Classic and Nonclassic Apparent Mineralocorticoid Excess Syndrome

Abstract Context Arterial hypertension (AHT) is one of the most frequent pathologies in the general population. Subtypes of essential hypertension characterized by low renin levels allowed the identification of 2 different clinical entities: aldosterone-mediated mineralocorticoid receptor (MR) activation and cortisol-mediated MR activation. Evidence Acquisition This review is based upon a search of Pubmed and Google Scholar databases, up to August 2019, for all publications relating to endocrine hypertension, apparent mineralocorticoid excess (AME) and cortisol (F) to cortisone (E) metabolism. Evidence Synthesis The spectrum of cortisol-mediated MR activation includes the classic AME syndrome to milder (nonclassic) forms of AME, the latter with a much higher prevalence (7.1%) than classic AME but different phenotype and genotype. Nonclassic AME (NC-AME) is mainly related to partial 11βHSD2 deficiency associated with genetic variations and epigenetic modifications (first hit) and potential additive actions of endogenous or exogenous inhibitors (ie, glycyrrhetinic acid-like factors [GALFS]) and other factors (ie, age, high sodium intake) (second hit). Subjects with NC-AME are characterized by a high F/E ratio, low E levels, normal to elevated blood pressure, low plasma renin and increased urinary potassium excretion. NC-AME condition should benefit from low-sodium and potassium diet recommendations and monotherapy with MR antagonists. Conclusion NC-AME has a higher prevalence and a milder phenotypical spectrum than AME. NC-AME etiology is associated to a first hit (gene and epigene level) and an additive second hit. NC-AME subjects are candidates to be treated with MR antagonists aimed to improve blood pressure, end-organ damage, and modulate the renin levels.

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Effects of Nifedipine during Low, Normal and High Intakes of Sodium in Patients with Essential Hypertension

Clinical Science ◽

10.1042/cs063447s ◽

1982 ◽

Vol 63 (s8) ◽

pp. 447s-450s ◽

Cited By ~ 9

Author(s):

Gloria Valdés ◽

M. Eugenia Soto ◽

Hector R. Croxatto ◽

Teresa Bellolio ◽

Ramón Corbalán ◽

...

Keyword(s):

Blood Pressure ◽

Essential Hypertension ◽

Sodium Intake ◽

Plasma Renin ◽

Hypotensive Effect ◽

Sodium Balance ◽

Hypotensive Action ◽

High Sodium ◽

High Sodium Intake ◽

Low Sodium Diet

1. Nifedipine (20 mg) was given by mouth to seven patients with moderate essential hypertension receiving a low, normal or high sodium intake. The drug produced an important hypotensive effect. Normal sodium intake enhanced the hypotensive action of the drug compared with that during the low and high sodium regimens. Blood pressure remained significantly lower 3 h after drug ingestion. 2. Increases in heart rate and plasma renin activity under all conditions reflected enhanced adrenergic activity. 3. A short-term natriuresis followed nifedipine ingestion in spite of increased aldosterone excretion during the low sodium diet and a decrease in urinary kallikrein during the low and high sodium diets. 4. Nifedipine increased urinary volume only during the high sodium intake. 5. Apart from vasodilatation, nifedipine induces important changes in neurogenic, renal and adrenal mechanisms that regulate blood pressure homoeostasis. Different conditions of sodium balance modulate most of these effects.

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Új szempontok a sószenzitív hypertoniák patomechanizmusában

Orvosi Hetilap ◽

10.1556/650.2019.31308 ◽

2019 ◽

Vol 160 (2) ◽

pp. 43-49

Author(s):

Endre Sulyok

Keyword(s):

