Mineralocorticoid Hypertension Research Articles

Role of the median preoptic nucleus in the development of chronic DOCA-salt hypertension

Lesions of the anteroventral third ventricle (AV3V region) are known to prevent many forms of experimental hypertension, including mineralocorticoid (DOCA-salt) hypertension in the rat. However, AV3V lesions include the organum vasculosum of the lamina terminalis (OVLT), portions of the median preoptic nucleus (MnPO), as well as efferent fibers from the subfornical organ (SFO), thereby limiting the ability to define the individual contribution of these structures to the prevention of experimental hypertension. We have previously reported that the SFO does not contribute to the chronic hypertensive response to DOCA-salt in rats, and yet the OVLT plays a significant role in the development of DOCA-salt hypertension. Since efferent fibers of the OVLT project to and through the MnPO, the present study was designed to test the hypothesis that the MnPO is necessary for DOCA-salt hypertension in the rat. Male Sprague-Dawley rats underwent unilateral nephrectomy followed by a week of recovery, and subsequent SHAM (n=5) or electrolytic lesion of the MnPO (MnPOx; n=7). Throughout another week of recovery and during the experimental protocol, rats consumed a 2% NaCl diet and 0.9% NaCl drinking solution. 24-hour mean arterial pressure (MAP) was recorded telemetrically 5 days before and 21 days after DOCA implantation (100 mg/rat; SQ). No differences in the 5-day average control MAP were observed between groups (MnPOx: 104 ± 1 mmHg; SHAM: 107±2 mmHg). The chronic pressor response to DOCA was attenuated in MnPOx rats by day 11 of treatment and continued such that MAP increased 25±3 mmHg in SHAM rats by day 21 of DOCA compared to 14±3 mmHg in MnPOx rats. These results support the hypothesis that the MnPO is an important brain site of action for the pathogenesis of DOCA-salt hypertension in the rat. University of Minnesota Grant In Aid #546839 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Urinary extracellular vesicles carry valuable hints through mRNA for the understanding of endocrine hypertension.

Urinary extracellular vesicles (uEVs), released from cells of the urogenital tract organs, carry precious information about originating tissues. The study of molecules transported through uEVs such as proteins, lipids and nucleic acids provides a deeper understanding of the function of the kidney, an organ involved in the pathogenesis of hypertension and a target of hypertension-mediated organ damage. Molecules derived from uEVs are often proposed for the study of disease pathophysiology or as possible disease diagnostic and prognostic biomarkers. Analysis of mRNA loading within uEVs may be a unique and readily obtainable way to assess gene expression patterns of renal cells, otherwise achievable only by an invasive biopsy procedure. Interestingly, the only few studies investigating transcriptomics of hypertension-related genes through the analysis of mRNA from uEVs are inherent to mineralocorticoid hypertension. More specifically, it has been observed that perturbation in human endocrine signalling through mineralcorticoid receptors (MR) activation parallels changes of mRNA transcripts in urine supernatant. Furthermore, an increased copy number of uEVs-extracted mRNA transcripts of the 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene were detected among subjects affected by apparent mineralocorticoid excess (AME), a hypertension-inducing autosomal recessive disorder due to a defective enzyme function. Moreover, by studying uEVs mRNA, it was observed that the renal sodium chloride cotransporter (NCC) gene expression is modulated under different conditions related to hypertension. Following this perspective, we illustrate here the state of the art and the possible future of uEVs transcriptomics towards a deeper knowledge of hypertension pathophysiology and ultimately more tailored investigational, diagnostic-prognostic approaches.

Hypertension due to a deoxycorticosterone-secreting adrenal tumour diagnosed during pregnancy.

