scholarly journals Pomc Knockout Mice Have Secondary Hyperaldosteronism Despite an Absence of Adrenocorticotropin

Endocrinology ◽  
2007 ◽  
Vol 149 (2) ◽  
pp. 681-686 ◽  
Author(s):  
Kirsten-Berit Linhart ◽  
Joseph A. Majzoub
Keyword(s):  
Angiotensin Ii ◽  
Plasma Aldosterone ◽  
Renin Activity ◽  
Postnatal Life ◽  
Secondary Adrenal Insufficiency ◽  
Aldosterone Production ◽  
Secondary Hyperaldosteronism ◽  
Urine Electrolytes ◽  
Glucocorticoid Deficiency

Aldosterone production is controlled by angiotensin II, potassium, and ACTH. Mice lacking Pomc and its pituitary product ACTH have been reported to have absent or low aldosterone levels, suggesting that ACTH is required for normal aldosterone production. However, this is at odds with the clinical finding that human aldosterone deficiency is not a component of secondary adrenal insufficiency. To resolve this, we measured plasma and urine electrolytes, together with plasma aldosterone and renin activity, in Pomc−/− mice. We found that these mice have secondary hyperaldosteronism (elevated aldosterone without suppression of renin activity), indicating that ACTH is not required for aldosterone production or release in vivo. Exogenous ACTH stimulates a further increase in aldosterone in Pomc−/− mice, whereas angiotensin II has no effect, and the combination of angiotensin II and ACTH is no more potent than ACTH alone. These data suggest that aldosterone production and release in vivo do not require the action of ACTH during development or postnatal life and that secondary hyperaldosteronism in Pomc−/− mice is a consequence of glucocorticoid deficiency.

Abstract 56: Candesartan And Valsartan, Contrary To Irbesartan, Are Potent Biased Antagonists Of Adrenal (beta)arrestin-dependent, Angiotensin II Type 1 Receptor-induced Aldosterone Production And Improve Cardiac Function Post-myocardial Infarction

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Anastasios Lymperopoulos ◽  
Karlee Walklett ◽  
Samalia Dabul ◽  
Ashley Siryk ◽  
Emmanuel Sturchler ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Angiotensin Ii ◽  
Cardiac Function ◽  
G Protein ◽  
Plasma Aldosterone ◽  
Post Myocardial Infarction ◽  
Aldosterone Production

Introduction: The scaffolding protein βarrestin1 (βarr1) by the angiotensin II (AngII) type 1 receptor (AT 1 R) mediates AngII-induced aldosterone production in vitro and physiologically in vivo, thereby exacerbating heart failure (HF) progression post-myocardial infarction (MI). Herein, we sought to investigate the relative potency of various AT 1 R antagonist drugs (sartans) at inhibiting βarr vs. G protein activation and hence aldosterone production in vitro and in vivo. We also investigated the alterations in plasma aldosterone levels conferred by these agents and their impact on cardiac function of post-MI rats. Methods: For the in vitro tests, transfected CHO and adrenocortical H295R cells were used. For in vivo studies, post-MI rats overexpressing βarr1 in their adrenals received 7-day-long treatments with the drugs of interest. Results: Among the sartans tested, candesartan and valsartan were the most potent βarr activation and βarr-mediated aldosterone production inhibitors in vitro, as well as the most “biased” antagonists towards βarr vs. G-protein inhibition. Conversely, losartan and irbesartan were the least potent βarr inhibitors and the least “biased” antagonists towards βarr inhibition. These in vitro findings were corroborated in vivo, since candesartan and valsartan, contrary to irbesartan, caused significant plasma aldosterone reductions in post-MI rats. Accordingly, cardiac ejection fraction (EF) and contractility were significantly augmented in candesartan- and valsartan-treated rats (EF: 41.1±1% and 40±1% respectively, vs. 35±0.3% for saline-treated), but further deteriorated in irbesartan-treated post-MI rats (EF: 32±1%, n=7 rats/group). Conclusions: These findings provide important insights that might aid pharmacotherapeutic decisions (i.e. individual agent selections) involving this commonly prescribed cardiovascular drug class (sartans).