Blood Pressure ◽

Extracellular Space ◽

Salt Intake ◽

Sodium Intake ◽

Organ Damage ◽

Blood Pressure Elevation ◽

High Sodium ◽

End Organ Damage ◽

Inactive Form ◽

Factor C

Abstract: This article shortly outlines the evolution of hypertonia from risk factors to end-organ damage. The pathogenetic role of salt intake is underlined and in the light of recent clinical and experimental observations, the importance of renal and extrarenal mechanism in the development of salt-sensitive hypertension is analysed. The generally accepted concept that the inefficient renal sodium excretion and the subsequent expansion of the extracellular space is the major factor in blood pressure elevation is challenged. Evidences have been provided that the retained sodium dissociates from the volume of extracellular space and, also from the blood pressure. It has been shown that the negatively charged macromolecules in the subcutaneous interstitium bind sodium ions in osmotically inactive form and store sodium reversibly. The local tissue hypertonicity induces monocytes/macrophages invasion and activation that causes increased expression of tonicity-responsive enhancer binding protein (TonEBP) and the secretion of vascular endothelial growth factor C that result in enhanced lymphangiogenesis. The expanded lymphatic system drains the excess sodium and volume back to the circulation. The reduction of buffer function of this system may contribute to the development or to worsening of hypertension. Similar buffer and barrier functions are attributed to the glycocalyx that covers the luminal surface of vascular endothelium. It is also recognised that the high sodium intake alone is an important pathogenetic factor in end-organ damage independent of hypertension. This may be accounted for by the induction and activation of Th17 cells as well as by the increased production of several pro-inflammatory and pro-fibrotic cytokines. Orv Hetil. 2019; 160(2): 43–49.

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MINERALOCORTICOID EXCESS IN TWO BROTHERS WITH DWARFISM, HYPOKALAEMIC ALKALOSIS AND NORMAL BLOOD PRESSURE

Acta Endocrinologica ◽

10.1530/acta.0.0550661 ◽

1967 ◽

Vol 55 (4) ◽

pp. 661-672 ◽

Cited By ~ 9

Author(s):

H. K. A. Visser ◽

H. J. Degenhart ◽

E. Desmit ◽

W. S. Cost

Keyword(s):

Blood Pressure ◽

Sodium Intake ◽

Plasma Renin ◽

High Plasma ◽

Normal Blood ◽

Normal Blood Pressure ◽

Primary Defect ◽

High Sodium ◽

Regular Control ◽

Renal Tubular

ABSTRACT Using isotope dilution methods the secretion rates of cortisol, aldosterone, deoxycorticosterone, corticosterone and 18-hydroxycorticosterone were determined in two brothers (76/12 and 108/12 years old) with dwarfism, chronic hypokalaemia alkalosis, tendency to hyponatraemia and normal blood pressure. Both patients showed a decreased response of the blood pressure to infused angiotensin. The urinary excretion of cortisol, cortisone, corticosterone, 11-dehydrocorticosterone and their tetrahydrometabolites as well as of aldosterone was determined. In general, results were in agreement with those of the secretion rate studies. The results suggest a relatively small mineralocorticoid excess (mainly corticosterone) to high plasma-renin concentrations. The differences in both the plasma-renin concentrations and the steroid secretory rates during low and high sodium intake indicate that the renin-angiotensin-mineralocorticoid system is still under regular control, although the normal regulatory process is severely disturbed. The primary defect in these patients is probably not a relative insensitivity of the arterial walls to the pressor effect of angiotensin as suggested by Bartter et al. (1962), but rather a renal tubular defect in the re-absorption of sodium.

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Effect of linoleic acid infusion on blood pressure in normotensive and hypertensive rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1989.257.2.h611 ◽

1989 ◽

Vol 257 (2) ◽

pp. H611-H617 ◽

Cited By ~ 1

Author(s):

S. R. Reddy ◽

R. Talwalkar ◽

J. Downs ◽

T. A. Kotchen

Keyword(s):

Blood Pressure ◽

Linoleic Acid ◽

Sodium Chloride ◽

Enzymatic Activity ◽

Plasma Renin ◽

Sprague Dawley ◽

Acid Infusion ◽

High Sodium ◽

Hypotensive Response

High dietary intake of linoleic acid lowers arterial pressure, and, in vitro, linoleic acid inhibits the enzymatic activity of renin. The purpose of the present study was 1) to evaluate the effect of intravenous infusion of linoleic acid on blood pressure in normotensive and hypertensive Sprague-Dawley rats and 2) to determine whether the hypotensive response to linoleic acid infusion is caused by inhibition of circulating renin. Blood pressure was decreased (P less than 0.01) by linoleic acid infusion in normotensive sodium chloride-deprived animals and in animals with two-kidney, one-clip hypertension. In contrast, linoleic acid infusion did not affect blood pressure in normotensive rats on a "normal" or high sodium chloride intake, in rats with deoxycorticosterone acetate (DOCA)-salt hypertension, and in anephric rats. In sodium chloride-deprived rats, the reduction of blood pressure by linoleic acid infusion was associated with increased plasma renin activity (P less than 0.05); serum angiotensin-converting enzyme activity was unchanged. The in vitro enzymatic activity of exogenous renin in plasma of anephric rats was not affected by linoleic acid infusion. In two-kidney, one-clip hypertensive animals, pretreatment with indomethacin did not alter the hypotensive response to linoleic acid. Thus, although linoleic acid infusion lowered blood pressure in high renin but not in low renin states, the reduction of blood pressure was not related to inhibition of circulating renin or to alterations of endogenous prostaglandin biosynthesis.

