scholarly journals Treatment of Primary Aldosteronism With mTORC1 Inhibitors

2019 ◽  
Vol 104 (10) ◽  
pp. 4703-4714 ◽  
Author(s):  
Beckey Trinh ◽  
Matthias Hepprich ◽  
Matthias J Betz ◽  
Thilo Burkard ◽  
Claudia Cavelti-Weder ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Steroid Hormones ◽  
Primary Aldosteronism ◽  
Mammalian Target Of Rapamycin ◽  
Plasma Renin ◽  
Plasma Aldosterone ◽  
Ang Ii ◽  
Hemodynamic Parameters ◽  
Open Label ◽  
Adrenal Steroid

Abstract Context Mammalian target of rapamycin complex 1 (mTORC1) activity is often increased in the adrenal cortex of patients with primary aldosteronism (PA), and mTORC1 inhibition decreases aldosterone production in adrenocortical cells, suggesting the mTORC1 pathway as a target for treatment of PA. Objective To investigate the effect of mTORC1 inhibition on adrenal steroid hormones and hemodynamic parameters in mice and in patients with PA. Design (i) Plasma aldosterone, corticosterone, and angiotensin II (Ang II) were measured in mice treated for 24 hours with vehicle or rapamycin. (ii) Plasma aldosterone levels after a saline infusion test, plasma renin, and 24-hour urine steroid hormone metabolome and hemodynamic parameters were measured during an open-label study in 12 patients with PA, before and after 2 weeks of treatment with everolimus and after a 2-week washout. Main Outcome Measures (i) Change in plasma aldosterone levels. (ii) Change in other steroid hormones, renin, Ang II, and hemodynamic parameters. Results Treatment of mice with rapamycin significantly decreased plasma aldosterone levels (P = 0.007). Overall, treatment of PA patients with everolimus significantly decreased blood pressure (P < 0.05) and increased renin levels (P = 0.001) but did not decrease aldosterone levels significantly. However, prominent reduction of aldosterone levels upon everolimus treatment was observed in four patients. Conclusion In mice, mTORC1 inhibition was associated with reduced plasma aldosterone levels. In patients with PA, mTORC1 inhibition was associated with improved blood pressure and renin suppression. In addition, mTORC1 inhibition appeared to reduce plasma aldosterone in a subset of patients.

Pre-operative evaluation of the prognosis of hypertension in primary aldosteronism owing to adenoma

1987 ◽  
Vol 116 (2) ◽  
pp. 229-234 ◽  
Author(s):  
Takao Saruta ◽  
Hiromichi Suzuki ◽  
Takashi Takita ◽  
Ikuo Saito ◽  
Masaru Murai ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Primary Aldosteronism ◽  
Plasma Renin ◽  
Plasma Aldosterone ◽  
The Other ◽  
Mean Blood Pressure ◽  
Plasma Aldosterone Concentration ◽  
Postoperative Prognosis ◽  
History Of ◽  
Family History Of Hypertension

Abstract. The prognosis of hypertension was evaluated pre-operatively in 40 patients with primary aldosteronism owing to adenoma by examining the severity of hypertension, family history of hypertension, age of the patients, duration of hypertension, plasma renin activity, plasma aldosterone concentration, and efficacy of spironolactone (100 mg per day for 10 days) on blood pressure. In 30 of the 40 patients, the blood pressure was reduced to below 160/95 mmHg within a year after adrenalectomy (responders). In the other 10 patients, the blood pressure was not markedly reduced and remained above 160/95 mmHg (nonresponders). There were no significant differences in the age of the patients, family history of hypertension, plasma renin activity or plasma aldosterone concentration between these two groups. The severity of hypertension as judged by the WHO classification and the duration of hypertension prior to operation seemed to be of some use in assessing the postoperative prognosis of hypertension, but the efficacy of spironolactone was far more useful. That is to say, a reduction in mean blood pressure of more than 15 mmHg after administration of spironolactone was observed in 29 of the 30 responders. The remaining one patient showed an 11 mmHg reduction in mean blood pressure. On the other hand, none of the nonresponders revealed a reduction in mean blood pressure of more than 15 mmHg after spironolactone administration. From these results it is concluded that the pre-operative response of blood pressure to administration of 100 mg per day of spironolactone for 10 days represents a useful indicator of the postoperative prognosis of hypertension in patients with primary aldosteronism owing to adenoma.

