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Experimental Physiology Jan 2010This brief review describes the role of neural and non-neural mechanisms during different phases of deoxycorticosterone acetate (DOCA)-salt hypertension. There are... (Review)
Review
This brief review describes the role of neural and non-neural mechanisms during different phases of deoxycorticosterone acetate (DOCA)-salt hypertension. There are contradictory data for and against a role of the sympathetic nervous system and neurohumoral agents, including endothelin and vasopressin. Elucidating the factors responsible for DOCA-salt hypertension will be helpful in understanding the causes of hypertension resulting from hypervolaemia, hyperaldosteronism and high salt intake.
Topics: Animals; Desoxycorticosterone; Disease Models, Animal; Humans; Hypertension; Neurotransmitter Agents; Rats; Sodium Chloride, Dietary
PubMed: 19700514
DOI: 10.1113/expphysiol.2008.046334 -
Endocrine Journal Oct 1995A 29-year-old woman with deoxycorticosterone (DOC)-producing adrenocortical adenoma had hypertension and hypokalemia but without Cushingoid features. Plasma renin... (Review)
Review
A 29-year-old woman with deoxycorticosterone (DOC)-producing adrenocortical adenoma had hypertension and hypokalemia but without Cushingoid features. Plasma renin activity and the aldosterone concentration were low, while the DOC concentration was high (6.10-10.3 ng/ml; normal range 0.03-0.33). Plasma cortisol, androgens, and estrogens as well as urinary 17-OHCS and 17-KS were within normal limits. Furosemide administration and two hours upright posture resulted in a 3-fold increase in plasma DOC, but the administration of ACTH, dexamethasone, or angiotensin III had no effect on plasma DOC. Following resection of a right adrenal tumor weighing 70 g, the hypertension and hypokalemia disappeared. DOC content in the tumor was high. On light microscopic examination, the tumor was encapsulated, composed of cells with clear cytoplasm and large nuclei and there were extensive areas of fibrosis and infiltration of lymphocytes. According to Weiss's criteria, the tumor was considered to be an adrenocortical adenoma. Immunohistochemically, P450scc, 3 beta HSD, P450C21 and P45011 beta were positive with heterogeneity of intra-tumoral expression. No immunoreactivity for P45017 alpha in this adenoma was detected. This is different from a previous report in which a relatively small number of cells in DOC-secreting adrenocortical carcinoma were positive for P45017 alpha.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Adenoma; Adult; Desoxycorticosterone; Female; Humans; Immunohistochemistry
PubMed: 8574286
DOI: 10.1507/endocrj.42.637 -
Psychopharmacology Nov 2013Neurosteroids are steroids synthesized within the brain with rapid effects on neuronal excitability. Allopregnanolone, allotetrahydrodeoxycorticosterone, and... (Review)
Review
Neurosteroid interactions with synaptic and extrasynaptic GABA(A) receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability.
RATIONALE
Neurosteroids are steroids synthesized within the brain with rapid effects on neuronal excitability. Allopregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol are three widely explored prototype endogenous neurosteroids. They have very different targets and functions compared to conventional steroid hormones. Neuronal γ-aminobutyric acid (GABA) type A (GABA(A)) receptors are one of the prime molecular targets of neurosteroids.
OBJECTIVE
This review provides a critical appraisal of recent advances in the pharmacology of endogenous neurosteroids that interact with GABA(A) receptors in the brain. Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance of the neuron, mainly via potentiation of GABA(A) receptors at low concentrations and direct activation of receptor chloride channel at higher concentrations. The GABA(A) receptor mediates two types of inhibition, now characterized as synaptic (phasic) and extrasynaptic (tonic) inhibition. Synaptic release of GABA results in the activation of low-affinity γ2-containing synaptic receptors, while high-affinity δ-containing extrasynaptic receptors are persistently activated by the ambient GABA present in the extracellular fluid. Neurosteroids are potent positive allosteric modulators of synaptic and extrasynaptic GABA(A) receptors and therefore enhance both phasic and tonic inhibition. Tonic inhibition is specifically more sensitive to neurosteroids. The resulting tonic conductance generates a form of shunting inhibition that controls neuronal network excitability, seizure susceptibility, and behavior.