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Abstract P276: A High Sodium Diet Reduces Cutaneous Microvascular Function In Normotensive Individuals With Salt Sensitive Blood Pressure

Hypertension ◽

10.1161/hyp.78.suppl_1.p276 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Jordan C Patik ◽

Joseph M Stock ◽

Nathan T Romberger ◽

Shannon L Lennon ◽

William B Farquhar ◽

...

Keyword(s):

Blood Pressure ◽

Vascular Function ◽

Sodium Intake ◽

Local Heating ◽

Urinary Sodium Excretion ◽

Microvascular Function ◽

Dietary Sodium ◽

Heating Unit ◽

Doppler Flowmetry ◽

High Sodium

Impaired vascular function likely contributes to the association between dietary sodium intake and the development of cardiovascular disease. Using the cutaneous microvasculature as a model, we have previously shown that a high sodium (HS) diet blunts local heating-induced vasodilation in normotensive individuals with salt resistant (SR) blood pressure (BP). However, the effect of a HS diet on the cutaneous microvasculature in normotensive salt sensitive (SS) individuals remains unclear. Therefore, we tested the hypothesis that cutaneous microvascular function is reduced by a HS diet to a greater degree in SS compared to SR individuals. After each 7-day controlled feeding diet (low sodium (LS) = 20 mmol/day; HS = 300 mmol/day), an intradermal microdialysis fiber was inserted in the ventral forearm and perfused with Ringer’s solution. Skin blood flow (SkBF) was continuously monitored via laser Doppler flowmetry and a local heating unit was placed over the fiber and heated to 42°C until SkBF reached a stable plateau. Site-specific maximal SkBF was determined by perfusing 28mM sodium nitroprusside and heating to 43°C. Mean arterial pressure (MAP) was assessed at regular intervals on the contralateral arm and was used to calculate cutaneous vascular conductance (CVC = SkBF / MAP). Subjects wore a 24-hr ambulatory BP monitor and collected their urine on the final day of each diet. Fourteen subjects (9W / 5M, 42 ± 14 yr) whose MAP increased >5 mmHg (Δ8 ± 1 mmHg) on the HS diet were defined as SS and were compared to 14 age- (43± 14 yr) and sex-matched SR subjects (Δ1 ± 3 mmHg). SS and SR had similar MAP at baseline (88 ± 9 vs. 90 ± 8 mmHg, P = 0.88) and urinary sodium excretion was increased similarly across groups by the HS diet (Δ239 ± 104 vs. Δ220 ± 66 mmol / 24 hr, P = 0.20). Cutaneous vasodilation in response to local heating was decreased on the HS diet relative to the LS diet in both SS (Δ-9 ± 9 %CVCmax, P = 0.005) and SR (Δ-9 ± 9 %CVCmax, P=0.005); however, there was not a group x diet interaction (P = 0.99). In contrast to our hypothesis, these results suggest that the deleterious effects of high sodium diets on cutaneous microvascular function are similar in normotensive salt sensitive and salt resistant individuals.

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Renal and cardiac oxidative/nitrosative stress in salt-loaded pregnant rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00090.2007 ◽

2007 ◽

Vol 293 (4) ◽

pp. R1657-R1665 ◽

Cited By ~ 4

Author(s):

Annie Beauséjour ◽

Véronique Houde ◽

Karine Bibeau ◽

Rébecca Gaudet ◽

Jean St-Louis ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Nitrosative Stress ◽