RESPONSES OF ALDOSTERONE-PRODUCING ADENOMAS TO ACTH AND ANGIOTENSINS

1979 ◽  
Vol 92 (4) ◽  
pp. 702-709 ◽  
Author(s):  
Takao Saruta ◽  
Tetsuji Okuno ◽  
Toyohisa Eguchi ◽  
Ryuichi Nakamura ◽  
Ikuo Saito ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Control Mechanism ◽  
Normal Subjects ◽  
Diurnal Variations ◽  
Plasma Aldosterone ◽  
Aldosterone Production ◽  
Aldosterone Producing Adenoma ◽  
Normal Controls

ABSTRACT To elucidate the control mechanism of aldosterone production in primary aldosteronism, in vivo and in vitro studies were done in 7 patients with aldosterone-producing adenomas. In the in vivo study, plasma aldosterone was stimulated more significantly by synthetic ACTH than by angiotensin II or furosemide. Diurnal variations of plasma aldosterone, which were studied in 4 patients, were similar to those seen in normal controls. In agreement with the results in the in vivo study, the in vitro study also revealed ACTH stimulated aldosterone and deoxycorticosterone (DOC) from the adenoma more markedly than angiotensin II or III. There was no adenoma which was more sensitive to angiotensin II or III than to ACTH. From these results it is considered that changes in plasma aldosterone induced by the exogenous administration of angiotensin II or ACTH in patients with aldosterone-producing adenoma are mainly based on changes in aldosterone production in the adenoma. Furthermore, in patients with an aldosterone-producing adenoma in whom diurnal variations of plasma aldosterone similar to those in normal subjects are observed, responses of aldosterone to angiotensin II are supposed to be less than those to ACTH.

scholarly journals Effects of Ramipril on the Aldosterone/Renin Ratio and the Aldosterone/Angiotensin II Ratio in Patients With Primary Aldosteronism

Hypertension ◽  
2020 ◽  
Vol 76 (2) ◽  
pp. 488-496 ◽  
Author(s):  
Zeng Guo ◽  
Marko Poglitsch ◽  
Diane Cowley ◽  
Oliver Domenig ◽  
Brett C. McWhinney ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Plasma Renin Activity ◽  
Ace Inhibitors ◽  
Primary Aldosteronism ◽  
Characteristic Curve ◽  
False Negative ◽  
Plasma Renin ◽  
Plasma Aldosterone ◽  
Renin Activity ◽  
Plasma Aldosterone Concentration

The aldosterone/renin ratio (ARR) is currently considered the most reliable approach for case detection of primary aldosteronism (PA). ACE (Angiotensin-converting enzyme) inhibitors are known to raise renin and lower aldosterone levels, thereby causing false-negative ARR results. Because ACE inhibitors lower angiotensin II levels, we hypothesized that the aldosterone/equilibrium angiotensin II (eqAngII) ratio (AA2R) would remain elevated in PA. Receiver operating characteristic curve analysis involving 60 patients with PA and 40 patients without PA revealed that the AA2R was not inferior to the ARR in screening for PA. When using liquid chromatography-tandem mass spectrometry to measure plasma aldosterone concentration, the predicted optimal AA2R cutoff for PA screening was 8.3 (pmol/L)/(pmol/L). We then compared the diagnostic performance of the AA2R with the ARR among 25 patients with PA administered ramipril (5 mg/day) for 2 weeks. Compared with basally, plasma levels of equilibrium angiotensin I (eqAngI) and direct renin concentration increased significantly ( P <0.01 or P <0.05) after ramipril treatment, whereas eqAngII and ACE activity (eqAngII/eqAngI) decreased significantly ( P <0.01). The changes of plasma renin activity and plasma aldosterone concentration in the current study were not significant. On day 14, 4 patients displayed false-negative results using ARR_direct renin concentration (plasma aldosterone concentration/direct renin concentration), 3 of whom also showed false-negative ARR_plasma renin activity (plasma aldosterone concentration/plasma renin activity). On day 15, 2 patients still demonstrated false-negative ARR_plasma renin activity, one of whom also showed a false-negative ARR_direct renin concentration. No false-negative AA2R results were observed on either day 14 or 15. In conclusion, compared with ARR which can be affected by ACE inhibitors causing false-negative screening results, the AA2R seems to be superior in detecting PA among subjects receiving ACE inhibitors.

