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Hypertension (Dallas, Tex. : 1979) Feb 2019
Topics: Fibrosis; Heart Atria; Humans; Mineralocorticoids; Receptors, Mineralocorticoid
PubMed: 30595119
DOI: 10.1161/HYPERTENSIONAHA.118.11604 -
Pharmacological Research Apr 2020Patients with uncontrolled hypertension are at risk for cardiovascular complications. The majority of them suffers from unidentified forms of hypertension and a fraction... (Review)
Review
Patients with uncontrolled hypertension are at risk for cardiovascular complications. The majority of them suffers from unidentified forms of hypertension and a fraction has so-called secondary hypertension with an identifiable cause. The patient's medications, its use of certain herbal supplements and over-the-counter agents represent potential causal factors for secondary hypertension that are often overlooked. The current review focuses on drugs that are likely to elevate blood pressure by affecting the human endocrine system at the level of steroid synthesis or metabolism, mineralocorticoid receptor activity, or by affecting the catecholaminergic system. Drugs with known adverse effects but where benefits outweigh their risks, drug candidates and market withdrawals are reviewed. Finally, potential therapeutic strategies are discussed.
Topics: Animals; Blood Pressure; Catecholamines; Drug-Related Side Effects and Adverse Reactions; Endocrine System; Humans; Hypertension; Mineralocorticoids
PubMed: 31212012
DOI: 10.1016/j.phrs.2019.104311 -
The Journal of Steroid Biochemistry and... Jun 2023The search for mineralocorticoids to explain some cases of low renin hypertension with suppressed aldosterone levels led to the isolation of the abundant steroid...
The search for mineralocorticoids to explain some cases of low renin hypertension with suppressed aldosterone levels led to the isolation of the abundant steroid 18-hydroxycortisol in human urine. 18-Hydroxycortisol proved to be inactive, but because of its similarity to precursors for the synthesis of aldosterone, bullfrog adrenals were incubated with cortisol, resulting in the discovery of 18-oxocortisol which is structurally similar to aldosterone, but with a 17α-hydroxy group like cortisol. 18-Oxocortisol is a weak mineralocorticoid. Its synthesis occurs primarily in the zona glomerulosa where co-expression of the CYP11B2 (aldosterone synthase) and the CYP17A1 (17α-hydroxylase) occurs in a variable number of cells. The clinical value of the measurement of 18-oxocortisol is that it serves to distinguish subtypes of primary aldosteronism. It is significantly elevated in patients with aldosterone-producing adenomas in comparison to those with idiopathic bilateral hyperaldosteronism and helps predict the type of somatic mutation in the aldosterone-producing adenomas, as it is higher in those with KCNJ5 mutations compared to other gene mutations.
Topics: Humans; Hydrocortisone; Aldosterone; Hyperaldosteronism; Mineralocorticoids; Cytochrome P-450 CYP11B2; Adenoma; G Protein-Coupled Inwardly-Rectifying Potassium Channels
PubMed: 36921907
DOI: 10.1016/j.jsbmb.2023.106291 -
American Journal of Physiology. Renal... Sep 2009Pharmacological and physiological phenomena suggest that cells somewhere inside the central nervous system are responsive to aldosterone. Here, we present the... (Review)
Review
Pharmacological and physiological phenomena suggest that cells somewhere inside the central nervous system are responsive to aldosterone. Here, we present the fundamental physiological limitations for aldosterone action in the brain, including its limited blood-brain barrier penetration and its substantial competition from glucocorticoids. Recently, a small group of neurons with unusual sensitivity to circulating aldosterone were identified in the nucleus of the solitary tract. We review the discovery and characterization of these neurons, which express the enzyme 11beta-hydroxysteroid dehydrogenase type 2, and consider alternative proposals regarding sites and mechanisms for mineralocorticoid action within the brain.
Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Aldosterone; Animals; Blood-Brain Barrier; Brain; Glucocorticoids; Humans; Mineralocorticoids; Neurons; Sodium; Solitary Nucleus
PubMed: 19261742
DOI: 10.1152/ajprenal.90399.2008 -
International Journal of Molecular... Aug 2022Systemic insulin resistance is characterized by reduced insulin metabolic signaling and glucose intolerance. Mineralocorticoid receptors (MRs), the principal receptors... (Review)
Review
Systemic insulin resistance is characterized by reduced insulin metabolic signaling and glucose intolerance. Mineralocorticoid receptors (MRs), the principal receptors for the hormone aldosterone, play an important role in regulating renal sodium handling and blood pressure. Recent studies suggest that MRs also exist in tissues outside the kidney, including vascular endothelial cells, smooth muscle cells, fibroblasts, perivascular adipose tissue, and immune cells. Risk factors, including excessive salt intake/salt sensitivity, hypertension, and obesity, can lead to the activation of vascular MRs to promote inflammation, oxidative stress, remodeling, and fibrosis, as well as cardiovascular stiffening and microcirculatory impairment. These pathophysiological changes are associated with a diminished ability of insulin to initiate appropriate intracellular signaling events, resulting in a reduced glucose uptake within the microcirculation and related vascular insulin resistance. Therefore, the pharmacological inhibition of MR activation provides a potential therapeutic option for improving vascular function, glucose uptake, and vascular insulin sensitivity. This review highlights recent experimental and clinical data that support the contribution of abnormal MR activation to the development of vascular insulin resistance and dysfunction.
Topics: Aldosterone; Blood Pressure; Endothelial Cells; Glucose; Humans; Insulin; Insulin Resistance; Microcirculation; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Receptors, Mineralocorticoid
PubMed: 36012219
DOI: 10.3390/ijms23168954 -
Environment International Dec 2019Endocrine-disrupting chemicals (EDCs) have received significant concern, since they ubiquitously exist in the environment and are able to induce adverse health effects... (Review)
Review
Endocrine-disrupting chemicals (EDCs) have received significant concern, since they ubiquitously exist in the environment and are able to induce adverse health effects on human and wildlife. Increasing evidence shows that the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), members of the steroid receptor subfamily, are potential targets for EDCs. GR and MR mediate the actions of glucocorticoids and mineralocorticoids, respectively, which are two main classes of corticosteroids involved in many physiological processes. The effects of EDCs on the homeostasis of these two classes of corticosteroids have also gained more attention recently. This review summarized the effects of environmental GR/MR ligands on receptor activity, and disruption of corticosteroid homeostasis. More than 130 chemicals classified into 7 main categories were reviewed, including metals, metalloids, pesticides, bisphenol analogues, flame retardants, other industrial chemicals and pharmaceuticals. The mechanisms by which EDCs interfere with GR/MR activity are primarily involved in ligand-receptor binding, nuclear translocation of the receptor complex, DNA-receptor binding, and changes in the expression of endogenous GR/MR genes. Besides directly interfering with receptors, enzyme-catalyzed synthesis and prereceptor regulation pathways of corticosteroids are also important targets for EDCs. The collected evidence suggests that corticosteroids and their receptors should be considered as potential targets for safety assessment of EDCs. The recognition of relevant xenobiotics and their underlying mechanisms of action is still a challenge in this emerging field of research.
Topics: Animals; Endocrine Disruptors; Environmental Pollutants; Glucocorticoids; Homeostasis; Humans; Receptors, Mineralocorticoid
PubMed: 31520960
DOI: 10.1016/j.envint.2019.105133 -
International Journal of Molecular... May 2021Sexual dimorphism involves differences between biological sexes that go beyond sexual characteristics. In mammals, differences between sexes have been demonstrated... (Review)
Review
Sexual dimorphism involves differences between biological sexes that go beyond sexual characteristics. In mammals, differences between sexes have been demonstrated regarding various biological processes, including blood pressure and predisposition to develop hypertension early in adulthood, which may rely on early events during development and in the neonatal period. Recent studies suggest that corticosteroid signaling pathways (comprising glucocorticoid and mineralocorticoid signaling pathways) have distinct tissue-specific expression and regulation during this specific temporal window in a sex-dependent manner, most notably in the kidney. This review outlines the evidence for a gender differential expression and activation of renal corticosteroid signaling pathways in the mammalian fetus and neonate, from mouse to human, that may favor mineralocorticoid signaling in females and glucocorticoid signaling in males. Determining the effects of such differences may shed light on short term and long term pathophysiological consequences, markedly for males.
