Action directe des antagonistes des minéralocorticoïdes sur la biosynthèse de l'aldostérone : activités comparées de plusieurs nouveaux composés

1983 ◽  
Vol 61 (1) ◽  
pp. 23-28 ◽  
Author(s):  
P. Netchitailo ◽  
I. Perroteau ◽  
C. Delarue ◽  
F. Leboulenger ◽  
M. H. Capron ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Inhibiting Activity ◽  
Mineralocorticoid Receptors ◽  
Strong Inhibitor ◽  
Aldosterone Antagonists ◽  
Angiotensin System ◽  
Inhibiting Effect ◽  
Spontaneous Production ◽  
Stimulation Of ◽  
Action Directe

Spironolactone is a diuretic steroid which is capable of blocking the binding of aldosterone to its cytosol receptor at the distal convoluted tubule. In addition, it has been shown that spironolactone is a strong inhibitor of steroidogenesis. More recently, new aldosterone antagonists have been discovered. Some of these compounds are more active than spironolactone in competing with aldosterone and have higher specificity for mineralocorticoid receptors. In this study we compare the direct activity of new antimineralocorticoids (SC 23133, SC 19886, SC 26304, and SC 27169) on aldosterone biosynthesis. Marked differences were found in the activity of these compounds upon steroidogenesis. SC 23133 gave rise to a strong inhibiting activity (90%). This activity was reversible (recovery of spontaneous production occurs 150 min after the end of the administration of SC 23133). SC 19886 totally inhibited aldosterone biosynthesis (95%) in a lasting mean. Conversely, SC 27169 and SC 26304 presented no or weak inhibiting effect. Further experiments showed that SC 27169 was unable to block the stimulation of aldosterone biosynthesis induced by corticotropic peptides, whereas the administration of SC 23133 and SC 19886 totally suppressed the stimulatory effect of ACTH and angiotensin II. Owing to the important stimulation of the renin–angiotensin system induced by antimineralocorticoid treatment, these results suggest that SC 23133 and SC 19886 will exert a higher antinatriuretic activity than SC 27169.

The renin–angiotensin system, bone marrow and progenitor cells

2012 ◽  
Vol 123 (4) ◽  
pp. 205-223 ◽  
Author(s):  
Matej Durik ◽  
Bruno Sevá Pessôa ◽  
Anton J. M. Roks
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Angiotensin Ii ◽  
Progenitor Cells ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Cardiovascular Therapy ◽  
Cardiovascular Cells ◽  
Stimulation Of

Modulation of the RAS (renin–angiotensin system), in particular of the function of the hormones AngII (angiotensin II) and Ang-(1–7) [angiotensin-(1–7)], is an important target for pharmacotherapy in the cardiovascular system. In the classical view, such modulation affects cardiovascular cells to decrease hypertrophy, fibrosis and endothelial dysfunction, and improves diuresis. In this view, excessive stimulation of AT1 receptors (AngII type 1 receptors) fulfils a detrimental role, as it promotes cardiovascular pathogenesis, and this is opposed by stimulation of the AT2 receptor (angiotensin II type 2 receptor) and the Ang-(1–7) receptor encoded by the Mas proto-oncogene. In recent years, this view has been broadened with the observation that the RAS regulates bone marrow stromal cells and stem cells, thus involving haematopoiesis and tissue regeneration by progenitor cells. This change of paradigm has enlarged the field of perspectives for therapeutic application of existing as well as newly developed medicines that alter angiotensin signalling, which now stretches beyond cardiovascular therapy. In the present article, we review the role of AngII and Ang-(1–7) and their respective receptors in haematopoietic and mesenchymal stem cells, and discuss possible pharmacotherapeutical implications.

scholarly journals Stimulation of the Renin-Angiotensin System by Endothelin Subtype A Receptor Blockade in Conscious Dogs

Hypertension ◽  
1999 ◽  
Vol 33 (6) ◽  
pp. 1420-1424 ◽  
Author(s):  
Heike Berthold ◽  
Klaus Münter ◽  
Armin Just ◽  
Hartmut R. Kirchheim ◽  
Heimo Ehmke
Keyword(s):  
Renin Angiotensin System ◽  
Conscious Dogs ◽  
Receptor Blockade ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Subtype A ◽  
Stimulation Of

scholarly journals Correcting the imbalanced protective RAS in COVID-19 with angiotensin AT2-receptor agonists

2020 ◽  
Vol 134 (22) ◽  
pp. 2987-3006 ◽  
Author(s):  
U. Muscha Steckelings ◽  
Colin Sumners
Keyword(s):  
Virus Disease ◽  
Renin Angiotensin System ◽  
Host Cells ◽  
Angiotensin System ◽  
Organ Systems ◽  
Membrane Bound ◽  
Compound 21 ◽  
The Brain ◽  
Entry Mechanism ◽  
Stimulation Of