Atrial natriuretic peptide inhibits the effect of endogenous angiotensin II on plasma aldosterone in conscious sodium-depleted rats

1987 ◽  
Vol 72 (1) ◽  
pp. 31-35 ◽  
Author(s):  
Lynn Chartier ◽  
Ernesto L. Schiffrin
Keyword(s):  
Angiotensin Ii ◽  
Atrial Natriuretic Peptide ◽  
Plasma Renin Activity ◽  
Natriuretic Peptide ◽  
Adrenocorticotropic Hormone ◽  
Plasma Renin ◽  
Plasma Aldosterone ◽  
Renin Activity ◽  
Aldosterone Secretion ◽  
Atrial Natriuretic

1. Previous studies have shown that atrial natriuretic peptide (ANP) inhibits the secretion of aldosterone by isolated adrenal glomerulosa cells stimulated by angiotensin II, adrenocorticotropic hormone and potassium in vitro. We have also demonstrated that this inhibitory effect of ANP on plasma aldosterone induced by angiotensin II and adrenocorticotropic hormone can be reproduced in vivo in conscious unrestrained rats. In this study, we have investigated the effect of an intravenous infusion of ANP on plasma aldosterone in conscious unrestrained sodium-depleted rats. 2. During sodium depletion, the rise in plasma renin activity which determines an increment in the circulating concentration of angiotensin II was accompanied by a rise in aldosterone secretion as expected. ANP infused intravenously at a dose which increased the plasma concentration of the peptide three- to five-fold, produced a significant decrement in the concentration of aldosterone in plasma after an infusion period of 120 min. There was no significant effect of ANP on plasma renin activity and plasma corticosterone concentration. 3. Since the increase in plasma aldosterone levels in sodium-depleted rats is mainly dependent on the activation of the renin–angiotensin system, we conclude that ANP may modulate the effect of endogenous as well as exogenous angiotensin II on plasma aldosterone secretion.

Effects of angiotensin II, ACTH, and KCl on the adrenal renin-angiotensin system in the rat

1990 ◽  
Vol 122 (3) ◽  
pp. 369-373 ◽  
Author(s):  
Hiroyuki Sasamura ◽  
Hiromichi Suzuki ◽  
Ryuichi Kato ◽  
Takao Saruta
Keyword(s):  
Angiotensin Ii ◽  
Statistical Significance ◽  
Renin Angiotensin System ◽  
Plasma Aldosterone ◽  
Aldosterone Secretion ◽  
Plasma Aldosterone Concentration ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Captopril Treatment

Abstract Angiotensin II, ACTH and potassium chloride were administered to rats for 6 days and the effects on adrenal renin-like activity and adrenal angiotensin II/III immunoreactivity were investigated. Rats infused with angiotensin II(140 pmol/min) either ip or sc showed increases in adrenal angiotensin II/III immunoreactivity (p<0.05) and plasma aldosterone concentration (p<0.05), but no change in adrenal renin-like activity. Captopril treatment of angiotensin Il-infused rats caused a slight decrease in angiotensin II/III immunoreactivity which did not reach statistical significance. In contrast, rats treated with ACTH (Cortrosyn-Z, 3 IU/day, sc) showed an increase in adrenal renin-like activity (p<0.01), but no significant change in adrenal angiotensin II/III immunoreactivity. Rats treated with KCl in drinking water showed increases (p<0.05) in adrenal renin-like activity, adrenal angiotensin II/III immunoreactivity, and plasma aldosterone. These results suggest that angiotensin II, ACTH and potassium, three major regulators of aldosterone secretion by the adrenal gland, have different effects on the adrenal renin-angiotensin system when administered in vivo.