Topics: Adrenal Cortex Hormones; Aldosterone; Animals; Blood Pressure; Gene Expression Regulation, Developmental; Glucocorticoids; Humans; Hypertension; Kidney; Mineralocorticoids; Organogenesis; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Sex Characteristics; Signal Transduction
PubMed: 34069759
DOI: 10.3390/ijms22105275 -
Nephron. Physiology 2014An increase in renal sodium chloride (salt) retention and an increase in sodium appetite are the body's responses to salt restriction or depletion in order to restore... (Review)
Review
An increase in renal sodium chloride (salt) retention and an increase in sodium appetite are the body's responses to salt restriction or depletion in order to restore salt balance. Renal salt retention and increased sodium appetite can also be maladaptive and sustain the pathophysiology in conditions like salt-sensitive hypertension and chronic heart failure. Here we review the central role of the mineralocorticoid aldosterone in both the increase in renal salt reabsorption and sodium appetite. We discuss the working hypothesis that aldosterone activates similar signaling and effector mechanisms in the kidney and brain, including the mineralocorticoid receptor, the serum- and glucocorticoid-induced kinase SGK1, the ubiquitin ligase NEDD4-2, and the epithelial sodium channel ENaC. The latter also mediates the gustatory salt sensing in the tongue, which is required for the manifestation of increased salt intake. Effects of aldosterone on both the brain and kidney synergize with the effects of angiotensin II. Thus, mineralocorticoids appear to induce similar molecular pathways in the kidney, brain, and possibly tongue, which could provide opportunities for more effective therapeutic interventions. Inhibition of renal salt reabsorption is compensated by stimulation of salt appetite and vice versa; targeting both mechanisms should be more effective. Inhibiting the arousal to consume salty food may improve a patient's compliance to reducing salt intake. While a better understanding of the molecular mechanisms is needed and will provide new therapeutic options, current pharmacological interventions that target both salt retention and sodium appetite include mineralocorticoid receptor antagonists and potentially inhibitors of angiotensin II and ENaC.
Topics: Aldosterone; Angiotensin II; Animals; Appetite; Blood Pressure; Epithelial Sodium Channels; Humans; Hypertension; Kidney; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Receptors, Mineralocorticoid; Signal Transduction; Sodium Chloride; Water-Electrolyte Balance
PubMed: 25376899
DOI: 10.1159/000368264 -
Hormone Research in Paediatrics 2018Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major... (Review)
Review
Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major branches of the steroidogenic machinery involved in the production of mineralocorticoids, glucocorticoids, and androgens. This mini review describes the principles of adrenal steroidogenesis, including the newly appreciated 11-oxygenated androgen pathway. This is followed by a description of pathophysiology, biochemistry, and clinical implications of steroidogenic disorders, including mutations affecting cholesterol import and steroid synthesis, the latter comprising both mutations affecting steroidogenic enzymes and co-factors required for efficient catalysis. A good understanding of adrenal steroidogenic pathways and their regulation is crucial as the basis for sound management of these disorders, which in the majority present in early childhood.
Topics: Adrenal Gland Diseases; Androgens; Cholesterol; Genetic Diseases, Inborn; Glucocorticoids; Humans; Mineralocorticoids; Mutation
PubMed: 29874650
DOI: 10.1159/000488034 -
Diabetologia Feb 2024The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart,... (Review)
Review
The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart, vasculature, adipose tissue and kidneys. The inhibition of the MR with classical MR antagonists (MRA) has successfully improved outcomes most evidently in heart failure. However, real and perceived risk of side effects and limited tolerability associated with classical MRA have represented barriers to implementing MRA in settings where they have been already proven efficacious (heart failure with reduced ejection fraction) and studying their potential role in settings where they might be beneficial but where risk of safety events is perceived to be higher (renal disease). Novel non-steroidal MRA have distinct properties that might translate into favourable clinical effects and better safety profiles as compared with MRA currently used in clinical practice. Randomised trials have shown benefits of non-steroidal MRA in a range of clinical contexts, including diabetic kidney disease, hypertension and heart failure. This review provides an overview of the literature on the systemic impact of MR overactivation across organ systems. Moreover, we summarise the evidence from preclinical studies and clinical trials that have set the stage for a potential new paradigm of MR antagonism.
Topics: Humans; Diabetic Nephropathies; Heart Failure; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Naphthyridines; Receptors, Mineralocorticoid
PubMed: 38127122
DOI: 10.1007/s00125-023-06031-1