CONCLUSION
The growing understanding of the mechanisms of neurosteroid regulation of the structure and function of the synaptic and extrasynaptic GABA(A) receptors provides many opportunities to create improved therapies for sleep, anxiety, stress, epilepsy, and other neuropsychiatric conditions.
Topics: Allosteric Regulation; Androstane-3,17-diol; Animals; Brain; Desoxycorticosterone; Humans; Nerve Net; Neural Inhibition; Neuronal Plasticity; Neurotransmitter Agents; Pregnanolone; Receptors, GABA-A
PubMed: 24071826
DOI: 10.1007/s00213-013-3276-5 -
ACS Chemical Biology Dec 2017Artificial receptors for hydrophobic molecules usually have moderate affinities and limited selectivities. We describe three new classes of high affinity hydrophobic...
Artificial receptors for hydrophobic molecules usually have moderate affinities and limited selectivities. We describe three new classes of high affinity hydrophobic receptors for nonaromatic steroids based on deoxyribonucleotides, obtained through five high stringency selections coupled with tailored counter-selections. The isolation of multiple classes of high affinity steroid receptors demonstrates the surprising breadth of moderately sized hydrophobic binding motifs (<40 nucleotides) available to natural nucleic acids. Studies of interactions with analogs indicate that two classes, four-way junctions and 4XG motifs, comprise receptors with shapes that prevent binding of specific steroid conjugates used in counter-selections. Furthermore, they strongly prefer nonhydroxylated steroid cores, which is typical for hydrophobic receptors. The third new class accommodates hydroxyl groups in high-affinity, high-selectivity binding pockets, thus reversing the preferences of the first two classes. The high-affinity binding of aptamers to targets efficiently inhibits double-helix formation in the presence of the complementary oligonucleotides. The high affinity of some of these receptors and tailored elimination of binding through counter-selections ensures that these new aptamers will enable clinical chemistry applications.
Topics: Dehydroepiandrosterone Sulfate; Desoxycorticosterone; Molecular Structure; Nucleic Acids; Receptors, Steroid; Steroids
PubMed: 29083858
DOI: 10.1021/acschembio.7b00634 -
Translational Psychiatry Jun 2022There is preliminary evidence that adrenal steroids other than cortisol may be valuable biomarkers for major depressive disorder (MDD). So far, studies have been...
There is preliminary evidence that adrenal steroids other than cortisol may be valuable biomarkers for major depressive disorder (MDD). So far, studies have been conducted in adults only, and conclusions are limited, mainly due to small sample sizes. Therefore, the present study assessed whether adrenal steroids serve as biomarkers for adolescent MDD. In 261 depressed adolescents (170 females) treated at a single psychiatric hospital, serum adrenal steroids (progesterone, 17-hydroxyprogesterone, 21-deoxycortisol, 11-deoxycortisol, cortisol, cortisone, deoxycorticosterone, corticosterone) were determined by liquid chromatography-tandem mass spectrometry. Findings were compared to that of an age- and sex-matched reference cohort (N = 255) by nonparametric analysis of variance. Nonparametric receiver operating characteristics (ROC) analyses were conducted to evaluate the diagnostic performance of single steroids and steroid ratios to classify depression status. Sensitivity analyses considered important confounders of adrenal functioning, and ROC results were verified by cross-validation. Compared to the reference cohort, levels of deoxycorticosterone and 21-deoxycortisol were decreased (P < 0.001). All other glucocorticoid- and mineralocorticoid-related steroids were increased (P < 0.001). The corticosterone to deoxycorticosterone ratio evidenced excellent classification characteristics, especially in females (AUC: 0.957; sensitivity: 0.902; specificity: 0.891). The adrenal steroid metabolome qualifies as a bio-readout reflecting adolescent MDD by a distinct steroid pattern that indicates dysfunction of the hypothalamus-pituitary-adrenal axis. Moreover, the corticosterone to deoxycorticosterone ratio may prospectively qualify to contribute to precision medicine in psychiatry by identifying those patients who might benefit from antiglucocorticoid treatment or those at risk for recurrence when adrenal dysfunction has not resolved.
