Low-renin Hypertension Research Articles

IL-18 (Interleukin-18) Produced by Renal Tubular Epithelial Cells Promotes Renal Inflammation and Injury During Deoxycorticosterone/Salt-Induced Hypertension in Mice.

IL-18 (interleukin-18) is elevated in hypertensive patients, but its contribution to high blood pressure and end-organ damage is unknown. We examined the role of IL-18 in the development of renal inflammation and injury in a mouse model of low-renin hypertension. Hypertension was induced in male C57BL6/J (WT) and IL-18−/− mice by uninephrectomy, deoxycorticosterone acetate (2.4 mg/d, s.c.) and 0.9% drinking saline (1K/DOCA/salt). Normotensive controls received uninephrectomy and placebo (1K/placebo). Blood pressure was measured via tail cuff or radiotelemetry. After 21 days, kidneys were harvested for (immuno)histochemical, quantitative-PCR and flow cytometric analyses of fibrosis, inflammation, and immune cell infiltration. 1K/DOCA/salt-treated WT mice developed hypertension, renal fibrosis, upregulation of proinflammatory genes, and accumulation of CD3+ T cells in the kidneys. They also displayed increased expression of IL-18 on tubular epithelial cells. IL-18−/− mice were profoundly protected from hypertension, renal fibrosis, and inflammation. Bone marrow transplantation between WT and IL-18−/− mice revealed that IL-18-deficiency in non-bone marrow-derived cells alone afforded equivalent protection against hypertension and renal injury as global IL-18 deficiency. IL-18 receptor subunits—interleukin-18 receptor 1 and IL-18R accessory protein—were upregulated in kidneys of 1K/DOCA/salt-treated WT mice and localized to T cells and tubular epithelial cells. T cells from kidneys of 1K/DOCA/salt-treated mice produced interferon-γ upon ex vivo stimulation with IL-18, whereas those from 1K/placebo mice did not. In conclusion, IL-18 production by tubular epithelial cells contributes to elevated blood pressure, renal inflammation, and fibrosis in 1K/DOCA/salt-treated mice, highlighting it as a promising therapeutic target for hypertension and kidney disease.

Monogenic forms of low-renin hypertension: clinical and molecular insights.

Monogenic disorders of hypertension are a distinct group of diseases causing dysregulation of the renin-angiotensin-aldosterone system and are characterized by low plasma renin activity. These can chiefly be classified as causing (i) excessive aldosterone synthesis (familial hyperaldosteronism), (ii) dysregulated adrenal steroid metabolism and action (apparent mineralocorticoid excess, congenital adrenal hyperplasia, activating mineralocorticoid receptor mutation, primary glucocorticoid resistance), and (iii) hyperactivity of sodium and chloride transporters in the distal tubule (Liddle syndrome and pseudohypoaldosteronism type 2). The final common pathway is plasma volume expansion and catecholamine/sympathetic excess that causes urinary potassium wasting; hypokalemia and early-onset refractory hypertension are characteristic. However, several single gene defects may show phenotypic heterogeneity, presenting with mild hypertension with normal electrolytes. Evaluation is based on careful attention to family history, physical examination, and measurement of blood levels of potassium, renin, and aldosterone. Genetic sequencing is essential for precise diagnosis and individualized therapy. Early recognition and specific management improves prognosis and prevents long-term sequelae of severe hypertension.

Low-renin hypertension with normal or high aldosterone levels is a cause of severe hypertension, and can be diagnosed by applying endocrine society hyperaldosteronism guidelines

