results are expressed as percentage of control cAMP production. ACTH (1 nmol/L) was incubated alone or with 10-4 mol/L DuP 753 for 24 hours in serum-free medium. *P<.001 compared with control; +P<.01 compared with ACTH-stimulated cAMP.

Fig 6 shows the effect of DuP 753 on renin activity in cells and medium. DuP 753 had no significant effect on basal active cell renin or on medium prorenin. DuP 753 did not block ACTH stimulation of renin. Furthermore, DuP 753 did not alter the gross or microscopic appearance of the cultured cells nor alter the ability of the cells to exclude trypan blue when compared with control cells.

View larger version (41K): [in this window] [in a new window]   Figure 6. Bar graph shows effects of DuP 753 (DuP) on renin activity in cells and medium. Percentage of control value ±SEM (control as 100%) of four separate experiments is shown; each treatment was carried out in two Petri plates. *P<.001 compared with control renin levels. Cells were treated with 100 µmol/L DuP 753 or 1 nmol/L corticotropin (ACTH) alone or in combination for 24 hours in serum-free medium, and then cells and medium were collected.

Effect of the AT₂ Receptor Antagonist PD 123319 on Aldosterone Secretion
The effects of PD 123319 on basal and Ang II–stimulated aldosterone secretion are shown in Fig 7. PD 123319 had no significant effect on basal or Ang II–stimulated aldosterone secretion in these cells. Furthermore, PD 123319 (100 µmol/L) had no significant effect on ACTH- or potassium-stimulated aldosterone (Fig 8).

View larger version (71K): [in this window] [in a new window]   Figure 7. Bar graphs show dose-dependent effect of PD 123319 (PD) on basal aldosterone secretion (top) and angiotensin II (AII)–stimulated aldosterone (bottom). Percentage of control value ±SEM (control as 100%) of three separate experiments is shown; each treatment was carried out in two Petri plates. *P<.01 compared with control values. Cells were treated with different doses of PD 123319 from 1 nmol/L to 100 µmol/L and also with PD 123319 (10 µmol/L and 100 µmol/L) in combination with angiotensin II (100 nmol/L) for 24 hours in serum-free medium.

View larger version (50K): [in this window] [in a new window]   Figure 8. Bar graph shows effect of PD 123319 (PD) on potassium- and corticotropin (ACTH)-stimulated aldosterone. Percentage of control value ±SEM (control as 100%) of two separate experiments is shown; each treatment was carried out in four Petri plates. *P<.001 compared with control values. Cells were treated with 100 µmol/L PD 123319, 1 nmol/L ACTH, and 12 mmol/L potassium alone and in combination for 24 hours in serum-free medium.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Ang II actions are mediated by specific receptors located on various target organs, including the adrenal cortex, kidney, uterus, brain, arterioles, and sympathetic nerve endings.^{4 5} Local Ang II production may exert a paracrine or autocrine function in a variety of tissues.¹⁸ Binding studies with new Ang II antagonists have revealed the existence of the AT₁ and AT₂ receptor subtypes. The physiological actions of Ang II appear to be mediated through the AT₁ receptor, which has been cloned from bovine zona glomerulosa cells.⁶ DuP 753, EXP 3174 (the active metabolite of DuP 753), and L158,809 are potent nonpeptide antagonists of the AT₁ receptor. PD 123319 is a nonpeptide antagonist of the AT₂ receptor.^{5 19} In addition to these membrane receptors, there are reports of Ang II binding to intracellular organelles such as the nucleus.²⁰

In the present study we examined the effects of AT₁ and AT₂ receptor antagonists on aldosterone secretion in adrenal bovine zona glomerulosa cells. Although it is possible that the fetal calf serum used in the initial culture media may partly contribute to the local renin-angiotensin system in the bovine zona glomerulosa cells, this contribution should have been considerably diminished by the fact that after cell attachment the cells were washed with serum-free media and incubated for the 24 hours of the experimental period in serum-free media. It is clear that the AT₁ receptor mediates the actions of Ang II in these cells, and our results confirm previous studies in rat⁷ and bovine⁸ adrenals. Of particular interest is the fact that AT₁ receptor antagonists inhibit basal, ACTH-, and K⁺-stimulated aldosterone production in a dose-dependent fashion, suggesting that local Ang II production is needed to allow the cells to respond to stimuli of aldosterone secretion. Although the doses of Ang II receptor antagonists used in these studies are high, it appears that bovine adrenocortical cells require higher doses of these Ang II receptor antagonists compared with rat and human adrenal cells.⁷ Also, the presence of bovine serum albumin in the serum-free culture medium binds the antagonist and reduces its potency.²¹ Furthermore, we found no evidence of toxicity, in that microscopic examination of the cultured cells was normal, and trypan blue exclusion studies showed no difference in cell viability between normal cells and those treated with DuP 753. In addition, DuP 753 did not inhibit basal or ACTH-stimulated renin synthesis and release, suggesting that protein synthesis by the cells was unimpaired.

