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Pseudohypoaldosteronism (PHA) is characterized by salt-wasting and failure to thrive in the newborn, accompanied by high urinary levels of sodium despite hyponatremia, hyperkalemia and metabolic acidosis, elevation of plasma renin activity, and high plasma aldosterone levels. PHA patients are resistant to mineralocorticoid administration, but their symptoms ameliorate after a period of sodium supplementation,...
In the course of my studies of patients with mineralocorticoid hypertensive disorders, unusual presentations led to unexpected findings, both clinically and in steroid etiologies and regulation. Unique circumstances permitted early studies in defining the autonomy of the aldosterone-producing adenoma. A chance referral brought the index case of 17α-hydroxylase deficiency to the research center....
19-Noraldosterone, which was recently shown to be synthesized and produced in the human adrenal gland, possesses potent mineralocorticoid and hypertensinogenic activities. 18,19-Dihydroxycorticosterone (18,19-(OH) 2 -B) and 18-hydroxy-19-norcorticosterone (18-OH-19-nor-B), a possible precursor of 19-noraldosterone, have been identified in human urine. These mineralocorticoid hormones are...
We have previously reported our studies on glucocorticoid (GC) effects on Na + influx in vascular smooth muscle (VSM) cells. We now report a parallel study on the effect of mineralocorticoid (MC) on Na + influx in VSM cells. Unidirectional influx of Na + was measured in cultured cells of rabbit aortic media with 22 Na as tracer. Cells were treated with near...
Mineralocorticoid hormones such as aldosterone modulate cellular ion homeostasis at least in part through the regulation of Na + ,K + -ATPase (NAKA) gene expression. While aldosterone acts at the transcriptional level through its ligand-inducible mineralocorticoid receptor (MR), tissue specific and other transcriptional factors may interact with the MR to modulate this regulatory...
Studies in extrarenal, nonepithelial cells such as human lymphocytes and smooth muscle cells indicate that aldosterone produces not only delayed genomic effects, but also rapid, non-genomic effects on transmembrane electrolyte movements. These non-genomic events involve the immediate activation of the sodium/proton-exchanger of the cell membrane at very low, physiological concentrations of aldosterone...
The present study was designed to clarify the transcriptional regulation of the human type 1 angiotensin II receptor (AT1) gene and its pathophysiological roles in steroidogenesis by adrenal tumors. A cDNA encoding type 1 angiotensin II receptor (AT1) was isolated from a human liver cDNA library encoding a protein of 359 amino acids with seven transmembrane segments. It is very likely that human...
Uninephrectomized rats maintained on 0.9% NaCl as drinking fluid and infused for 8 weeks with aldosterone 0.75 μg/h via subcutaneous osmotic minipumps respond with hypertension, cardiac hypertrophy, and both interstitial and perivascular cardiac fibrosis. Similar animals injected with desoxycorticosterone (20 mg/week), or the glucocorticoid antagonist RU 486 (2 mg/day) show interstitial cardiac fibrosis...
Chronic mineralocorticoid (MC) excess, whether due to elevated plasma aldosterone (ALDO) or deoxycorticosterone (DOC), is associated with a perivascular fibrosis of systemic and coronary arterioles. This remodeling of resistance vessels contributes to the appearance of hypertension. Chronic MC excess is also accompanied by cardiac myocyte necrosis, secondary to myocardial potassium depletion, and...
In this work we confirm by a metabolic method the existence of at least two enzymes with 11β- and 18-hydroxylase activities in rat adrenal mitochondria. The method was based on the ability of cortisol (F), a foreign alternative substrate, to inhibit competitively metabolite productions from various precursors. F inhibited a) aldosterone (ALDO) production from 11-deoxycorticosterone (DOC) without...
Pseudohypoaldosteronism was first described in 1958 by Cheek and Perry, who reported an infant with severe salt wasting in the absence of any renal or adrenal defect. Since then several reports have described patients affected by symptoms consistent with resistance to mineralocorticoid action. The clinical picture is characterized by salt wasting and failure to thrive and is resistant to the administration...
Endogenous 17β-estradiol (E2) and low parenteral doses of exogenous E2 are vasodilators. High dose estrogens, especially ethinylestradiol (EE) and mestranol, stimulate the synthesis of hepatic proteins including coagulation factors, sex hormone binding globulin, and angiotensinogen (Aogen). In the steady state, high plasma levels of Aogen produce only a very small increase of angiotensin II (AII)...
In uninephrectomized rats on 1% NaCl solution to drink, aldosterone (0.75 μg/h subcutaneously for 8 weeks) raises blood pressure and causes marked interstitial and perivascular cardiac fibrosis, effects not seen in animals on a low salt intake. In extending these initial findings, we have shown that cardiac fibrosis (i) is not reversed by correction of mineralocorticoid-induced hypokalemia; (ii)...
Through its collaboration with the ETH in Zurich (Ruzicka's group) and later on with the University of Basel (Reichstein's group), Ciba became involved very early in steroid chemistry. The main task of the chemists consisted at that time of the synthesis of natural hormones and their derivatives. Cholesterol served for several years as the preferred starting material, and efficient procedures were...
The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of hypertension in which 11β-hydroxysteroid dehydrogenase (11-HSD) is defective. This enzyme converts cortisol to its inactive metabolite, cortisone. The deficiency allows mineralocorticoid receptors to be occupied by cortisol, because these receptors themselves have similar affinities for cortisol and aldosterone. There...
In this paper, we studied the effect of heme availability on corticosterone and aldosterone synthesis in rat adrenal. We found that hemin stimulated corticosterone and aldosterone production in adrenal homogenates in a dose-dependent fashion. Hemin administration to rats also provoked an increase in both corticosterone and aldosterone content in adrenal. 3,5-Diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine...
In the present paper, we report that an inositolphosphoglycan (IPG), derived from a Trypanosoma cruziglycoinositolphosphoceramide (LPPG), is able to inhibit ACTH-mediated accumulation of a glucocorticoid, cortisol, in calf adrenocortical cells. This IPG is also able to inhibit the stimulation by ACTH of the production of the main glucocorticoid, corticosterone and the main mineralocorticoid, aldosterone,...
The possibility that non-ACTH proopiomelanocortin-derived fragments may stimulate aldosterone production has previously been studied using nonhuman cells with inconsistent results. We have examined the response of aldosterone to β-endorphin (β-End) and joining peptide (JP) and compared these with the response to ACTH using eight cell suspensions prepared from human adrenal glands. ACTH, 10 - ...
Aldosterone at normal physiological levels induces rapid increases in intracellular calcium and pH in human distal colon. The end target of these rapid signaling responses are basolateral K + channels. Using spectrofluorescence microscopy and Ussing chamber techniques, we have shown that aldosterone activates basolateral Na/H exchange via a protein kinase C and calcium-dependent signaling...
Initiation of transcription is an early step in steroid hormone action. We investigated by means of atomic force microscopy (AFM) and fluorescence imaging the role of nuclear pore complexes (NPCs) in mediating signal transduction of the mineralocorticoid hormone aldosterone from the extracellular space into the cell nucleus. With AFM, we imaged single NPCs of isolated nuclear envelopes under native...
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