SummaryMineralocorticoid hypertension is most often caused by autonomous overproduction of aldosterone, but excess of other mineralocorticoid precursors can lead to a similar presentation. 11-Deoxycorticosterone (DOC) excess, which can occur in 11-β hydroxylase or 17-α hydroxylase deficiencies, in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. We report a 35-year-old woman who in the third trimester of pregnancy was found to have a large adrenal mass on routine obstetric ultrasound. On referral to our unit, persistent hypertension and long-standing hypokalaemia was noted, despite good compliance with multiple antihypertensives. Ten years earlier, she had hypertension noted in pregnancy which had persisted after delivery. A MRI scan confirmed the presence of a 12 cm adrenal mass and biochemistry revealed high levels of DOC and low/normal renin, aldosterone and dehydroepiandrosterone, with normal catecholamine levels. The patient was treated with antihypertensives until obstetric delivery, following which she underwent an adrenalectomy. Histology confirmed a large adrenal cortical neoplasm of uncertain malignant potential. Postoperatively, blood pressure and serum potassium normalised, and the antihypertensive medication was stopped. Over 10 years of follow-up, she remains asymptomatic with normal DOC measurements. This case should alert clinicians to the possibility of a diagnosis of a DOC-producing adrenal tumours in patients with adrenal nodules and apparent mineralocorticoid hypertension in the presence of low or normal levels of aldosterone. The associated diagnostic and management challenges are discussed.Learning points:Hypermineralocorticoidism is characterised by hypertension, volume expansion and hypokalaemic alkalosis and is most commonly due to overproduction of aldosterone. However, excess of other mineralocorticoid products, such as DOC, lead to the same syndrome but with normal or low aldosterone levels.The differential diagnosis of resistant hypertension with low renin and low/normal aldosterone includes congenital adrenal hyperplasia, syndrome of apparent mineralocorticoid excess, Cushing’s syndrome, Liddle’s syndrome and 11-deoxycorticosterone-producing tumours.DOC is one intermediate product in the mineralocorticoid synthesis with weaker activity than aldosterone. However, marked DOC excess seen in 11-β hydroxylase or 17-α hydroxylase deficiencies in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension.Excessive production of DOC in adrenocortical tumours has been attributed to reduced activity of the enzymes 11-β hydroxylase and 17-α hydroxylase and increased activity of 21-α hydroxylase.The diagnosis of DOC-producing adrenal tumours is challenging because of its rarity and poor availability of DOC laboratory assays.

MECHANISMS IN ENDOCRINOLOGY: Rare defects in adrenal steroidogenesis.

Congenital adrenal hyperplasia (CAH) is a group of genetic disorders of adrenal steroidogenesis that impair cortisol synthesis, with compensatory increases in ACTH leading to hyperplastic adrenals. The term 'CAH' is generally used to mean 'steroid 21-hydroxylase deficiency' (21OHD) as 21OHD accounts for about 95% of CAH in most populations; the incidences of the rare forms of CAH vary with ethnicity and geography. These forms of CAH are easily understood on the basis of the biochemistry of steroidogenesis. Defects in the steroidogenic acute regulatory protein, StAR, disrupt all steroidogenesis and are the second-most common form of CAH in Japan and Korea; very rare defects in the cholesterol side-chain cleavage enzyme, P450scc, are clinically indistinguishable from StAR defects. Defects in 3β-hydroxysteroid dehydrogenase, which also causes disordered sexual development, were once thought to be fairly common, but genetic analyses show that steroid measurements are generally unreliable for this disorder. Defects in 17-hydroxylase/17,20-lyase ablate synthesis of sex steroids and also cause mineralocorticoid hypertension; these are common in Brazil and in China. Isolated 17,20-lyase deficiency can be caused by rare mutations in at least three different proteins. P450 oxidoreductase (POR) is a co-factor used by 21-hydroxylase, 17-hydroxylase/17,20-lyase and aromatase; various POR defects, found in different populations, affect these enzymes differently. 11-Hydroxylase deficiency is the second-most common form of CAH in European populations but the retention of aldosterone synthesis distinguishes it from 21OHD. Aldosterone synthase deficiency is a rare salt-losing disorder. Mild, 'non-classic' defects in all of these factors have been described. Both the severe and non-classic disorders can be treated if recognized.

Mineralocorticoid hypertension and hypokalaemia induced by posaconazole.