The fact that the AT₂ receptor antagonist PD 123319 at high concentrations did not inhibit basal, Ang II–, ACTH-, or K⁺-stimulated aldosterone also suggests that the AT₁ receptor is specifically involved. Furthermore, while these studies were in progress, Chiou et al²² reported that DuP 753 at 10 and 100 µmol/L (10^-5 and 10^-4 mol/L) inhibited potassium-stimulated aldosterone secretion by superfused rat adrenal glomerulosa cells without altering the potassium stimulation of Ang II secretion.

Although ACTH-stimulated cAMP was partially inhibited by DuP 753, this decrease alone cannot account for the blockade of ACTH on aldosterone production. Only a small increase in cAMP production is needed for steroidogenesis.^{23 24}

Previous studies from our laboratory with rat adrenal explant cultures demonstrated that endogenous Ang II production and K⁺-stimulated aldosterone production were reduced by the angiotensin-converting enzyme lisinopril. Using rat glomerulosa cells in monolayer culture, we reported an inhibition of K⁺- and ACTH-stimulated aldosterone production by lisinopril.¹

Studies by other investigators also support an interaction between Ang II and K⁺ on aldosterone production. In dogs, potassium-mediated aldosterone stimulation was blunted in the presence of captopril in vivo, demonstrating an essential role of Ang II in potassium stimulation of aldosterone secretion.²⁵ In vivo treatment of rats with captopril resulted in suppression of the aldosterone response by adrenal cells to potassium in vitro.¹³ Kifor et al²⁶ superfused rat adrenal capsules with potassium and stimulated adrenal Ang II production, with a highly significant correlation between Ang II and aldosterone release. Furthermore, Horiba et al¹¹ have shown net Ang II production by cultured bovine adrenal zona glomerulosa cells. Captopril treatment of the cells reduced both Ang II and aldosterone production. In humans, captopril treatment reduced ACTH stimulation of aldosterone.^{27 28 29} These results from other investigators support our findings, which indicate that a functioning renin-angiotensin system may be necessary for various stimuli of aldosterone production to be optimally effective. The fact that DuP 753 inhibited basal (at high concentrations) Ang II, K⁺, and ACTH stimulation of aldosterone lends credence to this possibility.

It is difficult to visualize the precise mechanism of the inhibition by the AT₁ receptor antagonist. One possibility is that Ang II is generated locally and binds to the cell surface receptor to stimulate second messengers that maintain the cell steroidogenic pathways at optimal activity. It should be pointed out that the present investigations studied aldosterone production over a 24-hour period, and the results may not apply to short-term studies with separated cells. To a certain extent, these results with DuP 753 are reminiscent of those obtained with atrial natriuretic factor. Atrial natriuretic factor inhibits basal, ACTH, K⁺, and Ang II stimulation of aldosterone production by unknown mechanisms.³⁰ With respect to the present experiments, our hypothesis is that the AT₁ receptor antagonist inhibits aldosterone production by inhibiting the action of Ang II generated within the glomerulosa cell. From previous discussion of References 1¹ , 13¹³ , 15¹⁵ , 25²⁵ , and 27²⁷ through 29²⁹ , it appears that local Ang II generation is necessary for optimal stimulation of aldosterone secretion.

	Acknowledgments

 
We thank Dr Ronald D. Smith (DuPont Merck Pharmaceutical Co) and Dr David G. Taylor (Parke-Davis) for the generous gifts of DuP 753, EXP 3174, L158,809, and PD 123319 as well as Mary Pat Perlinski for excellent secretarial help.

	Footnotes

 
Previously presented as an abstract at the 47th Annual Fall Conference and Scientific Sessions of the Council for High Blood Pressure Research, San Francisco, Calif, September 28 to October 1, 1993.

Received August 19, 1994; first decision October 3, 1994; accepted November 15, 1994.

	References

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