A new transgenic rat model overexpressing the angiotensin II type 2 receptor provides evidence for inhibition of cell proliferation in the outer adrenal cortex

2012 ◽  
Vol 302 (9) ◽  
pp. E1044-E1054 ◽  
Author(s):  
Barbara Peters ◽  
Dirk Podlich ◽  
Michael Ritter ◽  
Anja Müller ◽  
Heike Wanka ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Angiotensin Ii ◽  
Binding Sites ◽  
Plasma Aldosterone ◽  
Transgenic Rat ◽  
Moderate Increase ◽  
Ang Ii ◽  
Ki 67 ◽  
Plasma Urea ◽  
Aldosterone Production

This study aimed to elucidate the role of the AT2 receptor (AT2R), which is expressed and upregulated in the adrenal zona glomerulosa (ZG) under conditions of increased aldosterone production. We developed a novel transgenic rat (TGR; TGRCXmAT2R) that overexpresses the AT2R in the adrenal gland, heart, kidney, brain, skeletal muscle, testes, lung, spleen, aorta, and vein. As a consequence the total angiotensin II (Ang II) binding sites increased 7.8-fold in the kidney, 25-fold in the heart, and twofold in the adrenals. The AT2R number amounted to 82–98% of total Ang II binding sites. In the ZG of TGRCXmAT2R, the AT2R density was elevated threefold relative to wild-type (WT) littermates, whereas AT1R density remained unchanged. TGRCXmAT2R rats were viable and exhibited normal reproduction, blood pressure, and kidney function. Notably, a slightly but significantly reduced body weight and a moderate increase in plasma urea were observed. With respect to adrenal function, 24-h urinary and plasma aldosterone concentrations were unaffected in TGRCXmAT2R at baseline. Three and 14 days of Ang II infusion (300 ng·min−1·kg−1) increased plasma aldosterone levels in WT and in TGR. These changes were completely abolished by the AT1R blocker losartan. Of note, glomerulosa cell proliferation, as indicated by the number of Ki-67-positive glomerulosa cells, was stimulated by Ang II in TGR and WT rats; however, this increase was significantly attenuated in TGR overexpressing the AT2R. In conclusion, AT2R in the adrenal ZG inhibits Ang II-induced cell proliferation but has no obvious lasting effect on the regulation of the aldosterone production at the investigated stages.

Inhibition of aldosterone turn-off phenomenon following chronic adrenocorticotropin treatment with in vivo administration of antiglucocorticoid and antioxidants in rats

1995 ◽  
Vol 133 (5) ◽  
pp. 578-584 ◽  
Author(s):  
Huiping Ni ◽  
Tomoatsu Mune ◽  
Hiroyuki Morita ◽  
Hisashi Daidoh ◽  
Junko Hanafusa ◽  
...  
Keyword(s):  
Body Weight ◽  
Vitamin E ◽  
Plasma Aldosterone ◽  
Type Ii ◽  
Plasma Acth ◽  
Aldosterone Level ◽  
Aldosterone Production ◽  
Plasma Aldosterone Level ◽  
In Vivo Administration