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

PENDRIN REDUCTION IS ASSOCIATED WITH ACUTE INTRAVENOUS SODIUM CHLORIDE LOADING IN PATIENTS WITH PRIMARY ALDOSTERONISM

Objective: Primary aldosteronism (PA) is a common, potentially curable form of hypertension characterised by excessive, autonomous aldosterone production. In the distal renal tubule, aldosterone is involved in volume homeostasis by modulation of NaCl reabsorption via the epithelial Na+ channel (ENaC), the NaCl cotransporter (NCC) and the Cl-/HCO3- exchanger (pendrin). Na+ loading suppresses plasma aldosterone but its effects on these proteins in humans remain unclear. Design and method: Urine samples were collected before and 1 h after a 4 h 2L 0.9% saline infusion from 13 (F9/M5) subjects including 10 confirmed with PA and 3 in which PA was excluded [herein designated low renin hypertension (LRH)]. Urinary exosomes were harvested by ultracentrifugation and analysed by LC-MS/MS. Results: Plasma aldosterone decreased (P < 0.05) from 623 [312, 2210] (median [range]) to 338 [197, 2330] pmol/L in confirmed PA and from 223 [180, 256] to 117 [110, 133] pmol/L in LRH. There were no changes in plasma K+ (pre 3.4 [2.6, 4.3] vs post 3.6 [2.6, 3.9] mmol/L in PA; pre 4.1 [3.6, 4.1] vs post 4.0 [3.9, 4.0] mmol/L in LRH). LC-MS/MS demonstrated decreases in abundance of pendrin (21.5%, P < 0.01) and aquaporin-2 (AQP2) (42.9%, P < 0.01) in urinary exosomes and a trend towards a decrease in NCC (20%, P = 0.07) in patients with PA. No changes were seen in those with LRH. PA patients had higher baseline pendrin abundance (1.2 [1.0, 2.1]) than LRH patients (0.7 [0.5, 1.0]) (P < 0.05), but there was no difference in baseline AQP2. In all 13 subjects combined, baseline pendrin correlated positively with plasma aldosterone (P = 0.02, r2 = 0.32) and negatively with plasma K+ (P = 0.02, r2 = 0.35), whilst no correlations were observed between AQP2 and aldosterone or K+. Delta Pendrin (P = 0.04, r2 = 0.3) and delta AQP2 (P = 0.01, r2 = 0.58) positively correlated with delta plasma aldosterone. Conclusions: In PA, reduction in pendrin during saline infusion may be due to falling plasma aldosterone in response to NaCl loading. Although also correlating with reduction in aldosterone, a more likely explanation for the reduction in AQP2 may be a fall in plasma vasopressin induced by water loading. Different observations in LRH require validation with larger numbers.

Real-World Effectiveness of Mineralocorticoid Receptor Antagonists in Primary Aldosteronism.

ObjectiveTo investigate how often target renin is pursued and achieved in patients with primary aldosteronism (PA) and other low renin hypertension (LRH) treated with mineralocorticoid receptor antagonists (MRAs), as reversal of renin suppression was shown to circumvent the enhanced cardiovascular and renal morbidity and mortality in these patients.Patients and MethodsWe conducted a retrospective cohort study of patients with PA and LRH treated with MRAs in an academic outpatient practice from January 1, 2000, through May 31, 2020.ResultsOf 30,777 patients with hypertension treated with MRAs, only 7.3% were evaluated for PA. 163 patients (123 with PA) had renin followed after MRA initiation. After a median follow-up of 124 [interquartile range, 65-335] days, 70 patients (43%) no longer had renin suppression at the last visit. The proportion of those who achieved target renin was higher in LRH than in PA (53% vs. 40%). Lower baseline serum potassium, lower MRA doses, and beta-blocker use were independently associated with lower odds of achieving target renin in PA, while male sex was associated with target renin in LRH. Overall, 50 patients (30.7%) had 55 adverse events, all from spironolactone, and 26 patients (52%) were switched to eplerenone or had a spironolactone dose reduction.ConclusionDespite evidence that reversal of renin suppression confers cardio-renal protection in patients with PA and LRH, renin targets are followed in very few and are achieved in under half of such patients seen in an academic setting, with possibly even lower rates in community practices.