SummaryWe describe severe hypokalaemia and hypertension due to a mineralocorticoid effect in a patient with myelodysplastic syndrome taking posaconazole as antifungal prophylaxis. Two distinct mechanisms due to posaconazole are identified: inhibition of 11β hydroxylase leading to the accumulation of the mineralocorticoid hormone 11-deoxycorticosterone (DOC) and secondly, inhibition of 11β hydroxysteroid dehydrogenase type 2 (11βHSD2), as demonstrated by an elevated serum cortisol-to-cortisone ratio. The effects were ameliorated by spironolactone. We also suggest that posaconazole may cause cortisol insufficiency. Patients taking posaconazole should therefore be monitored for hypokalaemia, hypertension and symptoms of hypocortisolaemia, at the onset of treatment and on a monthly basis. Treatment with mineralocorticoid antagonists (spironolactone or eplerenone), supplementation of glucocorticoids (e.g. hydrocortisone) or dose reduction or cessation of posaconazole should all be considered as management strategies.Learning points:Combined hypertension and hypokalaemia are suggestive of mineralocorticoid excess; further investigation is appropriate.If serum aldosterone is suppressed, then further investigation to assess for an alternative mineralocorticoid is appropriate, potentially using urine steroid profiling and/or serum steroid panelling.Posaconazole can cause both hypokalaemia and hypertension, and we propose that this is due to two mechanisms – both 11β hydroxylase inhibition and 11β HSD2 inhibition.Posaconazole treatment may lead to cortisol insufficiency, which may require treatment; however, in this clinical case, the effect was mild.First-line treatment of this presentation would likely be use of a mineralocorticoid antagonist.Patients taking posaconazole should be monitored for hypertension and hypokalaemia on initiation and monthly thereafter.

17α-Hydroxylase Deficiency is an Underdiagnosed Disease: High Frequency of Misdiagnoses in a Large Cohort of Brazilian Patients

17α-Hydroxylase deficiency (P450c17D) is characterized by hypogonadism and mineralocorticoid hypertension. We aimed to estimate the relative incidence and spectrum of preliminary misdiagnoses in Brazilian P450c17D patients. In this cross-sectional study, we reviewed, updated, and analyzed data of 40 P450c17D patients (21 XY, 19 XX). Complete data were unavailable for 2 patients. Seven patients were relatives of an index case. Of the 31 index cases, 29 (94%) received a total of 16 misdiagnoses (1-4 per patient) before confirmation of P450c17D. Essential hypertension (55%), pure gonadal dysgenesis (35%), and androgen resistance syndrome (21%) were the most frequent misdiagnoses. Median ages at initial and final diagnosis were 13.2 and 16.5 years, respectively, with an average interval to diagnosis of 3.2 years. Initially, 38 (95%) patients had hypertension, and 75% had hypokalemia. Primary amenorrhea and sexual infantilism were present in 95% patients, and 73% were at Tanner stage I. All had low-to-undetectable estrogens and androgens with elevated gonadotropins and progesterone (580 ± 53 ng/dL). Several had recurrent infections in childhood and neurological issues prior to final diagnosis and/or had siblings who died of infectious diseases or unknown causes before puberty. The high percentage of prior misdiagnoses in P450c17D patients may be attributable to the rarity of and relative unfamiliarity with the disease, its varied clinical presentation, and the limited access to critical steroid dosages and genotyping. Reduced sex steroids, and elevated gonadotropins and progesterone levels, in addition to mineralocorticoid hypertension, are pathognomonic of P450c17D. CYP17A1 gene mutations provide a definitive diagnosis. ACTH = adrenocorticotropic hormone CAH = congenital adrenal hyperplasia CYP17A1 = 17α-hydroxylase enzyme DOC = deoxycorticosterone HH = hypergonadotropic hypogonadism P450c17D = 17α-hydroxylase deficiency TS = Tanner stage.

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor mutations.

Aldosterone and the mineralocorticoid receptor (MR) are key elements for maintaining fluid and electrolyte homeostasis as well as regulation of blood pressure. Loss-of-function mutations of the MR are responsible for renal pseudohypoaldosteronism type 1 (PHA1), a rare disease of mineralocorticoid resistance presenting in the newborn with weight loss, failure to thrive, vomiting and dehydration, associated with hyperkalemia and metabolic acidosis, despite extremely elevated levels of plasma renin and aldosterone. In contrast, a MR gain-of-function mutation has been associated with a familial form of inherited mineralocorticoid hypertension exacerbated by pregnancy. In addition to rare variants, frequent functional single nucleotide polymorphisms of the MR are associated with salt sensitivity, blood pressure, stress response and depression in the general population. This review will summarize our knowledge on MR mutations in PHA1, reporting our experience on the genetic diagnosis in a large number of patients performed in the last 10 years at a national reference center for the disease. We will also discuss the influence of rare MR variants on blood pressure and salt sensitivity as well as on stress and cognitive functions in the general population.