Ni H, Mune T, Morita H, Daidoh H, Hanafusa J, Shibata T, Yamakita N, Yasuda K. Inhibition of aldosterone turn-off phenomenon following chronic adrenocorticotropin treatment with in vivo administration of antiglucocorticoid and antioxidants in rats. Eur J Endocrinol 1995;133:578–84. ISSN 0804–4643 Chronic adrenocorticotropin (ACTH) treatment in rats leads to a fall in aldosterone secretion (aldosterone turn-off or "aldosterone escape" phenomenon) with a concomitant rise in corticosterone. To elucidate whether ACTH-induced aldosterone suppression is mediated by steroid type II receptor or related to a free-radical effect by over-synthesized corticosterone, we examined the effects of a glucocorticoid antagonist, RU486, and antioxidants dimethyl sulfoxide (DMSO) and vitamin E, on the aldosterone turn-off phenomenon in rats. Each rat received daily for 5 days a different dose of ACTH-Z (5, 10, 20 or 40 μg/100 g body weight) 1 mg RU486/100 g body weight, 100 μl (1.3 mmol) DMSO/100 g body weight or 2 mg vitamin E/100 g body weight with subcutaneous injection. Plasma steroid levels and in vitro release of steroids from the adrenal capsule were measured. The ACTH-Z treatment caused a dose-dependent increase in corticosterone and a decrease in aldosterone in both plasma and adrenal capsule experiments, as well as an increase in adrenal weights. For the following study 5 μg/100 g body weight of ACTH-Z was used. Administration of RU486 alone caused no change in plasma aldosterone level compared to controls, even though the steroid type II receptor was blocked, as evidenced by significant increases in plasma ACTH and corticosterone levels. Concomitant administration of RU486 and ACTH-Z increased both plasma corticosterone and aldosterone levels (p< 0.01) but decreased adrenal capsule corticosterone production (p< 0.05) compared to the rats treated with ACTH-Z alone. Treatment with DMSO alone caused a significant increase in plasma ACTH and corticosterone level (p< 0.05) but no change in plasma aldosterone level or adrenal capsule corticosterone and aldosterone production. The ACTH-induced aldosterone decrease was completely prevented by DMSO administration in both plasma and adrenal capsule experiments (p< 0.01). Vitamin E administration resulted in the elevation of plasma levels of ACTH and corticosterone (p< 0.01 and < 0.05) but not aldosterone, and it also increased adrenal capsule corticosterone production (p< 0.01) but not aldosterone production. By vitamin E administration, the ACTH-induced aldosterone decrease was suppressed almost completely in plasma (p< 0.01) and partially in adrenal capsule experiments (p< 0.01) compared to rats treated with ACTH-Z alone. Our findings suggest that RU486, DMSO and vitamin E inhibit the ACTH-induced aldosterone turn-off phenomenon in plasma, possibly due to the increase in activity of P-450aldo through antioxidant action or a steroid type II receptor blocking action. Keigo Yasuda, Third Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu MZ500, Japan

Adenovirus-mediated human prostasin gene delivery is linked to increased aldosterone production and hypertension in rats

2003 ◽  
Vol 284 (4) ◽  
pp. R1031-R1036 ◽  
Author(s):  
Cindy Wang ◽  
Julie Chao ◽  
Lee Chao
Keyword(s):  
Blood Pressure ◽  
Gene Transfer ◽  
Plasma Renin Activity ◽  
Plasma Renin ◽  
Plasma Aldosterone ◽  
Renin Activity ◽  
Sodium Reabsorption ◽  
Elevated Plasma ◽  
Aldosterone Production ◽  
Renal Kallikrein

Prostasin has been demonstrated to be an activator of epithelial sodium channels in cultured renal and bronchial epithelial cells. In this study, we evaluated the effects of adenovirus-mediated gene transfer of human prostasin on blood pressure regulation and sodium reabsorption in Wistar rats. Expression of human prostasin mRNA was identified in rat adrenal gland, liver, kidney, heart, lung, and aorta, and immunoreactive human prostasin was detected in the circulation and urine of rats receiving prostasin gene transfer. A single injection of adenovirus carrying the prostasin gene caused prolonged increases in blood pressure for 3–4 wk. Blood pressure increase was accompanied by elevated plasma aldosterone levels and reduced plasma renin activity. The increase in blood pressure and plasma aldosterone levels as well as the reduction of plasma renin activity correlated with the expression of human prostasin transgene. Elevated plasma aldosterone levels were detected at 3 days after gene transfer before the development of hypertension, indicating that stimulation of mineralocorticoid production is the primary target of prostasin. Prostasin gene transfer significantly reduced urinary K+ excretion but increased urinary Na+ and kallikrein excretion. Elevated renal kallikrein levels promote natriuresis, which may lead to sodium escape and prevent further increases of blood pressure after prostasin gene transfer. In summary, these results suggest that prostasin participates in blood pressure and electrolyte homeostasis by regulating the renin-angiotensin-aldosterone and kallikrein-kinin systems.