Further evidence against the role renal medullary perfusion in short-term control of arterial pressure in normotensive and mildly or overtly hypertensive rats

Earlier evidence from studies of rat hypertension models undermines the widespread view that the rate of renal medullary blood flow (MBF) is critical in control of arterial pressure (MAP). Here, we examined the role of MBF in rats that were normotensive, with modest short-lasting pressure elevation, or with overt established hypertension. The groups studied were anaesthetised Sprague-Dawley rats: (1) normotensive, (2) with acute i.v. norepinephrine-induced MAP elevation, and (3) with hypertension induced by unilateral nephrectomy followed by administration of deoxycorticosterone-acetate (DOCA) and 1% NaCl drinking fluid for 3 weeks. MBF was measured (laser-Doppler probe) and selectively increased using 4-h renal medullary infusion of bradykinin. MAP, renal excretion parameters and post-experiment medullary tissue osmolality and sodium concentration were determined. In the three experimental groups, baseline MAP was 117, 151 and 171 mmHg, respectively. Intramedullary bradykinin increased MBF by 45%, 65% and 70%, respectively, but this was not associated with a change in MAP. In normotensive rats a significant decrease in medullary tissue sodium was seen. The intramedullary bradykinin specifically increased renal excretion of water, sodium and total solutes in norepinephrine-treated rats but not in the two other groups. As previously shown in models of rat hypertension, in the normotensive rats and those with acute mild pressure elevation (resembling labile borderline human hypertension), 4-h renal medullary hyperperfusion failed to decrease MAP. Nor did it decrease in DOCA-salt model mimicking low-renin human hypertension. Evidently, within the 4-h observation, medullary perfusion was not a critical determinant of MAP in normotensive and hypertensive rats.

Mechanical activation of the angiotensin II type 1 receptor contributes to abdominal aortic aneurysm formation

ObjectiveThe angiotensin II type 1 receptor (AT1R) can be activated under conditions of mechanical stretch in some cellular systems. Whether this activity influences signaling within the abdominal aorta to promote to abdominal aortic aneurysm (AAA) development remains unknown. We evaluated the hypothesis that mechanical AT1R activation can occur under conditions of hypertension (HTN) and contribute to AAA formation. MethodsBPH/2 mice, which demonstrate spontaneous neurogenic, low-renin HTN, and normotensive BPN/3 mice underwent AAA induction via the calcium chloride model, with or without an osmotic minipump delivering 30 mg/kg/d of the AT1R blocker Losartan. Systolic blood pressure (SBP) was measured at baseline and weekly via a tail cuff. The aortic diameter (AoD) was measured at baseline and terminal surgery at 21 days by digital microscopy. Aortic tissue was harvested for immunoblotting (phosphorylated extracellular signal-regulated kinase-1 and -2 [pERK1/2] to ERK1/2 ratio) and expressed as the fold-change from the BPN/3 control mice. Aortic vascular smooth muscle cells (VSMCs) underwent stretch with or without Losartan (1 μM) treatment to assess the mechanical stimulation of ERK1/2 activity. Statistical analysis of the blood pressure, AoD, and VSMC ERK1/2 activity was performed using analysis of variance. However, the data distribution was determined to be log-normal (Shapiro-Wilk test) for ERK1/2 activity. Therefore, it was logarithmically transformed before analysis of variance. ResultsAt baseline, the SBP was elevated in the BPH/2 mice relative to the BPN/3 mice (P < .05). Losartan treatment significantly reduced the SBP in both mouse strains (P < .05). AAA induction did not affect the SBP. At 21 days after induction, the percentage of increase in the AoD from baseline was significantly greater in the BPH/2 mice than in the BPN/3 mice (101.28% ± 4.19% vs 75.59% ± 1.67% above baseline; P < .05). Losartan treatment significantly attenuated AAA growth in both BPH/2 and BPN/3 mice (33.88% ± 2.97% and 43.96% ± 3.05% above baseline, respectively; P < .05). ERK1/2 activity was increased approximately fivefold in the BPH/2 control mice relative to the BPN/3 control mice (P < .05). In the BPH/2 and BPN/3 mice with AAA, ERK1/2 activity was significantly increased relative to the respective baseline control (P < .05) and effectively reduced by concomitant Losartan therapy (P < .05). Biaxial stretch of the VSMCs in the absence of angiotensin II demonstrated increased ERK1/2 activation (P < .05 vs static control), which was significantly inhibited by Losartan. ConclusionsIn BPH/2 mice with spontaneous neurogenic, low-renin HTN, AAA growth was amplified compared with the normotensive control and was effectively attenuated using Losartan. ERK1/2 activity was significantly elevated in the BPH/2 mice and after AAA induction in the normotensive and hypertensive mice but was attenuated by Losartan treatment. These data suggest that AT1R activation contributes to AAA development. Therefore, further investigation into this signaling pathway could establish targets for pharmacotherapeutic engineering to slow AAA growth. (JVS–Vascular Science 2021;2:194-206.) Clinical RelevanceHypertension (HTN) and abdominal aortic aneurysm (AAA) have been epidemiologically linked for decades; however, a biomechanical link has not yet been identified. Using a murine model of spontaneous neurogenic HTN experimentally demonstrated to have low circulating renin, mechanical activation of the angiotensin II type 1 receptor (AT1R) was identified with elevated blood pressure and AAA induction. HTN amplified AAA growth. However, more importantly, blocking the activation of AT1R with the angiotensin receptor blocker Losartan effectively abrogated AAA development. Although inhibiting the production of angiotensin II has previously been unsuccessful in altering AAA growth, the results from the present study suggest that blocking the activation of AT1R through direct ligand binding or mechanical stimulation might alter aortic wall signaling and warrants further investigation.