Gestational Hypertension ◽

Sodium Intake ◽

Pregnant Rats ◽

High Sodium ◽

High Sodium Intake ◽

Arterial Blood ◽

Cardiac Ventricle

Sodium supplementation given for 1 wk to nonpregnant rats induces changes that are adequate to maintain renal and circulatory homeostasis as well as arterial blood pressure. However, in pregnant rats, proteinuria, fetal growth restriction, and placental oxidative stress are observed. Moreover, the decrease in blood pressure and expansion of circulatory volume, normally associated with pregnancy, are prevented by high-sodium intake. We hypothesized that, in these pregnant rats, a loss of the balance between prooxidation and antioxidation, particularly in kidneys and heart, disturbs the normal course of pregnancy and leads to manifestations such as gestational hypertension. We thus investigated the presence of oxidative/nitrosative stress in heart and kidneys following high-sodium intake in pregnant rats. Markers of this stress [8-isoprostaglandin F2α (8-iso-PGF2α) and nitrotyrosine], producer of nitric oxide [nitric oxide synthases (NOSs)], and antioxidants [superoxide dismutase (SOD) and catalase] were measured. Then, molecules (Na+-K+-ATPase and aconitase) or process [apoptosis (Bax and Bcl-2), inflammation (monocyte chemoattractant protein-1, connective tissue growth factor, and TNF-α)] susceptible to free radicals was determined. In kidneys from pregnant rats on 1.8% NaCl-water, NOSs, apoptotic index, and nitrotyrosine expression were increased, whereas Na+-K+-ATPase mRNA and activity were decreased. In the left cardiac ventricle of these rats, heightened nitrotyrosine, 8-iso-PGF2α, and catalase activity together with reduced endothelial NOS protein expression and SOD and aconitase activities were observed. These findings suggest that oxidative/nitrosative stress in kidney and left cardiac ventricle destabilizes the normal course of pregnancy and could lead to gestational hypertension.

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SAT-558 A Dedicated Endocrine Hypertension Service Increases the Timely Diagnosis of Primary Aldosteronism

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1146 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Jun Yang ◽

Yin Y Lim ◽

Renata Libianto ◽

Jimmy Shen ◽

Morag Jennifer Young ◽

...

Keyword(s):

Blood Pressure ◽

Primary Care ◽

Primary Aldosteronism ◽

Pressure Control ◽

Organ Damage ◽

Antihypertensive Medications ◽

Endocrine Hypertension ◽

Treatment Naïve ◽

Hypertension Diagnosis ◽

The Impact

Abstract Background: Primary aldosteronism (PA) accounts for 3.2-12.7% of hypertension in primary care but is often diagnosed late, if at all. A delayed or missed diagnosis leads to poor blood pressure control and greater cardiovascular risk that could be averted with targeted treatment. An Endocrine Hypertension Service (EHS), encompassing an education program, streamlined diagnostic tests and dedicated PA clinic, was developed to address this issue. Aims: To analyse the impact of Victoria’s first dedicated EHS on the pattern of PA diagnoses. Methods: Socio-demographic and clinical data from all patients who attended the EHS since July 2016 (N=267) was collected prospectively. Patients were divided into Year 1 (Y1), Year 2 (Y2), and Year 3 (Y3), based on their first visit. Results: The proportion of referrals from primary care increased (20% in Y1 to 52% in Y3) with more referrals being made for treatment-naive hypertension (3% in Y1 to 19% in Y3). Patients with a hypertension diagnosis of 5 years or less at the time of referral to EHS increased from 34% in Y1 to 45% in Y3 whilst the percentage of patients with a hypertension diagnosis of more than 10 years decreased from 50% in Y1 to 35% in Y3. Consistent with an earlier presentation, the proportion of patients with end-organ damage at the time of referral decreased from 44% in Y1 to 29% in Y3. Almost a third of the PA patients had unilateral disease; all of those who underwent adrenalectomy had biochemical cure. Patients with bilateral PA were treated with spironolactone. Their systolic/diastolic blood pressure decreased by 15/12 mmHg in Y1, 17/13 mmHg in Y2 and 23/11 mmHg in Y3; while the mean number of antihypertensive medications decreased from 2.9 to 1.8 in Y1, 2.7 to 2.0 in Y2 and 2.2 to 1.6 in Y3 Conclusion: The EHS has facilitated an increase in referrals for PA screening from primary care, resulting in the earlier diagnosis of PA, when less complications are present, and optimised patient outcomes. A broader uptake of such a clinical service, integrated with education outreach, will bridge the gap between the reported high prevalence of PA and the actual low diagnostic rates.

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Renal sodium handling in normal humans subjected to low, normal, and extremely high sodium supplies

AJP Renal Physiology ◽

10.1152/ajprenal.1985.249.6.f941 ◽

1985 ◽

Vol 249 (6) ◽

pp. F941-F947 ◽

Cited By ~ 8

Author(s):

J. C. Roos ◽

H. A. Koomans ◽

E. J. Dorhout Mees ◽

I. M. Delawi

Keyword(s):