Type A Aortic Dissection, Apparent Mineralocorticoid Excess Syndrome, and Syndromic Aortic Root Dilatation

ABSTRACT Objective: To determine the cause of acute life-threatening aortic root dissection in a 36-year-old male with a long-standing history of apparent mineralocorticoid excess (AME) and hypertension since childhood. Methods: Cortisol metabolites were analyzed by urine tandem mass spectrometry. Screening for DNA variants was performed using the Marfan Syndrome and Related Aortopathies NextGen Sequencing Panel (Collagen Diagnostic Laboratory, University of Washington, Seattle). Cytogenetic microarray analysis (CombiMatrix, CA) was performed. Sequencing of the 11β-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) in a region of homozygosity (ROH) identified on microarray analysis was targeted using Sanger sequencing (Prevention Genetics) on an ABI 3730x1 capillary sequencer. Results: There was reduced urinary excretion of all 11-carboxyl containing steroids and high excretion of free cortisol and its metabolites, consistent with a diagnosis of AME. Microarray analysis revealed 4 ROHs. One ROH contained ...

Citosine-Adenine-Repeat Microsatellite of 11β-hydroxysteroid dehydrogenase 2 Gene in Hypertensive Children.

The impairment of 11β-hydroxysteroid dehydrogenase type 2 enzyme (11βHSD2) results in an inefficient conversion of cortisol to cortisone, which triggers hypertension. Cytosine-adenine repeat (CA repeat) microsatellite has been associated with low HSD11B2 gene expression. To determine whether the CA-repeat length in intron 1 affect the serum cortisol to cortisone (F/E) ratio and/or blood pressure (BP) levels in pediatric subjects. Eighty-one hypertensive (HT) and 117 normotensive (NT) subjects participated in this study. We measured BP levels, as well as the F and E and F/E ratio in morning sera and 12-hour urine samples. The length of CA repeats was determined through fragment analysis. We compared the allele distribution between the HT and NT groups, and the patients were dichotomized into groups with short alleles (S) (<21 CA repeats) or long alleles (L), and also in groups according genotype (allele combination: S/S and S/L + L/L). We found no differences in the distribution of CA-repeat allelic length between the NT and HT groups (P = 0.7807), and there was no correlation between the CA-repeat allelic length and BP (P = 0.1151) levels or the serum F/E ratio (P = 0.6778). However, the serum F/E ratio was higher in the HT group than in the NT group (P = 0.0251). The serum F/E ratio was associated with systolic BP index independent of body mass index only in HT group. The CA-repeat length did not influence BP levels or serum F/E ratios in pediatric subjects. However, the serum F/E ratio was associated with BP, suggesting a role of 11βHSD2 in mineralocorticoid hypertension.

RESISTANT HYPERTЕNSION PATIENT WITH PRIMARY ALDOSTERONISM

Mineralocorticoid hypertension, including Conn's syndrome, occurs significantly more frequently than is recognized. Despite modern diagnostic capabilities and the availability of treatment methods, it cannot be diagnosed simply because (they) know little about it. Recall clinico-pathological variants of mineralocorticoid hypertension and the peculiarities of their management. Here is a fairly typical clinical case Conn's syndrome, recognized for many years later than it needed to be done. Pay attention to the fact that mineralocorticoid hypertension should be considered in patients with resistant nature of the response to treatment.

Why isn't endogenous ouabain more widely accepted?

A new idea is the most quickly acting antigen known to science . —Wilfred Trotter During the past few years, several distinguished senior colleagues who visited our department and inquired about the status of endogenous ouabain (EO) have asked, “How come I didn't know about these [published]

Abstract 83: Differential inhibitory effects of galeterone, abiraterone, orteronel and ketoconazole on CYP17A1 and steroidogenesis.