PECULIARITIES OF HEMODYNAMIC AND METABOLIC INDICATORS IN PATIENTS WITH ARTERIAL HYPERTENSION AND CONCOMITANT OBESITY DEPENDING ON PLASMA RENIN ACTIVITY

The aim of the research: to evaluate the effect of plasma renin activity on the state of hemodynamic and neurohumoral parameters in obese hypertensive patients. Anthropometric, biochemical, automated methods of immune analysis, spectrophotometric, instrumental, statistical methods were used to examine 200 hypertensive patients with class I–II obesity aged 45–55 years. Patients were divided into two groups depending on plasma renin activity: the first group included 21 patients with low-renin hypertension, the second – 179 patients with high-renin hypertension. Patients with HRAH had higher blood pressure BP (DBP, p = 0.004, SBP and mean blood pressure, p&lt;0.001 for both indicators), higher CIMT bifurcation (p = 0.003) and cPWV (p = 0.023), larger size of the left ventricle and its MM (p = 0.039) compared with patients with LRAH. The HRAH was associated with a more pronounced imbalance of the oxidative stress system – antioxidant protection, higher levels of leptin, total cholesterol and LDL cholesterol. In the absence of differences in glycemic levels, patients with HRAH had significantly higher insulin levels and more pronounced IR, as assessed by the HOMA index. Patients with low plasma renin activity had significantly lower serum aldosterone levels with significantly higher ARR levels than patients with high plasma renin activity. Features of cardiovascular remodeling and neurohumoral status depending on the phenotype of hypertension in patients with concomitant obesity have been established.

Primary aldosteronism – the expanding spectrum of unsolved practical issues

Primary aldosteronism is the most frequent cause of hormonal hypertension. Recent findings support the concept of continuous spectrum of autonomous aldosterone secretion with mild or subclinical forms being even more common than was suspected. Assumptions emerge that a considerable number of low-renin hypertensives might actually have aldosterone overproduction. However, the awareness of the disease and its consequences is still unsatisfactory. Nowadays experts are still trying to manage some unanswered questions and on-going debate on who should be screened for primary aldosteronism and how to do so.

Pregnancy hypertension diagnosis and care in COVID-19 era and beyond.

Pregnancy hypertension diagnosis and care in COVID-19 era and beyond.

SAT-564 Effectiveness of Treatment with Mineralocorticoid Receptor Antagonistsin Primary Aldosteronism