Blood Pressure ◽

Plasma Renin Activity ◽

Sodium Intake ◽

Extracellular Fluid ◽

Plasma Renin ◽

Renin Activity ◽

Sodium Reabsorption ◽

Lithium Clearance ◽

Renal Sodium Handling ◽

Sodium Handling

We studied renal sodium handling, extracellular fluid volume (ECFV), plasma renin activity, aldosterone and norepinephrine, and blood pressure in eight healthy volunteers after equilibration on intakes of 20, 200, and 1,128 +/- 141 meq sodium, respectively. Renal sodium handling was assessed by means of clearance studies during maximal water diuresis and lithium clearance. Urinary sodium excretions were 22 +/- 4, 202 +/- 19, and 1,052 +/- 86 meq/day. From the lower to the upper sodium intake level, 24-h creatinine clearance rose from 111 +/- 7 to 136 +/- 11 ml/min and inulin clearance from 103 +/- 9 to 129 +/- 9 ml/min, whereas proximal and distal fractional sodium reabsorption (FSRprox and FSRdist, respectively) fell from 86.8 +/- 1.3 to 79.0 +/- 2.7% and from 96.5 +/- 0.5 to 76.0 +/- 1.9%, respectively. During the normal sodium intake (200 meq), intermediate values were recorded. The changes in fractional lithium clearance were less consistent but correlated with FSRprox (r = 0.78, P less than 0.001) and not with FSRdist. Major changes in plasma renin activity, aldosterone, and, to a lesser extent, norepinephrine accompanied these changes in kidney function, displaying inverse and exponential correlations with daily sodium excretion and ECFV. No consistent rise in blood pressure was detected. These observations indicate that in healthy humans renal adaptation to vast variations in sodium intake includes resetting of glomerular filtration rate, FSRprox, and, in particular, FSRdist. Alterations in neurohumoral factors may play a dominant role in this adaptation.

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Sodium Intake and Target Organ Damage in Hypertension—An Update about the Role of a Real Villain

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17082811 ◽

2020 ◽

Vol 17 (8) ◽

pp. 2811 ◽

Cited By ~ 2

Author(s):

Federica Nista ◽

Federico Gatto ◽

Manuela Albertelli ◽

Natale Musso

Keyword(s):

Blood Pressure ◽

Cardiovascular Risk ◽

Sodium Intake ◽

Target Organ Damage ◽

Organ Damage ◽

Left Ventricular ◽

Target Organ ◽

Main Role ◽

Sodium Consumption

Salt intake is too high for safety nowadays. The main active ion in salt is sodium. The vast majority of scientific evidence points out the importance of sodium restriction for decreasing cardiovascular risk. International Guidelines recommend a large reduction in sodium consumption to help reduce blood pressure, organ damage, and cardiovascular risk. Regulatory authorities across the globe suggest a general restriction of sodium intake to prevent cardiovascular diseases. In spite of this seemingly unanimous consensus, some researchers claim to have evidence of the unhealthy effects of a reduction of sodium intake, and have data to support their claims. Evidence is against dissenting scientists, because prospective, observational, and basic research studies indicate that sodium is the real villain: actual sodium consumption around the globe is far higher than the safe range. Sodium intake is directly related to increased blood pressure, and independently to the enlargement of cardiac mass, with a possible independent role in inducing left ventricular hypertrophy. This may represent the basis of myocardial ischemia, congestive heart failure, and cardiac mortality. Although debated, a high sodium intake may induce initial renal damage and progression in both hypertensive and normotensive subjects. Conversely, there is general agreement about the adverse role of sodium in cerebrovascular disease. These factors point to the possible main role of sodium intake in target organ damage and cardiovascular events including mortality. This review will endeavor to outline the existing evidence.

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Sodium Intake and Hypertension

Nutrients ◽

10.3390/nu11091970 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1970 ◽

Cited By ~ 28

Author(s):

Grillo ◽

Salvi ◽

Coruzzi ◽

Salvi ◽

Parati

Keyword(s):

Blood Pressure ◽

Salt Intake ◽

Sodium Intake ◽

Peripheral Resistance ◽

Dietary Sodium ◽

Dietary Salt ◽

High Sodium ◽

Close Relationship ◽

And Function ◽

Modest Reduction

The close relationship between hypertension and dietary sodium intake is widely recognized and supported by several studies. A reduction in dietary sodium not only decreases the blood pressure and the incidence of hypertension, but is also associated with a reduction in morbidity and mortality from cardiovascular diseases. Prolonged modest reduction in salt intake induces a relevant fall in blood pressure in both hypertensive and normotensive individuals, irrespective of sex and ethnic group, with larger falls in systolic blood pressure for larger reductions in dietary salt. The high sodium intake and the increase in blood pressure levels are related to water retention, increase in systemic peripheral resistance, alterations in the endothelial function, changes in the structure and function of large elastic arteries, modification in sympathetic activity, and in the autonomic neuronal modulation of the cardiovascular system. In this review, we have focused on the effects of sodium intake on vascular hemodynamics and their implication in the pathogenesis of hypertension.

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