Topics: Adolescent; Adult; Corticosterone; Depression; Depressive Disorder, Major; Desoxycorticosterone; Female; Humans; Hydrocortisone; Steroids
PubMed: 35717450
DOI: 10.1038/s41398-022-01966-2 -
Hypertension (Dallas, Tex. : 1979) May 2014
Topics: Animals; Blood Pressure; Cardiovascular Physiological Phenomena; Desoxycorticosterone; Endothelium, Vascular; Humans; Receptors, Mineralocorticoid; Sodium Chloride; Ventricular Remodeling
PubMed: 24566083
DOI: 10.1161/HYPERTENSIONAHA.114.01997 -
British Journal of Pharmacology Mar 2021Fibrosis is a hallmark of chronic kidney disease (CKD) that significantly contributes to renal dysfunction, and impairs the efficacy of stem cell-based therapies. This...
BACKGROUND AND PURPOSE
Fibrosis is a hallmark of chronic kidney disease (CKD) that significantly contributes to renal dysfunction, and impairs the efficacy of stem cell-based therapies. This study determined whether combining bone marrow-derived mesenchymal stem cells (BM-MSCs) with the renoprotective effects of recombinant human relaxin (serelaxin) could therapeutically reduce renal fibrosis in mice with one kidney/deoxycorticosterone acetate/salt (1K/DOCA/salt)-induced hypertension, compared with the effects of the ACE inhibitor, perindopril.
EXPERIMENTAL APPROACH
Adult male C57BL/6 mice were uni-nephrectomised and received deoxycorticosterone acetate and saline to drink (1K/DOCA/salt) for 21 days. Control mice were uni-nephrectomised but received water over the same time period. Sub-groups of 1K/DOCA/salt-injured mice (n = 5-8 per group) were treated with either serelaxin (0.5 mg·kg ·day ) or BM-MSCs (1 × 10 per mouse) alone; both treatments combined (with 0.5 × 10 or 1 × 10 BM-MSCs per mouse); or perindopril (2 mg·kg ·day ) from days 14-21.
KEY RESULTS
1K/DOCA/salt-injured mice developed elevated BP and hypertension-induced renal damage, inflammation and fibrosis. BM-MSCs alone reduced the injury-induced fibrosis and attenuated BP to a similar extent as perindopril. Serelaxin alone modestly reduced renal fibrosis and effectively reduced tubular injury. Strikingly, the combined effects of BM-MSCs (at both doses) with serelaxin significantly inhibited renal fibrosis and proximal tubular epithelial injury while restoring renal architecture, to a greater extent than either therapy alone, and over the effects of perindopril.
CONCLUSION AND IMPLICATIONS
Combining BM-MSCs and serelaxin provided broader renoprotection over either therapy alone or perindopril and might represent a novel treatment for hypertensive CKD.
Topics: Animals; Blood Pressure; Desoxycorticosterone; Desoxycorticosterone Acetate; Hypertension; Hypertension, Renal; Kidney; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL
PubMed: 33450051
DOI: 10.1111/bph.15361 -
Hypertension (Dallas, Tex. : 1979) Sep 2009
Topics: Aldosterone; Animals; Blood Pressure; Desoxycorticosterone; Fibrosis; Macrophages; Mice; Mice, Knockout; Models, Biological; Monocytes; Myocardium; Receptors, Mineralocorticoid; Sodium Chloride, Dietary
PubMed: 19635984
DOI: 10.1161/HYPERTENSIONAHA.109.135855 -
Metabolism: Clinical and Experimental May 2022High salt intake and aldosterone are both associated with vascular stiffening in humans. However, our preliminary work showed that high dietary salt alone did not...
