Plasma renin activity and urinary aldosterone in Cushing's syndrome.

The renin-angiotensin-aldosterone system has been evaluated in 19 patients with Cushing's syndrome due to bilateral adrenal hyperplasia and in 2 patients with unilateral adenoma. In the first group urinary aldosterone was within the normal limits with a mean of 8.3 +/- 1.86 microgram/24 h. Aldosterone excretion did not change significantly after furosemide administration, ACTH infusion or dexamethasone. Upright PRA was suppressed in 9/16 patients with a mean of 4.9 +/- 1.85 ng/ml/3 h and showed only a slight response to furosemide. Dexamethasone alone did not produce any change. Both aldosterone and PRA were to some extent stimulated by an association of dexamethasone and furosemide. In the 2 patients with adenoma, aldosterone excretion was also normal, but PRA was very elevated. From our data it is concluded that in Cushing's syndrome due to bilateral hyperplasia, PRA and aldosterone excretion are partially suppressed. From our results on plasma deoxycorticosterone and corticosterone concentration it seems unlikely that these mineralocorticoids are the major cause of this phenomenon. However, it may not be excluded that other yet unidentified hormones could play some role in the pathogenesis of hypertension and renin suppression in Cushing's syndrome.     

The renin-angiotensin-aldosterone system in Cushing's syndrome and pheochromocytoma

We investigated the status of the renin-angiotensin-aldosterone axis in 5 patients with Cushing's syndrome and 7 patients with pheochromocytoma. In most of the patients with Cushing's syndrome no significant abnormalities of the renin-angiotensin-aldosterone system could be detected. In 4 out of 7 patients with pheochromocytoma, plasma renin activity remained high after saline suppression and decreased into the normal range in all 4 patients after removal of pheochromocytoma. These results imply that the postulated mineralocorticoid excess was not present in the patients with Cushing's syndrome studied. In pheochromocytoma, high levels of plasma catecholamines contribute to a high renin state which may have pathophysiologic implications.     

Renin-angiotensin system in antarctic fishes

• 1.1. The presence of a renin-angiotensin-like system has been investigated in the Antarctic fishes Chionodraco hamatus (Fam. Channichthydae) and Pagothenia (Trematomus) bernacchii (Fam. Notothenidae).
• 2.2. A renin-like activity is present in plasma and kidney of both the white blooded (Chionodraco) and the red blooded (Pagothenia) species.
• 3.3. An angiotensin converting enzyme-like activity has been demonstrated in plasma, gills and kidneys of both species. The activity is inhibited by high temperature.
• 4.4. From our data a renin-angiotensin-like system is present in the Antarctic fishes studied but the cascade of enzymes is active only at low temperatures.

     

Renin-angiotensin system and vascular remodelling

The renin-angiotensin system (RAS) is compartmented between circulating blood and tissue pericellular space. Whereas renin and its substrate diffuse easily from one compartment to another, the angiotensin peptides act in the compartment where there are generated: blood or pericellular space. Renin is trapped in tissues by low and high affinity receptors. In the target cells, angiotensin II/AT1 receptor interaction generates different signals including an immediate functional calcium-dependent response, secondary hypertrophy and a late proinflammatory and procoagulant response. These late pathological effects are mediated by NADPH oxydase-generated free oxygen radicals and NFkappaB activation. In vivo, the tissue binding of renin and the induction of converting enzyme are the main determinants of the involvement of the RAS in vascular remodeling. The target cells of interstitial angiotensin II are mainly the vascular smooth muscle cells and fibroblasts, whereas the endothelial cells and circulating leukocytes are the main targets of circulating angiotensin II. In vivo, angiotensin II participates in the vascular wall hypertrophy associated with hypertension. In diabetes, as in other localized fibrotic cardiovascular diseases, the tissue effects of angiotensin II are mainly dependent on its ability to induce TGF-beta expression. In experimental atherosclerosis, angiotensin II infusion induces aneurysm formation mediated by activation of circulating leucocytes. In these models, the administration of angiotensin II antagonists has beneficial effects on pathological remodeling. Such beneficial effects of angiotensin II antagonists in localized pathological remodeling have not yet been demonstrated in humans.     

Somatostatin suppresses plasma aldosterone concentration in a case of Bartter's syndrome

The study was conducted to examine the effect of somatostatin on activated renin-angiotensin-aldosterone system in a case of Bartter's syndrome. After 60 minutes of 500 micrograms of somatostatin infusion, the plasma aldosterone concentration was reduced from the basal level of 250 pg/ml to 140 pg/ml, whereas plasma renin activity remained at the basal level. This result suggests that somatostatin may specifically inhibit aldosterone secretion in Bartter's syndrome and the agent can be applied to a treatment of this syndrome.     

Cushing's syndrome in childhood

A patient with Cushing''s syndrome whose clinical manifestations began at approximately 9 years of age was followed for a period of four years. Initial laboratory studies revealed urinary 170HCS and 17 KS levels which were elevated for her age, with a normal diurnal variation of plasma cortisol and normal suppression of urinary 170HCS by 1.5 mg. of dexamethasone daily. It was not until four years after the onset of the disease that laboratory studies unequivocally supported the diagnosis of Cushing''s syndrome resulting in definitive therapy. Clinical features consisted primarily of cessation of growth, obesity, and hirsutism, with no evidence of protein depletion. It is suggested that the clinical and laboratory features of Cushing''s syndrome in childhood may present differences from those found in the adult. Failure to recognize these differences may result in delay in therapy with subsequent persisting stigmata of the disorder.     