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is responsible for the global corona virus disease 2019 (COVID-19) pandemic enters host cells via a mechanism that includes binding to angiotensin converting enzyme (ACE) 2 (ACE2). Membrane-bound ACE2 is depleted as a result of this entry mechanism. The consequence is that the protective renin–angiotensin system (RAS), of which ACE2 is an essential component, is compromised through lack of production of the protective peptides angiotensin-(1-7) and angiotensin-(1-9), and therefore decreased stimulation of Mas (receptor Mas) and angiotensin AT2-receptors (AT2Rs), while angiotensin AT1-receptors (AT1Rs) are overstimulated due to less degradation of angiotensin II (Ang II) by ACE2. The protective RAS has numerous beneficial actions, including anti-inflammatory, anti-coagulative, anti-fibrotic effects along with endothelial and neural protection; opposite to the deleterious effects caused by heightened stimulation of angiotensin AT1R. Given that patients with severe COVID-19 exhibit an excessive immune response, endothelial dysfunction, increased clotting, thromboses and stroke, enhancing the activity of the protective RAS is likely beneficial. In this article, we discuss the evidence for a dysfunctional protective RAS in COVID and develop a rationale that the protective RAS imbalance in COVID-19 may be corrected by using AT2R agonists. We further review preclinical studies with AT2R agonists which suggest that AT2R stimulation may be therapeutically effective to treat COVID-19-induced disorders of various organ systems such as lung, vasculature, or the brain. Finally, we provide information on the design of a clinical trial in which patients with COVID-19 were treated with the AT2R agonist Compound 21 (C21). This trial has been completed, but results have not yet been reported.

Renin Gene Transfer Restores Angiogenesis and VEGF Expression in Dahl S Rats

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 730-730
Author(s):  
Sandra L Amaral ◽  
Richard J Roman ◽  
Andrew S Greene
Keyword(s):  
Skeletal Muscle ◽  
Electrical Stimulation ◽  
Renin Angiotensin System ◽  
Complementation Test ◽  
Vegf Expression ◽  
Angiotensin System ◽  
Angiogenic Response ◽  
Electrical Stimulator ◽  
The Right ◽  
Stimulation Of

P204 To evaluate the importance of the renin angiotensin system (RAS) in VEGF expression and angiogenesis in skeletal muscle, we compared the angiogenic response to electrical stimulation in congenic strains of SS/Jr/Hsd rats using a complementation test design. We have previously demonstrated that both increases in VEGF expression and angiogenesis induced by electrical stimulation of skeletal muscle were absent in inbred Dahl S rats having a wildtype renin allele (S/ren ss ). In contrast, the congenic S/ren rr in which a 10 cM segment of chromosome 13 containing the normally functioning salt resistant renin allele was transferred onto the Dahl S background, exhibit the expected changes in renin. In the present study we investigate the effects of electrical stimulation on VEGF expression and angiogenesis in these rats. Congenic S/ren rr and S/ren ss rats, fed a 0.4% salt diet were surgically prepared by chronic implantation of an electrical stimulator. Another group of S/ren rr rats was treated with lisinopril, 2 days before the surgery and throughout the stimulation protocol. Rats without any drug treatment were used as control. The right tibialis anterior (TA) and extensor digitorum longus (EDL) were stimulated (10 Hz, 0.3 ms duration) for 8 hours per day for 7 days. The contralateral muscles served as controls. Western blot analysis was performed to identify VEGF protein expression in these muscles. Seven days of electrical stimulation of the skeletal muscles produced no change in vessel density of S/ren ss (Δ=5.50 ± 3.8 % and 8.14 ± 2.0 % for EDL and TA respectively). Transfer of the resistant renin allele (S/ren rr ) restored the angiogenic response (Δ=16% and 30% for EDL and TA, respectively) despite a significantly higher blood pressure (113.5 ± 2.25 mmHg and 148.67 ± 1.12 mmHg for S/ren ss and S/ren rr , respectively). Blockade of the RAS in S/ren rr restored the phenotype observed in the S/ren ss (Δ=1.46% and 1.9% to EDL and TA, respectively, p<0.05). In addition, increases in VEGF expression to electrical stimulation were observed only in S/ren rr . These results demonstrate that RAS plays an important role in the regulation of VEGF expression and angiogenesis in skeletal muscle.