Abstract Prostate cancer growth is dependent on androgens. Because the CYP17A1 enzyme plays a central role in converting progestogens to androgens, inhibitors of CYP17A1 have been developed to treat castration-resistant prostate cancer (CRPC). CYP17A1 has both hydroxylase and lyase catalytic functions. However, hydroxylase inhibition causes build-up of progestogens and mineralocorticoids while also reducing cortisol. This syndrome, referred to secondary mineralocorticoid excess, causes edema, hypokalemia and hypertension and is treated clinically with concomitant steroids. We analyzed four inhibitors for their effects on CYP17A1 hydroxylase and lyase activities, and more globally on the steroidogenic pathway. Human CYP17A1 expressed in yeast microsomes was incubated with pregnenolone or 17α-hydroxypregnenolone and products quantitated using LC/MS/MS. Galeterone, abiraterone, orteronel or ketoconazole were added, and hydroxylase or lyase IC50 values calculated. In a separate experiment, H295R human adrenocortical carcinoma cells were incubated with a range of drug concentrations between 0.316 nM and 10 μM for 24 hours and media was analyzed for steroid production by LC/MS/MS. We observed that all drugs inhibited CYP17A1. However, potency and selectivity for hydroxylase and lyase varied significantly. Galeterone was the most potent CYP17A1 lyase inhibitor that also exhibited selectivity (3x more selective for lyase than hydroxylase). In contrast, abiraterone most selectively inhibited CYP17A1 hydroxylase (by 1.7-fold), while orteronel and ketoconazole were less potent lyase inhibitors than galeterone. In the cell-based assay, all drugs at 1 μM inhibited testosterone synthesis by ≥94%. However, while galeterone produced only moderate changes in cortisol (decreased 14%) and other intermediate precursors, evidence of hydroxylase inhibition for the other inhibitors was supported by significant elevation of progesterone (increased 293-fold by abiraterone), mineralocorticoids (orteronel increased DOC 74-fold), or reductions in cortisol (abiraterone, orteronel, ketoconazole reduced by 91%, 70% and 94%, respectively). Steroid changes across a range of drug concentrations from 0.316 nM to 10 μM showed evidence of different potencies for CYP17 hydroxylase and lyase, as well as potential off-target effects on other enzymes in the steroidogenic pathway. In summary, we found that galeterone is a selective and potent CYP17A1 lyase inhibitor that also antagonizes and degrades the AR, and exhibits minimal evidence of deleterious steroid changes associated with secondary mineralocorticoid excess. These experimental data recapitulate the Phase 1 clinical experience where no mineralocorticoid excess was observed, or prednisone required in CRPC patients receiving galeterone therapy. ARMOR2, a phase 2 clinical study in CRPC, is being initiated in 2012. Citation Format: Douglas Jacoby, Martin Williams. Differential inhibitory effects of galeterone, abiraterone, orteronel and ketoconazole on CYP17A1 and steroidogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 83. doi:10.1158/1538-7445.AM2013-83

A rare cause of hypertension in a healthy 2-year-old female: Answers

This patient has 17α-hydroxylase deficiency, a rare form of congenital adrenal hyperplasia (CAH) and one of the rarer forms of monogenic hypertension. This autosomal recessive disorder results from a complete or partial deficiency of the P450c17 enzyme, which has both 17α-hydroxylase and 17,20-lyase activity (see Fig. 1) [1]. The enzymatic defect leads to impaired formation of cortisol and sex hormones, with retained functioning of the mineralocorticoid pathway. The first case of 17α-hydroxylase deficiency was reported in 1966 by Biglieri, who described a 35-year-old woman who was hypertensive and hypokalemic and had not entered puberty [2]. Since that time, more than 200 cases have been reported in the literature [3]. Overall, 17α-hydroxylase deficiency constitutes approximately 1 % of CAH cases [4]. It has been more commonly identified in certain ethnic populations, including Brazilians and Japanese [5, 6]. As in other forms of CAH, cortisol deficiency stimulates adrenocorticotropic hormone (ACTH) production, ultimately resulting in adrenal gland hyperplasia. In 17αhydroxylase deficiency, this leads to an accumulation of deoxycorticosterone (DOC) and corticosterone (see Fig. 1). In this patient, DOC was elevated at 116 ng/dL (normal range 2–34 ng/dL) and corticosterone was also elevated at 14,948 ng/dL (normal range 135–1860 ng/dL). Hypertension, hypokalemia and metabolic alkalosis result from elevated DOC, which has mineralocorticoid activity. The extent of hypertension may vary significantly in this condition. In one of the larger cohorts described, average blood pressure prior to treatment was 146/100 mmHg at a median age of 18 years [5]. Malignant hypertension may also be seen [7]. Interestingly, 17α-hydroxylase deficiency does not present with adrenal crisis despite the lack of cortisol, as the elevated corticosterone provides sufficient glucocorticoid activity. Although one might anticipate that these patients would have elevated aldosterone levels, the opposite is typically true. 17-α-Hydroxylase deficiency causes a non-aldosterone mineralocorticoid hypertension, also known as pseudoaldosteronism. In this condition, high levels of DOC cause volume expansion, leading to suppression of the renin– angiotensin system and subsequent low levels of renin and aldosterone [8]. It is important to note that hypokalemia is not consistently observed, as demonstrated in this case and previously documented in the literature [5]. Thus, a normal serum potassium should not sway one from considering the diagnosis. As with This article refers to the article that can be found at http://dx.doi.org/ 10.1007/s00467-012-2161-5.