Background: Medical treatment with mineralocorticoid receptor antagonists (MRAs) is preferred for patients with primary aldosteronism (PA) who are not surgical candidates. Adequate mineralocorticoid receptor blockade, as suggested by renin elevation above suppression levels, has been associated with lower rates of cardiovascular and renal complications as compared with PA with sustained renin suppression. Objectives: To assess the timeline and rates of achieving target renin levels in patients with PA and low renin hypertension treated with MRAs. Patients and Methods: We conducted a retrospective cohort study of adult patients with hypertension who were treated with MRAs in an academic center between 2003-2019. Of these, we included patients who had suppressed renin at baseline, and repeated renin measurement(s) during MRAs therapy. Renin suppression was defined as plasma renin activity (PRA) 1.0 ng/mL/h or direct renin concentration (DRC) 8.0 pg/mL. We excluded patients with adrenal cancer, end-stage renal disease, exogenous glucocorticoids, and critically ill. Mann-Whitney test, Wilcoxon signed rank test, Chi-Square test and multiple logistic regression analysis were employed, as appropriate. Results: So far, 89 patients (45 men), median age 56 (range, 19-84), have been included. Of these, 46% had confirmed PA; 25% had positive PA screening, but no confirmatory tests; and 29% had other forms of low-renin hypertension. On average, patients were on 2.9 1.6 antihypertensive agents; 62% of patients were prescribed beta blockers, and 38% were on K+ supplements. Overall, renin (PRA in 69 cases, and DRC in 20 cases) increased after MRA treatment (from 0.40 [0.10, 0.60] ng/mL/h to 1.10 [0.60, 2.23] ng/mL/h; and from 2.1 [2.1, 3.7] pg/mL to 5.7 [2.9, 16.7] pg/mL, respectively, p<0.0001 for both). The cumulative proportions of patients in whom renin reached target levels during MRA treatment were: 25% at 2 weeks; 38.9% at 1 month; 34.2% at 3 months; 39.5% at 6 months; and 47.2% at 1 year. Age, sex, race, blood pressure, use of beta blockers, renal function, serum K+ and aldosterone concentrations were similar between patients with target vs. suppressed renin. Multiple logistic regression analysis suggested that after adjusting for age and sex, higher MRA dose and higher BMI were associated with higher likelihood of achieving target renin during MRA therapy (odds ratio (95%CI): 1.021 (1.001-1.041) and 1.097 (1.008-1.193), respectively, p<0.05 for both); conversely, beta blockers use tended to be less often associated with target renin (odds ratio, 0.37 (0.13-1.008), p=0.052). Conclusion: Although raising renin above suppression levels is important for reducing the cardiovascular risk associated with PA, this goal is achieved in less than half of patients, even after one year of treatment with MRAs, in an academic setting. Strategies for optimizing PA treatment are critically needed.

Mechanisms of sodium retention in nephrotic syndrome.

Proteinuria in nephrotic syndrome is associated with sodium retention and edema. Recent studies from mice, rats and humans have shown that the sodium retention depends on urinary serine proteases and that it can be mitigated by blockers (amiloride, triamterene) of the epithelial sodium channel ENaC. The present review outlines the mechanisms of protease-stimulated sodium retention during proteinuric diseases. Inhibition of protease activity in nephrotic mice using aprotinin alleviates sodium retention. From both human and mice studies, an increased proteolytic cleavage of the γENaC subunit plays a role in ENaC activation. In animal models, urokinase-plasmin contributes but not as sole mediators of sodium retention. Across experimental models, human case reports and small intervention trials, amiloride alleviates nephrotic sodium retention and low-renin hypertension with high efficacy. Although the exact mechanisms for proteolytic ENaC activation are not resolved, multiple, redundant proteases are involved. Experimental and clinical evidence indicate that aberrant proteolytic ENaC activation is a primary driver of sodium retention in nephrotic syndrome and contributes to hypertension in conditions with low-grade proteinuria. Thus, we foresee increased and personalized use of amiloride treatment of nephrotic and other proteinuric disease patients with associated sodium retention and hypertension.

Hereditary causes of primary aldosteronism and other disorders of apparent excess mineralocorticoid activity.

Secondary hypertension is a common condition with a broad differential diagnosis. Identification of the true cause of hypertension can be critical for guiding appropriate management. Here, we review hereditary conditions underlying the most common cause of secondary hypertension, primary aldosteronism, as well as other disorders impacting various levels of mineralocorticoid action. Recently, several pathogenic variants of ion channels have been described as etiologies of familial aldosteronism. Defects in steroid hormone synthesis cause hypertension in 11β-hydroxylase deficiency and 17α-hydroxylase deficiency, two types of congenital adrenal hyperplasia. Inappropriate activation of mineralocorticoid receptors underlies the syndrome of apparent mineralocorticoid excess and constitutive activation of the mineralocorticoid receptor. Finally, Liddle syndrome and pseudohypoaldosteronism type 2 are disorders impacting the function of renal sodium channels, the endpoint of mineralocorticoid action. We discuss the pathophysiology, clinical presentation, diagnosis and management of these low renin hypertension states that ultimately result in apparent excess mineralocorticoid activity.