Renin-angiotensin system in the carotid body

Research studies have been done on the influence of the renin-angiotensin system (RAS) on numerous tissues and organs. The local RAS, which is frequently of paracrine/autocrine origin, caters to specific organ and tissue needs through actions that add to, or differ from, the circulating RAS. Recent data have demonstrated a functional expression of RAS in the carotid body, wherein the carotid chemoreceptors play a major physiological role in the regulation of autonomic responses to changes in arterial chemical content. However, the angiotensin II and other vasoactive substances can directly modulate the excitability of the chemoreceptor. Long-term hypoxia modifies the level of gene expression in the carotid body by increasing the expression of AT(1) receptors along with sensitivity of the chemoreceptor to angiotensin II. Even though these findings support a physiological role of RAS in the carotid body, it has yet to be clearly defined. As a result this review will present current information about expression and localization of AT(1) receptors, and show that local RAS exists in the carotid body. The regulation of RAS by chronic hypoxia, the significance of its changes and clinical relevance in the carotid body, are also addressed.     

Effect of aminoglutethimide on ACTH plasma levels in Cushing's disease and Nelson syndrome]

Out of all steroidogenesis inhibitors aminoglutethimide is most frequently used agent for so-called chemical adrenalectomy, especially in oncological cases. The present studies aimed at assessing an effect of the inhibition of cortisol synthesis on plasma ACTH in patients treated with aminoglutethimide. According to the rules of negative feedback, an increase in plasma ACTH should be expected. Aminoglutethimide has been administered to 24 patients with Cushing's disease for 1-6 months. Plasma ACTH did not increase but statistically significantly decreased despite a decrease in blood cortisol. It indicates that aminoglutethimide directly inhibits ACTH secretion. No return of the normal circadian rhythm of cortisol and ACTH release suggests that the drug exerts an effect on ACTH release regulating mechanisms. No definite results were achieved in patients with Nelson syndrome treated with aminoglutethimide for a short period of time. Plasma ACTH levels tend to decrease but no statistical significance was observed in comparison with placebo. It may depend on markedly increased corticotrophin secretion in Nelson tumors.     

Renin-angiotensin system and sympathetic nervous system in cardiac pressure-overload hypertrophy

Angiotensin II and norepinephrine (NE) have been implicated in the neurohumoral response to pressure overload and the development of left ventricular hypertrophy. The purpose of this study was to determine the temporal sequence for activation of the renin-angiotensin and sympathetic nervous systems in the rat after 3-60 days of pressure overload induced by aortic constriction. Initially on pressure overload, there was transient activation of the systemic renin-angiotensin system coinciding with the appearance of left ventricular hypertrophy (day 3). At day 10, there was a marked increase in AT(1) receptor density in the left ventricle, increased plasma NE concentration, and elevated cardiac epinephrine content. Moreover, the inotropic response to isoproterenol was reduced in the isolated, perfused heart at 10 days of pressure overload. The affinity of the beta(2)-adrenergic receptor in the left ventricle was decreased at 60 days. Despite these alterations, there was no decline in resting left ventricular function, beta-adrenergic receptor density, or the relative distribution of beta(1)- and beta(2)-receptor sites in the left ventricle over 60 days of pressure overload. Thus activation of the renin-angiotensin system is an early response to pressure overload and may contribute to the initial development of cardiac hypertrophy and sympathetic activation in the compensated heart.     

Insulin resistance in Cushing's syndrome

Insulin resistance is well established in Cushing's syndrome, but its mechanisms are not completely understood. We performed the euglycemic insulin clamp technique on four patients with Cushing's syndrome, five obese patients and five normal volunteers, in order to determine the role of impairments in insulin responsiveness and insulin clearance in hypercorticism and obesity. Insulin was infused at 0.3, 1, 3 and 10 mU/kg/min, and steady-state glucose-infusion rates required to maintain euglycemia were determined. Glucose disposal at maximal insulin levels was 11.9 +/- 0.4 mg/kg/min in normals, with a 29% decrease in obese and a 42% decrease in Cushing's syndrome patients. Half maximally effective insulin concentrations were increased in both abnormal groups compared to normals. Maximal insulin clearance rates were 1460 +/- 200 ml/min/m2 in normals, not significantly changed in obese and 40% decreased in Cushing's syndrome patients. These results indicate that the insulin resistance in Cushing's syndrome is distinct from that occurring in obesity and is characterized by both decreased insulin responsiveness and decreased insulin clearance. These impairments could be caused by a common defect which may be at or distal to the glucose transport level.     

Renin-angiotensin system inhibition in COVID-19 patients

Netherlands Heart Journal - Angiotensin-converting enzyme (ACE) inhibitors (ACEIs) and angiotensin II type?1 receptor blockers (ARBs) are among the most widely prescribed drugs for...     

Aberrant receptor-mediated Cushing's syndrome

Multiple alterations of G-protein-coupled receptors and G-proteins regulating intracellular transduction signal have been described in endocrine tumours. In Cushing's syndrome, aberrant or 'illicit' expression of membrane receptors (mainly G-protein-coupled receptors) has been observed in adrenal adenomas and adrenocorticotropic hormone (ACTH)-independent macronodular bilateral adrenal hyperplasia. The best characterized example to date is the aberrant expression of the gastric inhibitory polypeptide receptor that causes 'food-dependent hypercortisolism'. Aberrant expression of the luteinizing hormone, 2-adrenergic, interleukin receptors have also been reported. The level of expression of the vasopressin V1a receptor correlates with the direct (ACTH-independent) cortisol response to vasopressin.