Secondary Hypertension Caused by Endocrine Disorders Except Primary Aldosteronism and Pheochromocytoma

Secondary hypertension can account for 15% of hypertension cases. The causes of secondary hypertension mostly come from renal diseases, such as renal parenchymal or renovascular disease, and endocrine diseases. The importance of diagnosing secondary hypertension lies in the fact that it may convert an incurable disease into a potentially curable disease. Even if the underlying disease may not be curable, being able to offer disease specific treatments may often make blood pressure control much easier. The causes of endocrine hypertension include primary aldosteronism, pheochromocytoma, Cushing`s syndrome, acromegaly, hyper- or hypothyroidism, hyperparathyroidism and other mineralocorticoid hypertension (e.g. apparent mineralocorticoid excess syndrome, Liddle`s syndrome). Primary aldosteronsim, pheochromocytoma, and Cushing`s syndrome are among the common causes of endocrine hypertension. The first step in evaluating a patient with suspected endocrine-related hypertension is to exclude other secondary causes, particularly renal disorders. An accurate diagnosis of endocrine hypertension provides the clinician a unique treatment opportunity. This topic review will summarize rare causes of endocrine hypertension except primary aldosteronism and pheochromocytoma. (Korean J Med 2012;82:411-416)

Vascular Remodeling in Hypertension

Over the past few years noninvasive and invasive techniques have allowed a better appreciation of vascular changes in hypertensive humans and experimental animals.1 Large arteries undergo outward hypertrophic remodeling and increased stiffness with aging,2–4 and in hypertension there may be an acceleration of this process leading to enhanced pulse pressure. A reduced aortic diameter in middle-aged hypertensive subjects may also play a role in increases in pulse pressure through increased specific impedance,5 contradicting the classic hypertensive aortic phenotype characterized by vascular wall degeneration and calcification and increased aortic diameter. In advanced hypertension, however, the elastic laminae undergo duplication and fragmentation, with increased deposition of collagen and fetal (EIIIA) fibronectin, contributing to increased stiffness. Classically the remodeling of small arteries in hypertension has been associated with increased media thickness, but recent studies have demonstrated that 2 types of remodeling are found, inward eutrophic or inward hypertrophic remodeling, depending on whether the media cross-sectional area is enlarged (true hypertrophy).6–9 Although eutrophic remodeling is usually found in essential (primary) hypertension in humans and spontaneously hypertensive rats (SHRs); in secondary hypertension such as in renovascular hypertension, primary aldosteronism, or in pheochromocytoma10; in hypertension associated with diabetes mellitus11,12; and in acromegaly,13 hypertrophic remodeling has been described. In mineralocorticoid hypertension in rodents14,15 and in salt-sensitive Dahl rats,16 in both of which the endothelin (ET) system is activated, remodeling of small arteries is also hypertrophic (see below). Thus, when the renin-angiotensin system is even mildly activated (primary hypertension and SHRs), remodeling is usually eutrophic. In salt-dependent hypertension, diabetes mellitus, and malignant hypertension, all conditions in which the ET system is activated, remodeling is hypertrophic.17 Hyperplasia of vascular smooth muscle cells (VSMCs) is found in small arteries of …