Mild primary aldosteronism (PA) followed by overt PA are possibly the most common forms of low renin hypertension: a single-center retrospective study.

Low renin hypertension (LRH) is a common condition in hypertensive patients, and mainly includes primary aldosteronism (PA) and low renin essential hypertension. To investigate the distributions and clinical manifestations of the main LRH forms, we reviewed 1267 hypertensive patients who underwent assessment for plasma renin activity (PRA) and plasma aldosterone concentration (PAC) by standardized protocols in our specialized center. LRH was defined as PRA < 1.0 ng/mL/h. A saline infusion test (SIT) was performed when LRH patients showed positive screening results for PA. The main LRH forms were defined as follows: post-SIT PAC > 10 ng/dL as 'overt PA', post-SIT PAC 5-10 ng/dL as 'mild PA', and post-SIT PAC < 5 ng/dL or negative screening results as 'non-PA'. Overall, 760 patients were defined as LRH, with 160 classified as overt PA, 268 as mild PA, and 332 as non-PA. The total proportion of PA amounted to 56.3% with 21.0% overt PA and 35.3% mild PA. Compared with the mild PA, patients with overt PA had higher systolic and diastolic blood pressures, lower serum potassium, higher urine potassium excretion, more frequent incidence of stage 3 hypertension, hypokalemia, diabetes mellitus, and classical unilateral adenoma on computerized tomography (P < 0.05). PA including overt and mild forms is indeed a major form of LRH. Clinical manifestations in mild PA are less severe than those in overt PA. Nevertheless, mild PA is more prevalent than overt PA in LRH and should be recognized.

P3568The relationship between plasma renin and aldosterone levels and the reduction of blood pressure with spironolactone in patients with resistant hypertension

Abstract The group of patients with resistant hypertension (RH) is not homogeneous on concentration of renin and aldosterone (AS). A lot of studies have shown that spironolactone (SP) was by far the most effective blood pressure-lowering treatment for patients with RH. However, it has been unknown whether SP would be the most effective in patients with different plasma renin profile. The aim was to determine whether plasma renin and AS predict the most effective treatment of SP. Methods 79 patients with RH were included in the study (a mean of 3.4±1.4 drugs per patient including diuretic, ACE-I or an ARB). The plasma AS and active renin concentration (ARC), the plasma aldosterone-to-renin ratio (ARR) were estimated at baseline. After chemical evaluation patients started on SP treatment with a mid-dose 25 mg daily (range 12.5–50 mg). At baseline and after 12 weeks of therapy patients underwent clinic and 24-hour BP measurement, also hematocrit, potassium (K), serum creatinine (C), eGFR were checked. Results In patients with RH the ARC varied widely and they were divided into low 46%, normal 29% and high renin 25% subgroups. All groups of patients had similar AS levels. Patients with high renin hypertension (HRH) had significantly worse renal function than patients with low renin (LRH) or normal renin hypertension (NRH), also hematocrit were significantly higher in HRH patients than in patients with LRH and NRH. At baseline in patients with RH was an excellent correlation between ARC and eGFR (P&lt;0.001). After SP in whole group, the change from baseline in the clinic BP was −13.4/−6.8 mm Hg (P&lt;0.0001 for both) and in 24-hour BP was −10.6/−6.1 mm Hg (P&lt;0.001 for both), but patients with HRH showed less efficacy than patients with LRH and NRH (−5.4/−3.1 mm Hg; P&lt;0.05 for both) and in 24-hour BP was −4.8/−2.9 mm Hg (P&lt;0.05 for both). Moreover, in HRH patients the hematocrit and C levels increased significantly after the start of SP (P&lt;0.001; P&lt;0.0001 respectively). By regression analysis in whole group patients RH ARC and AS levels were not associated with the changes in BP, only eGFR was significantly associated with BP change for DBP (0.391, P&lt;0.05); in patients with LRH and NRH was a mild relation between the change for SBP and ARR (P&lt;0.05 for both), but not for HRH patients. Conclusion SP showed additional antihypertensive effect in the whole group of patients with RH, but in patients with HRH was less effective than in patients with LRH and NRH and lead to the worsening of renal function. In the whole group of patients with RH plasma renin and aldosterone levels were not associated with BP response to SP, but the change in DBP was correlated with baseline eGFR. Only in patients with LRH and NRH was a mild association between BP response to SP and ARR. So, we can't treat all RH patients with the help of one universal algorytm and treatment should be tailored to each patient according to neurohumoral profile and renal function.