INTRODUCTION
High salt intake and aldosterone are both associated with vascular stiffening in humans. However, our preliminary work showed that high dietary salt alone did not increase endothelial cell (EC) or vascular stiffness or endothelial sodium channel (EnNaC) activation in mice, presumably because aldosterone production was significantly suppressed as a result of the high salt diet. We thus hypothesized that high salt consumption along with an exogenous mineralocorticoid would substantially increase EC and vascular stiffness via activation of the EnNaC.
METHODS AND RESULTS
Mice were implanted with slow-release DOCA pellets and given salt in their drinking water for 21 days. Mice with either specific deletion of the alpha subunit of EnNaC or treated with a pharmacological inhibitor of mTOR, a downstream signaling molecule involved in mineralocorticoid receptor activation of EnNaC, were studied. DOCA-salt treated control mice had increased blood pressure, EC Na transport activity, EC and arterial stiffness, which were attenuated in both the αEnNaC and mTOR inhibitor treated groups. Further, depletion of αEnNaC prevented DOCA-salt-induced impairment in EC-dependent vascular relaxation.
CONCLUSION
While high salt consumption alone does not cause EC or vascular stiffening, the combination of EC MR activation and high salt causes activation of EnNaC which increases EC and arterial stiffness and impairs vascular relaxation. Underlying mechanisms appear to include mTOR signaling.
Topics: Animals; Blood Pressure; Desoxycorticosterone Acetate; Endothelial Cells; Epithelial Sodium Channels; Hypertension; Mice; Sodium; Vascular Stiffness
PubMed: 35183546
DOI: 10.1016/j.metabol.2022.155165 -
International Journal of Molecular... Dec 2023Hypertension is a global civilization disease and one of the most common causes of death in the world. Organ dysfunction is a serious health consequence of hypertension,...
Evaluation of the Expression and Localization of the Multifunctional Protein CacyBP/SIP and Elements of the MAPK Signaling Pathway in the Adrenal Glands of Rats with Primary and Secondary Hypertension.
Hypertension is a global civilization disease and one of the most common causes of death in the world. Organ dysfunction is a serious health consequence of hypertension, which involves damage to the heart, kidneys and adrenals. The interaction of recently discovered multifunctional protein-CacyBP/SIP with ERK1/2 and p38 kinases by regulating the activity and intracellular localization of these kinases may play an important role in the signaling pathways involved in the pathogenesis of hypertension. Due to the lack of data on this subject, we decided to investigate the localization, expression and possible relationship between the studied parameters in the adrenals under arterial hypertension. The study was conducted on the adrenals of rats with spontaneous and DOCA-salt hypertension. The expression of CacyBP/SIP, p-ERK1/2 and p-p38 was detected by immunohistochemistry and qRT-PCR. The results show a statistically significant decrease in CacyBP/SIP expression in the adrenal glands of hypertensive rats. With ERK1/2, there was a decrease in cortical immunoreactivity and an increase in the adrenal medulla of primary hypertensive rats. In contrast, in the adrenals of DOCA-salt rats, ERK1/2 immunoreactivity increased in the cortex and decreased in the medulla. In turn, p38 expression was higher in the adrenal glands of rats with primary and secondary hypertension. The obtained results may suggest the involvement of CacyBP/SIP in the regulation of signaling pathways in which MAP kinases play an important role and provide new insight into molecular events in hypertension. Moreover, they show the participation of CacyBP/SIP in response to oxidative stress.
Topics: Animals; Rats; MAP Kinase Signaling System; Desoxycorticosterone Acetate; Signal Transduction; Adrenal Glands; Hypertension; Sodium Chloride; Sodium Chloride, Dietary; Intracellular Signaling Peptides and Proteins
PubMed: 38203261
DOI: 10.3390/ijms25010084