Relative contributions of mitochondria and NADPH oxidase to deoxycorticosterone acetate-salt hypertension in mice

We assessed the relative contribution of the mitochondrial respiratory chain and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase to deoxycorticosterone acetate (DOCA)-salt hypertension in mice. The daily mean arterial pressure was monitored by radiotelemetry in DOCA-salt-treated mice given vehicle or the mitochondrial respiratory chain complex I inhibitor rotenone. This treatment produced remarkable attenuation of DOCA-salt hypertension. Similar results were obtained with other inhibitors of mitochondrial function, including 5-hydroxydecanoate (specific for mitochondrial potassium-ATP channels), benzylguanidine (complexes I and III), and the cell-permeable manganese tetrakis (4-benzoic acid) porphyrin (a mimic of mitochondrial superoxide dismutase). In parallel with the blood pressure-lowering effect of rotenone, the DOCA-salt-induced increases in urinary 8-isoprostane excretion and in reactive oxygen species production of isolated kidney mitochondria were both significantly attenuated. Conversely, the DOCA-salt-induced reduction of urinary nitrate/nitrite excretion was significantly elevated. Following DOCA-salt treatment, mice deficient in NADPH oxidase subunits gp91(phox) or p47(phox) exhibited a partial attenuation of the hypertensive response at early but not later time points. Thus, the mitochondrial respiratory chain is a major source of oxidative stress in DOCA-salt hypertension, whereas NADPH oxidase may have a relatively minor role during the early stage of hypertension.

Inherited forms of mineralocorticoid hypertension

Inherited forms of mineralocorticoid hypertension are a group of monogenic disorders that, although rare, have enlightened our understanding of normal physiology, and subsequent processes implicated in the pathogenesis of 'essential' hypertension. They often present in early life and can be a cause of major morbidity and mortality that can be effectively treated with simple but targeted pharmacological therapy. Interestingly, all the conditions centre on the regulation of sodium transport through its epithelial channel, either directly or through mediators that act via the mineralocorticoid receptor. In recent years, molecular mechanisms of these conditions and their functional consequences have been elucidated. Diagnosis has been facilitated by plasma and urinary biomarkers. We provide an overview and diagnostic approach to apparent mineralocorticoid excess, glucocorticoid remediable aldosteronism, familial hyperaldosteronism type 2, Liddle's syndrome, Gordon's syndrome, activating mutations of the mineralocorticoid receptor, generalized glucocorticoid resistance and hypertensive forms of congenital adrenal hyperplasia.

Extracellular Signal–Regulated Kinase 1/2 Activation, via Downregulation of Mitogen-Activated Protein Kinase Phosphatase 1, Mediates Sex Differences in Desoxycorticosterone Acetate-Salt Hypertension Vascular Reactivity

Extracellular signal–regulated kinase (ERK)1/2 has been reported to play a role in vascular dysfunction associated with mineralocorticoid hypertension. We hypothesized that, compared with female rats, an upregulation of ERK1/2 signaling in the vasculature of male rats contributes to augmented contractile responses in mineralocorticoid hypertension. Uninephrectomized male and female Sprague-Dawley rats received desoxycorticosterone acetate (DOCA) pellets (200 mg per animal) and saline to drink for 3 weeks. Control uninephrectomized rats received tap water to drink. Blood pressure, measured by telemetry, was significantly higher in male DOCA rats (191±3 mm Hg) compared with female DOCA rats (172±7 mm Hg; n=5). DOCA treatment resulted in augmented contractile responses to phenylephrine in aorta (22±3 mN; n=6) and small mesenteric arteries (13±2 mN; n=6) from male DOCA rats versus uninephrectomized male rats (16±3 and 10±2 mN, respectively; P &lt;0.05) and female DOCA rats (15±1 and 11±1 mN, respectively). ERK1/2 inhibition with PD-98059 (10 μmol/L) abrogated increased contraction to phenylephrine in aorta (14±2 mN) and small mesenteric arteries (10±2 mN) from male DOCA rats, without any effects in arteries from male uninephrectomized or female animals. Compared with the other groups, phosphorylated ERK1/2 levels were increased in the aorta from male DOCA rats, whereas mitogen-activated protein kinase phosphatase 1 expression was decreased. Interleukin-10 plasma levels, which positively regulate mitogen-activated protein kinase phosphatase 1 activity, were reduced in male DOCA-salt rats. We speculate that augmented vascular reactivity in male hypertensive rats is mediated via activation of the ERK1/2 pathway. In addition, mitogen-activated protein kinase phosphatase 1 and interleukin 10 play regulatory roles in this process.