Modulation of the intrahepatic renin–angiotensin system after stimulation of the gastric sodium monitor in the rat

1999 ◽  
Vol 98 (1) ◽  
pp. 57-64
Author(s):  
V. Z. C. YE ◽  
K. A. DUGGAN
Keyword(s):  
Renin Angiotensin System ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Angiotensin System ◽  
Low Sodium Diet ◽  
Low Sodium ◽  
Sprague Dawley Rats ◽  
Sodium Load ◽  
Ace Activity ◽  
Stimulation Of

Changes in the rate of formation of angiotensin II (ANG II) participate in mediating the natriuresis that occurs in direct response to a gastric sodium stimulus (upper-gut sodium monitor). As this natriuresis is also dependent on intrahepatic events, we investigated whether changes in hepatic and plasma angiotensinogen levels and hepatic angiotensin-converting enzyme (ACE) activity might explain the decrease in ANG II synthesis. Male Sprague–Dawley rats, equilibrated on a low-sodium diet, were anaesthetized and received a sodium load of 1.5 mmol/kg (using 3× normal saline) either intragastrically or intravenously. Blood and livers were sampled before and at various times after sodium administration. ACE activity in serum and tissues was determined by generation of histidyl-leucine. Angiotensinogen was determined by radioimmunoassay of angiotensin I generated by incubation in the presence of exogenous renin. Plasma angiotensinogen had decreased significantly by 15 min after sodium administration (P< 0.005), while hepatic angiotensinogen was also decreased significantly from 30 min after the sodium load (P< 0.01). Hepatic ACE activity decreased in response to sodium (P< 0.005) from 30 min. We conclude that stimulation of the gastric sodium monitor regulates angiotensinogen synthesis and secretion by the liver, as well as hepatic ACE activity.

Angiotensin mediates stimulation of ventilation after vasopressin V1 receptor blockade

1994 ◽  
Vol 76 (6) ◽  
pp. 2517-2526 ◽  
Author(s):  
J. K. Walker ◽  
D. B. Jennings
Keyword(s):  
Respiratory Control ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Circumventricular Organs ◽  
Receptor Blockade ◽  
Ang Ii ◽  
Angiotensin System ◽  
Control Protocol ◽  
Respiratory Stimulation ◽  
Stimulation Of

We tested the hypothesis that respiration would be stimulated after vasopressin (AVP) V1 receptor blockade because of disinhibition and activation of the renin-angiotensin system. Intravenous infusion of angiotensin II (ANG II) stimulates respiration, presumably centrally, via circumventricular organs. In the present study, the AVP V1 receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid),2-(O-methyl)tyrosine]-Arg8-AVP (PMP; 10 micrograms/kg i.v.) was administered to six awake resting dogs. Measurements were made 30 min prior, and 60 min subsequent, to injection of PMP (protocol 1). In three other protocols, the ANG II blocker saralasin (0.5 microgram.kg-1.min-1 i.v.) was infused starting 20 min before PMP (protocol 2) and 30 min after PMP (protocol 4) and saline was infused (0.2 ml/min) over 90 min as a control (protocol 3). After PMP in protocol 1, alveolar ventilation increased and arterial PCO2 decreased (approximately 3 Torr). ANG II receptor blockade prevented (protocol 2) and reversed (protocol 4) respiratory stimulation by PMP. Despite ventilatory stimulation, plasma renin activity and ANG II were not increased after PMP relative to control (protocol 3). We conclude that AVP acts at V1 receptors to inhibit formation of brain ANG II. Brain ANG II must modulate respiratory control via a circumventricular organ, because systemically administered saralasin, which does not cross the blood-brain barrier, blocked stimulation of respiration.

scholarly journals Therapeutic Perspectives of Angiotensin-(1-7) in the Treatment of Cardiovascular Disease

2009 ◽  
Vol 3 (1) ◽  
pp. 17-20 ◽  
Author(s):  
Christian Höcht ◽  
Marcos Mayer ◽  
Carlos A. Taira
Keyword(s):  
Cardiovascular Disease ◽  
Renin Angiotensin System ◽  
Therapeutic Strategies ◽  
Biologically Active ◽  
Ang Ii ◽  
Active Components ◽  
Aldosterone Antagonists ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Beneficial Effects

In the last decade, new biologically active components of the renin-angiotensin system were found. Angiotensin-(1-7) (Ang-(1-7)), a metabolite of angiotensin I and angiotensin II (Ang II), is considered the most pleiotropic component of the renin-angiotensin system, acting as a counterregulatory mediator of Ang II. Ang-(1-7) exerts beneficial effects on the cardiovascular system, including reduction of blood pressure, myocardial antihypertrofic and antifibrotic actions, and reversal of renal dysfunction, among others. Recent discovery of enzymatic pathways involved in Ang-(1-7) synthesis, such as the angiotensin-converting enzyme-2 (ACE2) and the existence of a specific receptor to this heptapeptide, the Mas receptor, have increased interest in the design of therapeutic strategies aimed at increasing the biological actions of Ang-(1-7). ACE inhibitors, AT receptor blockers and aldosterone antagonists enhance Ang-(1-7) levels by different mechanisms. Actually, non-peptidic Ang-(1-7) agonists and ACE2 activators are under development and could have a role in the treatment of cardiovascular diseases. The aim of the present review is to describe the biochemical and physiological actions of Ang-(1-7), the therapeutic strategies designed to enhance Ang-(1-7) activity foccusing in their possible role and limitations in the treatment of cardiovascular disease.

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