OR09-6 Selective and Durable Suppression of Aldosterone Production in Non-Human Primates by a Novel Aldosterone Synthase Inhibitor

Primary aldosteronism (PA) is a common form of secondary hypertension driven by the autonomous production of aldosterone. Often described as low-renin hypertension, PA is a major public health concern given its prevalence and associated cardiovascular and renal pathology. Compared to patients with essential hypertension, patients with PA are at greater risk for stroke, coronary artery disease, atrial fibrillation, and heart failure. Aldosterone excess is also linked to vascular inflammation, fibrosis and oxidative stress. Aldosterone is produced in the adrenal glands by the enzyme CYP11B2 (aldosterone synthase). CYP11B2 belongs to the cytochrome P450 family of enzymes that also control cortisol (CYP11B1) and sex steroid synthesis (e.g. CYP17, CYP19). Thus, to safely suppress aldosterone synthesis in states of excess, a selective CYP11B2 inhibitor is required. SE-6440 is a novel CYP11B2 inhibitor; it is >200-fold selective over the closely related CYP11B1 enzyme as well as related adrenal and liver cytochrome P450 enzymes. Herein we describe the pharmacology of SE-6440 in non-human primate models of steroidogenesis using two different physiological inducers of aldosterone synthesis (Angiotensin II and ACTH). In monkeys, an i.v. bolus of Angiotensin II stimulates aldosterone synthesis and transiently elevates plasma aldosterone levels. Single oral doses of SE-6440 at 1 and 0.2 mg/kg suppressed aldosterone production in a dose-related manner to 3% and 26% that of vehicle-treated animals, respectively, without effect on cortisol synthesis. To determine if this selective inhibitory effect on aldosterone was durable, we dosed monkeys for 14-days with SE-6440 at 0.6 and 0.12 mg/kg orally once daily. Prior to SE-6440 treatment, animals received an i.v. bolus of ACTH to stimulate adrenal steroidogenesis. This ACTH stimulation test mimics that used clinically to diagnose adrenal insufficiency. Following ACTH administration, plasma aldosterone and cortisol pathway steroids were then measured for 8 hours. Each animal was used as its own control when ACTH was similarly administered on day 7 and day 14 of treatment with SE-6440. SE-6440 reduced plasma aldosterone levels, relative to pre-treatment levels, in a dose-related manner. The 0.6 mg/kg dose significantly inhibited aldosterone synthesis and yielded plasma aldosterone levels 13% and 15% that of control on days 7 and 14, respectively, while the 0.12 mg/kg daily dose reduced plasma aldosterone levels to 46% and 49% that of control on days 7 and 14, respectively. In both dose groups, there was no inhibition of CYP11B1 enzyme activity, based on the plasma cortisol, deoxycortisol, and DOC concentrations. These data demonstrate that, regardless of the stimulus, SE-6440 selectively inhibits aldosterone formation without affecting cortisol synthesis and that this inhibition is durable when administered orally once daily for 14 days.

Update in the clinical management of low renin hypertension

The renin-angiotensin-aldosterone system modulates volume, sodium and potassium homeostasis. In the setting of a high sodium diet, up to 30% of patients with hypertension have a low or suppressed renin and increased volume. This phenotype of low renin hypertension (LRH) is multifactorial and includes infrequent inherited genetic syndromes, milder phenotypes of classic diseases and environmental exposures. All these conditions have in common a higher cardiovascular risk mediated by the over activation of the mineralocorticoid receptor (MR), present not only in the kidney, but also in vasculature, myocardium and adipocytes. Consequently, the aim of LRH treatment goes beyond the control of blood pressure and requires antagonizing MR with specific pharmacologic agents, pursuing normalization of renin as a clinical objective. Due to the unusual evaluation of renin status by non-endocrinologists and lack of disease awareness, only a minority of hypertensive patients receive this pathophysiologically-driven treatment that should reduce cardiovascular outcomes.