Dissociation in plasma renin and adrenal ANG II and aldosterone responses to sodium restriction in rats

1991 ◽  
Vol 261 (4) ◽  
pp. E487-E494 ◽  
Author(s):  
A. Menachery ◽  
L. M. Braley ◽  
I. Kifor ◽  
R. Gleason ◽  
G. H. Williams
Keyword(s):  
Plasma Renin ◽  
Fold Increase ◽  
Plasma Aldosterone ◽  
Delayed Response ◽  
Ang Ii ◽  
Sodium Restriction ◽  
Sodium Depletion ◽  
Pathway Activity

In rats, plasma renin activity (PRA) increases sharply, reaching a plateau within hours of sodium restriction. Plasma aldosterone increases gradually, not reaching a plateau for 1-2 days. To determine whether this dissociation is secondary to the time needed to modify adrenal sensitivity to angiotensin II (ANG II) and to assess the role of locally produced ANG II in this process, rats were salt restricted for 0-120 h. Plasma hormone levels were assessed, adrenal ANG II was measured, and basal and ANG II (1 x 10(-8) M)-stimulated steroidogenesis were determined in vitro. Although PRA attained an elevated plateau within 8 h, plasma aldosterone did not peak until after 48 h of sodium depletion. The in vitro aldosterone sensitivity to exogenous ANG II was not apparent until rats had been salt restricted for 16 h. A plateau (4-fold increase above the ANG II response on high salt) was achieved between 24 and 48 h. Adrenal ANG II also exhibited a similar delayed response that correlates significantly with changes in aldosterone biosynthesis and late pathway activity. Thus the dissociation between PRA and plasma aldosterone may be secondary to a lag in the zona glomerulosa's (ZG) steroidogenic response to ANG II as well as a parallel lag in tissue ANG II production, suggesting that changes in tissue ANG II may mediate ZG sensitivity to ANG II during sodium deprivation.

Central effects of angiotensin II and dopamine in sodium-depleted sheep

1985 ◽  
Vol 248 (5) ◽  
pp. R541-R548
Author(s):  
B. S. Huang ◽  
R. L. Malvin ◽  
R. J. Grekin
Keyword(s):  
Angiotensin Ii ◽  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Plasma Aldosterone ◽  
Ang Ii ◽  
Angiotensin System ◽  
Aldosterone Level ◽  
Central Effects ◽  
Dopaminergic Pathway

The effects of intracerebroventricular (IVT) infusion of angiotensin II (ANG II), the converting enzyme inhibitor SQ 20881, and dopamine were studied in 15 conscious Na-depleted sheep. IVT ANG II (25 ng/min) significantly increased plasma aldosterone (163 +/- 24%) and vasopressin (ADH) (533 +/- 100%). Plasma renin activity (PRA) was decreased to 64 +/- 10% of basal. IVT SQ (1 microgram/min) decreased aldosterone to 70 +/- 10% and ADH to 55 +/- 9% of basal. PRA increased to 124 +/- 10%. There were no significant changes in plasma Na, K, or cortisol levels nor in mean arterial or intracranial pressure after either infusion. Increasing the dose of SQ to 10 micrograms/min resulted in an increased magnitude of change in the same variables. IVT SQ (1 microgram/min) significantly decreased aldosterone level in five nephrectomized sheep. The responses to IVT dopamine (20 micrograms/min) were qualitatively similar to those elicited by IVT SQ. These data support the existence of an endogenous brain renin-angiotensin system (RAS) independent of the renal RAS. ANG II acts centrally to regulate plasma ADH, aldosterone, and PRA levels. The similarity of the responses to SQ and dopamine suggests that a dopaminergic pathway may be involved in these responses.

