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.

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).

Stimulation by serum of aldosterone production from rat adrenal glomerulosa cells in vitro: relationships to K+, serotonin and angiotensin II

1981 ◽  
Vol 97 (2) ◽  
pp. 231-242 ◽  
Author(s):  
F. A. O. Mendelsohn ◽  
Christine D. Kachel
Keyword(s):  
Angiotensin Ii ◽  
Human Serum ◽  
Normal Subjects ◽  
Normal Human Serum ◽  
Rpmi Medium ◽  
High K ◽  
Aldosterone Production ◽  
Normal Human ◽  
Glomerulosa Cells

Abstract. Normal human serum markedly stimulated aldosterone production from rat adrenal glomerulosa cells incubated in Krebs Ringer bicarbonate medium (KRBGA). The effect was dose-related. In [K+] 3.6 mm KRBGA medium, serum stimulated aldosterone output to higher levels than those produced by maximal doses of serotonin (5 HT), angiotensin II (AII) or high [K+] (8.4 mm). Cells maximally stimulated by high [K+], 5 HT or AII in KRBGA medium were further stimulated by serum. The angiotensin analogue, [Sar1, Ala8]-AII abolished the effect of AII but not that of high [K+] or serum. Basal and ACTH-stimulated corticosterone outputs of rat fasciculata cells were not significantly affected by sera known to stimulate glomerulosa cells. Aldosterone stimulating activity of serum was dialysable and fully recovered in a serum ultrafiltrate. The serotonin blockers methysergide and metergoline abolished the aldosterone stimulating activity of serum but also depressed basal aldosterone output and methysergide reduced K+-stimulated output. Chymotrypsin digestion abolished the aldosterone stimulating activity of AII but not that of serotonin or serum. 5 HT concentration of sera was measured and found to be near the threshold for aldosterone stimulation. Sodium loading and depletion of 4 normal subjects did not consistently modify the aldosterone stimulating activity of their sera. In a supplemented medium (RPMI 1640), basal and K+-stimulated aldosterone outputs were higher than in KRBGA medium. Under these conditions serum stimulated aldosterone output in normal [K+] medium but only marginally in high [K+] medium. In RPMI medium, serum did not further stimulate cells maximally stimulated with serotonin. Serum appears to stimulate aldosterone production from glomerulsoa cells by two different mechanisms: One is probably due to a serotonin-like substance. A separate effect of serum, seen only in KRBGA medium, is to enhance aldosterone output of glomerulosa cells maximally stimulated by K+, 5 HT or AII.

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.

scholarly journals An adrenal  -arrestin 1-mediated signaling pathway underlies angiotensin II-induced aldosterone production in vitro and in vivo

2009 ◽  
Vol 106 (14) ◽  
pp. 5825-5830 ◽  
Author(s):  
A. Lymperopoulos ◽  
G. Rengo ◽  
C. Zincarelli ◽  
J. Kim ◽  
S. Soltys ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Signaling Pathway ◽  
Aldosterone Production

EFFECTS OF VARIOUS PEPTIDES ON ALDOSTERONE PRODUCTION OF SODIUM DEFICIENT RATS

1968 ◽  
Vol 59 (2) ◽  
pp. 186-192 ◽  
Author(s):  
B. van der Wal ◽  
D. de Wied
Keyword(s):  
Angiotensin Ii ◽  
The Other ◽  
Adrenal Tissue ◽  
Acth Fragments ◽  
Aldosterone Production ◽  
Hypophysectomized Rats

ABSTRACT The effect of angiotensin II, vasopressin, ACTH, α- and β-MSH and several ACTH fragments was studied on the production of aldosterone in sodium-deficient intact and hypophysectomized rats and in animals pretreated with dexamethasone-pentobarbitone (D-N) or pentobarbitone-chlorpromazine (N-CPZ). As an index of the production of aldosterone in vivo the rate of aldosterone production by excised adrenal tissue in vitro was used. The effect of angiotensin II and vasopressin on aldosterone production was inhibited by previous hypophysectomy or by pretreatment with large amounts of dexamethasone while the action of ACTH was not affected by these measures. Except for α-MSH, none of the other ACTH-fragments was capable of stimulating the rate of aldosterone production in D-N rats. This was interpreted as indicating that the stimulatory effect of ACTH on aldosterone production in sodium-deficient rats is a property of the whole ACTH-molecule.

Effects of heparin treatments in vivo and in vitro on adrenal angiotensin II receptors and angiotensin II-induced aldosterone production in rats

1988 ◽  
Vol 119 (3) ◽  
pp. 367-372 ◽  
Author(s):  
Sadahide Azukizawa ◽  
Ikuyo Iwasaki ◽  
Toshikazu Kigoshi ◽  
Kenzo Uchida ◽  
Shinpei Morimoto
Keyword(s):  
Angiotensin Ii ◽  
Benzyl Alcohol ◽  
Specific Binding ◽  
Angiotensin Ii Receptors ◽  
Scatchard Analysis ◽  
Aldosterone Production ◽  
Glomerulosa Cells ◽  
Heparin Preparation