scholarly journals GRK2-Mediated Crosstalk Between β-Adrenergic and Angiotensin II Receptors Enhances Adrenocortical Aldosterone Production In Vitro and In Vivo

2020 ◽  
Vol 21 (2) ◽  
pp. 574
Author(s):  
Celina M. Pollard ◽  
Jennifer Ghandour ◽  
Natalie Cora ◽  
Arianna Perez ◽  
Barbara M. Parker ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
Adrenal Cortex ◽  
Zona Glomerulosa ◽  
Type I ◽  
Signaling Crosstalk ◽  
Aldosterone Production ◽  
Steroidogenic Acute Regulatory

Aldosterone is produced by adrenocortical zona glomerulosa (AZG) cells in response to angiotensin II (AngII) acting through its type I receptors (AT1Rs). AT1R is a G protein-coupled receptor (GPCR) that induces aldosterone via both G proteins and the adapter protein βarrestin1, which binds the receptor following its phosphorylation by GPCR-kinases (GRKs) to initiate G protein-independent signaling. β-adrenergic receptors (ARs) also induce aldosterone production in AZG cells. Herein, we investigated whether GRK2 or GRK5, the two major adrenal GRKs, is involved in the catecholaminergic regulation of AngII-dependent aldosterone production. In human AZG (H295R) cells in vitro, the βAR agonist isoproterenol significantly augmented both AngII-dependent aldosterone secretion and synthesis, as measured by the steroidogenic acute regulatory (StAR) protein and CYP11B2 (aldosterone synthase) mRNA inductions. Importantly, GRK2, but not GRK5, was indispensable for the βAR-mediated enhancement of aldosterone in response to AngII. Specifically, GRK2 inhibition with Cmpd101 abolished isoproterenol’s effects on AngII-induced aldosterone synthesis/secretion, whereas the GRK5 knockout via CRISPR/Cas9 had no effect. It is worth noting that these findings were confirmed in vivo, since rats overexpressing GRK2, but not GRK5, in their adrenals had elevated circulating aldosterone levels compared to the control animals. However, treatment with the β-blocker propranolol prevented hyperaldosteronism in the adrenal GRK2-overexpressing rats. In conclusion, GRK2 mediates a βAR-AT1R signaling crosstalk in the adrenal cortex leading to elevated aldosterone production. This suggests that adrenal GRK2 may be a molecular link connecting the sympathetic nervous and renin-angiotensin systems at the level of the adrenal cortex and that its inhibition might be therapeutically advantageous in hyperaldosteronism-related conditions.

EFFECT OF TWO CONSECUTIVE ACUTE STIMULI ON PLASMA ALDOSTERONE

1972 ◽  
Vol 71 (1) ◽  
pp. 153-159 ◽  
Author(s):  
Fred H. Katz ◽  
Peggy Romfh ◽  
Judith A. Smith
Keyword(s):  
Angiotensin Ii ◽  
Plasma Renin Activity ◽  
Adrenal Cortex ◽  
Plasma Renin ◽  
Plasma Aldosterone ◽  
Renin Activity ◽  
Upright Posture ◽  
Aldosterone Secretion ◽  
Stimulation Of

ABSTRACT The increase in plasma aldosterone and reduction in plasma renin activity induced by 30 to 60 minutes of mildly pressor angiotensin II infusion in man can be largely abolished when recent prior stimulation of the adrenal cortex by upright posture has been applied. A similar prevention of the ACTH-induced increase in plasma aldosterone can be achieved by previous upright ambulation. These results indicate the intermittent refractoriness of aldosterone secretion and that care must be exerted in the timing of any tests of aldosterone stimulation.

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