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.

scholarly journals Deficiency of T-type Ca2+ channels Cav3.1 and Cav3.2 has no effect on angiotensin II-induced hypertension but differential effect on plasma aldosterone in mice

2019 ◽  
Vol 317 (2) ◽  
pp. F254-F263
Author(s):  
Anne D. Thuesen ◽  
Stine H. Finsen ◽  
Louise L. Rasmussen ◽  
Ditte C. Andersen ◽  
Boye L. Jensen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Mineralocorticoid Receptor ◽  
Plasma Aldosterone ◽  
Receptor Blocker ◽  
Ang Ii ◽  
Induced Hypertension

T-type Ca2+ channel Cav3.1 promotes microvessel contraction ex vivo. It was hypothesized that in vivo, functional deletion of Cav3.1, but not Cav3.2, protects mice against angiotensin II (ANG II)-induced hypertension. Mean arterial blood pressure (MAP) and heart rate were measured continuously with chronically indwelling catheters during infusion of ANG II (30 ng·kg−1·min−1, 7 days) in wild-type (WT), Cav3.1−/−, and Cav3.2−/− mice. Plasma aldosterone and renin concentrations were measured by radioimmunoassays. In a separate series, WT mice were infused with ANG II (100 ng·kg−1·min−1) with and without the mineralocorticoid receptor blocker canrenoate. Cav3.1−/− and Cav3.2−/− mice exhibited no baseline difference in MAP compared with WT mice, but day-night variation was blunted in both Cav3.1 and Cav3.2−/− mice. ANG II increased significantly MAP in WT, Cav3.1−/−, and Cav3.2−/− mice with no differences between genotypes. Heart rate was significantly lower in Cav3.1−/− and Cav3.2−/− mice compared with control mice. After ANG II infusion, plasma aldosterone concentration was significantly lower in Cav3.1−/− compared with Cav3.2−/− mice. In response to ANG II, fibrosis was observed in heart sections from both WT and Cav3.1−/− mice and while cardiac atrial natriuretic peptide mRNA was similar, the brain natriuretic peptide mRNA increase was mitigated in Cav3.1−/− mice ANG II at 100 ng/kg yielded elevated pressure and an increased heart weight-to-body weight ratio in WT mice. Cardiac hypertrophy, but not hypertension, was prevented by the mineralocorticoid receptor blocker canrenoate. In conclusion, T-type channels Cav3.1and Cav3.2 do not contribute to baseline blood pressure levels and ANG II-induced hypertension. Cav3.1, but not Cav3.2, contributes to aldosterone secretion. Aldosterone promotes cardiac hypertrophy during hypertension.

The effect of prostaglandin E1 upon the pressor and hormonal response to exogenous angiotensin II in human pregnancy

1987 ◽  
Vol 72 (3) ◽  
pp. 351-357 ◽  
Author(s):  
F. Broughton Pipkin ◽  
R. Morrison ◽  
P. M. S. O'Brien
Keyword(s):  
Blood Pressure ◽  
Dose Response ◽  
Prostaglandin E1 ◽  
Age Groups ◽  
Plasma Aldosterone ◽  
Ang Ii ◽  
Hormonal Response ◽  
Response Curves ◽  
Basal Blood Pressure ◽  
Dose Response Curves

1. The effect of prostaglandin E1 (PGE1) on the pressor and hormonal response to angiotensin (ANG) II has been studied in 22 women in second trimester pregnancy. Three-point dose–response curves were initially determined for all women. Eleven then received an infusion of PGE1 while the remainder received an infusion of normal saline as controls. The dose–response curves to ANG II were re-studied after a period of stabilization. 2. Although assignation to treatment group was random, differences were found in age and basal blood pressure between the control group and those given PGE1. The pressor data from the PGE1 group were thus split by age for analysis. 3. The administration of ANG II alone was associated with significant (P<0.001 at all doses) pressor effects without accompanying bradycardia. Plasma renin concentration (PRC) was suppressed (P<0.001). Plasma aldosterone concentration rose (P<0.001), the magnitude of the rise being directly associated with the plasma ANG II concentrations achieved (P<0.05). 4. The infusion of PGE, had no significant effect on basal blood pressure, but evoked a sustained tachycardia in both age groups (P<0.001). Basal hormone concentrations were unchanged. 5. The pressor response to ANG II was blunted in the presence of PGE1, in both age groups, the overall effect being greatest when the initial response had been large (P<0.05). Measured plasma concentrations of ANG II were lower under these circumstances (P<0.02). PRC fell (P<0.05 for both groups) and plasma aldosterone concentrations rose (P<0.005 for the treated and P<0.001 for the control groups), but the magnitude of these changes did not differ significantly in the two groups. 6. These data support the hypothesis of a for the vasodilator prostaglandins in minimizing the potential pressor effects of the raised ANG II concentrations seen in pregnancy.

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