Abstract. To evaluate the heparin effects in vivo and in vitro on adrenal angiotensin II receptors and angiotensin II-induced aldosterone production, we examined the angiotensin II binding and the maximum angiotensin II-induced aldosterone production using adrenal glomerulosa cells from rats treated with a heparin preparation containing benzyl alcohol (1500 IU/kg, twice daily for 6 weeks) or cells to which heparin (300 IU/l) was directly added. Comparison was made using the cells from rats treated with vehicle or the cells to which vehicle was directly added. Specific binding of [125I]iodo-angiotensin II was decreased in the cells from heparin-treated rats or in the heparin-treated cells. Scatchard analysis showed that the decrease in binding was due to a decrease in both the number and the affinity of angiotensin II receptors in the cells from heparin-treated rats and a decrease in the number, but not the affinity, of the receptors in the heparin-treated cells. Heparin also caused a decrease in the maximum angiotensin Il-induced production, but not the basal production, of aldosterone in the cells from heparin-treated rats and in the heparin-treated cells. These data suggest that heparin interacts with adrenal angiotensin II receptors to inhibit the angiotensin Il-induced aldosterone production.

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.

Effects of β-Lipotropin on Aldosterone Production in Rats

1980 ◽  
Vol 59 (s6) ◽  
pp. 91s-94s ◽  
Author(s):  
Hiroaki Matsuoka ◽  
Patrick J. Mulrow ◽  
Roberto Franco-Saenz ◽  
Choh Hao Li
Keyword(s):  
Angiotensin Ii ◽  
Cyclic Amp ◽  
Aldosterone Production

1. β-Lipotropin has a potent aldosterone stimulating effect in vitro and in vivo in rats. 2. The maximum aldosterone response to β-lipotropin was the same as to ACTH and greater than to angiotensin II. 3. Although doses of ACTH which maximally stimulated aldosterone significantly increased cyclic AMP production, maximally stimulating doses of sheep β-lipotropin did not increase cyclic AMP production significantly. 4. These data suggest that β-lipotropin may play a role in aldosterone regulation through a mechanism different from that of ACTH.

In vivo and in vitro effects of metoclopramide on aldosterone secretion in rats

1983 ◽  
Vol 102 (4) ◽  
pp. 589-593 ◽  
Author(s):  
Shusaku Nagahama ◽  
Masaki Fujimaki ◽  
Hiroko Suzuki ◽  
Hiroshi Kawabe ◽  
Ikuo Saito ◽  
...  
Keyword(s):  
Sodium Intake ◽  
Plasma Renin ◽  
Zona Glomerulosa ◽  
Plasma Aldosterone ◽  
Dopamine Antagonist ◽  
High Sodium ◽  
Aldosterone Production ◽  
In Vitro Effects

Abstract. This study was designed to investigate the effects of metoclopramide, a dopamine antagonist, on in vivo and in vitro aldosterone production in the rat. In addition, we examined the effect of various levels of sodium intake on the response of plasma aldosterone to metoclopramide. Metoclopramide (2–50 mg/kg) was given by ip injection to conscious rats. Metoclopramide induced a dose-related increase in plasma aldosterone, whereas it only increased plasma renin activity at high doses (20 and 50 mg/kg). The response of plasma aldosterone to 10 mg/kg of metoclopramide in the low-sodium group was greater than that in the high-sodium group. Metoclopramide had no effect on aldosterone production in isolated zona glomerulosa cells in vitro.

Evaluation of 99mTc-Label led Vitamin K4 as an Agent for Testicular Imaging

1991 ◽  
Vol 30 (01) ◽  
pp. 35-39 ◽  
Author(s):  
H. S. Durak ◽  
M. Kitapgi ◽  
B. E. Caner ◽  
R. Senekowitsch ◽  
M. T. Ercan
Keyword(s):  
Soft Tissue ◽  
Room Temperature ◽  
Normal Subjects ◽  
Left Testis ◽  
Wide Range ◽  
Activity Ratios ◽  
The Right ◽  
Radioactivity Levels

Vitamin K4 was labelled with 99mTc with an efficiency higher than 97%. The compound was stable up to 24 h at room temperature, and its biodistribution in NMRI mice indicated its in vivo stability. Blood radioactivity levels were high over a wide range. 10% of the injected activity remained in blood after 24 h. Excretion was mostly via kidneys. Only the liver and kidneys concentrated appreciable amounts of radioactivity. Testis/soft tissue ratios were 1.4 and 1.57 at 6 and 24 h, respectively. Testis/blood ratios were lower than 1. In vitro studies with mouse blood indicated that 33.9 ±9.6% of the radioactivity was associated with RBCs; it was washed out almost completely with saline. Protein binding was 28.7 ±6.3% as determined by TCA precipitation. Blood clearance of 99mTc-l<4 in normal subjects showed a slow decrease of radioactivity, reaching a plateau after 16 h at 20% of the injected activity. In scintigraphic images in men the testes could be well visualized. The right/left testis ratio was 1.08 ±0.13. Testis/soft tissue and testis/blood activity ratios were highest at 3 h. These ratios were higher than those obtained with pertechnetate at 20 min post injection.99mTc-l<4 appears to be a promising radiopharmaceutical for the scintigraphic visualization of testes.

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