Genetics of Hypertension in African Americans and Others of African Descent.

Hypertension is the leading cause of cardiovascular disease in the United States, affecting up to one-third of adults. When compared to other ethnic or racial groups in the United States, African Americans and other people of African descent show a higher incidence of hypertension and its related comorbidities; however, the genetics of hypertension in these populations has not been studied adequately. Several genes have been identified to play a role in the genetics of hypertension. They include genes regulating the renin-aldosterone-angiotensin system (RAAS), such as Sodium Channel Epithelial 1 Beta Subunit (SCNN1B), Armadillo Repeat Containing 5 (ARMC5), G Protein-Coupled Receptor Kinase 4 (GRK4), and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D). In this review, we focus on recent genetic findings available in the public domain for potential differences between African Americans and other populations. We also cover some recent and relevant discoveries in the field of low-renin hypertension from our laboratory at the National Institutes of Health. Understanding the different genetics of hypertension among various groups is essential for effective precision-guided medical therapy of high blood pressure.

Adrenal Tissue-Specific Deletion of TASK Channels Causes Aldosterone-Driven Angiotensin II-Independent Hypertension.

The renin-angiotensin system tightly controls aldosterone synthesis. Dysregulation is evident in hypertension (primary aldosteronism), low renin, and resistant hypertension) but also can exist in normotension. Whether chronic, mild aldosterone autonomy can elicit hypertension remains untested. Previously, we reported that global genetic deletion of 2 pore-domain TWIK-relative acid-sensitive potassium channels, TASK-1 and TASK-3, from mice produces striking aldosterone excess, low renin, and hypertension. Here, we deleted TASK-1 and TASK-3 channels selectively from zona glomerulosa cells and generated a model of mild aldosterone autonomy with attendant hypertension that is aldosterone-driven and Ang II (angiotensin II)-independent. This study shows that a zona glomerulosa-specific channel defect can produce mild autonomous hyperaldosteronism sufficient to cause chronic blood pressure elevation.

Genetics and pathophysiology of low-renin arterial hypertension

The review is devoted to the consideration of genetic determination and pathophysiology of one of the forms of hypertensive disease known as low-renin hypertension. At frst glance, the development of low-renin hypertension is “unnatural”, as renin, as a key enzyme of the renin-angiotensin system, which plays an important role in the development of hypertensive disease, is suppressed in low-renin hypertension. At the same time, the most important drugs actual in the treatment of hypertensive disease belong to the renin-angiotensin system blockers. This contradiction was resolved by a study of genetic and pathophysiological mechanisms of hypertension in some groups of patients with characteristic symptoms bringing these people together. Genetic studies of some recent decades using both family analysis and modern molecular genetic technologies have revealed the main mechanisms underlying low-renin hypertension, which can be classifed as certain syndromes with well-defned genetic and clinical features. These syndromes include cases of sporadically occurring somatic mutations in the cells of the adrenal cortex, which begin to produce aldosterone in increased amounts. Also, several oligogenic forms of low-renin hypertension were studied, some of which are associated with the hyperproduction of aldosterone, but in the others the development of low-renin hypertension was associated with mutations of genes involved in regulation of the functioning of the kidney ion channels. The discovery of some types of arterial hypertension with known mechanisms of their development is of paramount importance for medicine, as it allows for targeted efective therapy and in some cases for achieving a complete cure. However, the main contingent of patients with low-renin hypertension belongs to cases with unexplained etiology, as their development is associated with polygenic systems and with a signifcant influence of numerous environmental factors. The study of genetic and physiological mechanisms of various forms of low-renin arterial hypertension provides a good example of how penetration into the intimate mechanisms of the blood pressure regulation in each personal case makes it possible to identify some specifc syndromes and establish its fnal causes. It seems that progress in understanding the causes and mechanisms of essential hypertension lies along this way.