The role of aldosterone in mediating the dependence of angiotensin hypertension on IL-6

Knockout (KO) of IL-6 has been shown to attenuate ANG II hypertension, and mineralocorticoid receptors (MR) have been reported to contribute to the increase in IL-6 during acute ANG II infusion. This study determined whether that MR action is sustained with chronic ANG II infusion and whether it plays a role in mediating ANG II hypertension. ANG II infusion (90 ng/min) increased plasma IL-6 from 1.6 +/- 0.6 to 22.7 +/- 2.2 and 19.9 +/- 3.2 pg/ml on days 7 and 14, respectively, and chronic MR blockade with spironolactone attenuated that only at day 7 (7.2 +/- 2.2 pg/ml). ANG II increased MAP (19 h/day with telemetry) approximately 40 mmHg, but in ANG II+spironolactone mice (25 or 50 mg*kg(-1)*day(-1)), mean arterial pressure (MAP) was not significantly different despite a tendency for lower pressure the first 6 days. To isolate further the mineralocorticoid link to IL-6 and blood pressure, DOCA-salt hypertension was induced in IL-6 KO and wild-type (WT) mice. Plasma IL-6 increased from 4.1 +/- 1.7 to 34.5 +/- 7.0 pg/ml by day 7 of DOCA treatment in the WT mice but was back to control levels by day 14. An IL-6 bioassay using the murine B9, B-cell hybridoma cell line demonstrated that plasma IL-6 measurements reflected actual IL-6 bioactivity. The hypertension was not different and virtually superimposable in WT vs. IL-6 KO mice, averaging 145 +/- 2 and 144 +/- 3 mmHg, respectively. Both experiments confirm chronic stimulation of IL-6 by mineralocorticoids but show that it is transient. In addition, IL-6 was not required for mineralocorticoid hypertension. This suggests that aldosterone contributes to the increase in plasma IL-6 in the early stage of ANG II hypertension but that the blood pressure actions of IL-6 in that model are linked most likely to ANG II rather than aldosterone.

DOCA‐salt hypertensive rats display decreased vascular reactivity to urotensin‐II

IntroductionUrotensin‐II (U‐II) is a vasoconstrictor peptide and its potency can be up to 100 fold greater than that of endothelin‐1 (ET‐1). ET‐1 plays a major role in the vascular changes associated with salt‐sensitive hypertension, but the effects of U‐II in arteries from these animals have not yet been defined.ObjectiveWe hypothesized that DOCA‐salt rats have increased vascular reactivity to U‐II.Methods and ResultsWistar rats were unilaterally nephrectomyzed and deoxycorticosterone‐acetate (DOCA) (200mg/Kg) pellets were implanted. DOCA rats received water containing 1% NaCl/0.2% KCl, for 5 weeks. Aortic rings were mounted in myograph chambers and functional studies were performed. DOCA rats displayed increased systolic pressure (Control: 117±1 vs DOCA: 179±3; mmHg). Maximal contractions (mN) to U‐II were decreased in endothelium‐intact (Control: 16.6±1 vs DOCA: 8.8±1) and endothelium‐denuded (Control: 21.3±1.1 vs DOCA: 10.4±0.9) aortas from DOCA rats. This difference was abolished in endothelium‐intact vessels incubated with 10−5M urantide (U‐II antagonist) (Control: 13.5±0.9 vs DOCA: 12.7±0.9).ConclusionOur results suggest that U‐II production/release is augmented in mineralocorticoid hypertension and that decreased vascular reactivity to the peptide may represent counter‐regulatory mechanisms that limit additional vascular damage to this potent vasoconstrictor.