Plasma Renin Levels Research Articles

In memoriam: Dr Norman M. Kaplan (1931–2020)

In memoriam: Dr Norman M. Kaplan (1931–2020)

1909-P: The Natriuretic Action of Glucagon-Like Peptide-1 in Humans Is Abolished by the GLP-1 Receptor Antagonist Exendin 9-39

We have recently demonstrated that renal extraction of GLP-1 is ∼45% and that extracellular fluid volume expansion in healthy participants uncovered a natriuretic action of GLP-1 probably via a tubular mechanism secondary to suppression of angiotensin II (ANG II) and independent of changes in renal hemodynamics. It is not known whether the high extraction is due to receptor binding. The present study was designed to test the hypotheses that the renal extraction and natriuretic effect of GLP-1 are mediated via GLP-1 receptor. Under fixed sodium intake for 4 days before each study day, 6 healthy male participants were recruited from our recent study1 and examined during a 3-h infusion of GLP-1 (1.5 pmol/kg/min) together with a 3.5-h infusion of the GLP-1 receptor antagonist, exendin 9-39 (Ex 9-39) (900 pmol/kg/min), initiated 30 minutes before start of GLP-1 infusion. Timed urine collections were conducted throughout the experiments. Renal plasma flow (RPF), glomerular filtration rate (GFR), and renal extraction of GLP-1 were measured via Fick’s principle after catheterization of a renal vein. Renal extraction of GLP-1 was ∼45% during infusion of GLP-1 alone and decreased significantly to ∼25% during co-infusion of GLP-1 and Ex 9-39. Urinary sodium and osmolar excretions remained at baseline levels during co-infusion of GLP-1 and Ex 9-39 compared to a mean 2-fold natriuretic effect during GLP-1 infusion alone. Arterial plasma ANG II levels were unaffected during the co-infusions, whereas ANG II decreased significantly during GLP-1 alone. Arterial plasma renin levels decreased similarly on the two study days, and arterial aldosterone levels remained unchanged on both days. RPF and GFR remained unchanged on both days. In conclusion, renal extraction of GLP-1 is partially and natriuresis is fully dependent on GLP-1 receptor activation, probably via GLP-1-mediated ANG II suppression. 1Asmar A et al. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2509-2519. Disclosure A. Asmar: None. P.K. Cramon: None. M. Asmar: None. L. Simonsen: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. C.M. Sorensen: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. P. Hovind: None. B.L. Jensen: None. J. Bülow: None.

Açaí seed extract prevents the renin-angiotensin system activation, oxidative stress and inflammation in white adipose tissue of high-fat diet–fed mice

The role of the renin-angiotensin system (RAS), oxidative stress, and inflammation on the development of obesity and its comorbidities has been extensively addressed. Euterpe oleracea Mart. (açaí) seed extract (ASE), with antioxidant and anti-inflammatory properties and capable to modulate plasma renin levels, has been evidenced as a potential regulator of body mass. We hypothesized that the supplementation with ASE might exert beneficial effects on obesity-related white adipose tissue changes and metabolic disorders by interfering with the local adipose tissue overexpression of RAS, inflammation, and oxidative stress in C57BL/6 mice fed a high-fat (HF) diet. The animals were fed a standard diet (10% fat, control), 60% fat (HF), HF + ASE (300 mg/kg per day) and HF + ENA (enalapril, 30 mg/kg per day) for 12 weeks. ASE and ENA prevented weight gain and adiposity, adipocyte hypertrophy, dyslipidemia, and insulin resistance. In adipose tissue, ASE increased the insulin receptor expression and reduced renin and AT1 receptor expression, which was associated with decreased plasma levels of renin and angiotensin II. Differently, ENA increased the expression of angiotensin-conversing enzyme 2, AT2, B2, and Mas receptors in adipose tissue. Also, ASE but not ENA decreased malondialdehyde and 8-isoprostane levels in adipose tissue. Finally, ASE and ENA reduced the adipose tissue inflammatory markers tumor necrosis factor alpha and interleukin 6. These results demonstrate that ASE prevented the adipocyte hypertrophy, obesity, hyperlipidemia, hyperglycemia, and insulin resistance in HF diet–fed mice. The downregulation of RAS in adipose tissue, reducing oxidative stress and inflammation, may contribute to the prevention of obesity-related disorders.

MON-LB035 Adrenal Venous Sampling in the Lateralization of Acth-Independent Cushing Syndrome With Bilateral Adrenal Masses: A Case With a 5-Year Follow-Up

Background Nearly 25% of adrenal Cushing syndrome (CS) patients with bilateral adrenal masses have unilateral hypercortisolism, making localization crucial for surgical planning. Since there is no standardized protocol for adrenal venous sampling (AVS) in lateralizing adrenal hypercortisolism, we share our experience with a case of CS with bilateral adrenal masses in which lateralization via AVS permitted unilateral adrenalectomy. Clinical Case A 59-year-old woman with hypertension, hyperlipidemia, and prediabetes was hospitalized for worsening back pain and hypertension. Her BMI was 26.5 kg/m2, BP 173/93 mmHg, HR 73/min, she was anxious, diaphoretic, and hirsute. Glucose was 118 mg/dL and HbA1c 6.6%. Abdominal computed tomography revealed a type B aortic dissection with both right (6.1 x 3.1cm and 3.6 x 2.4cm), and left (largest 1.7 cm) sided adrenal masses. Plasma and 24 hour-urine metanephrine, normetanephrine and catecholamines, as well as plasma renin and aldosterone levels, were normal. AM cortisol on three different occasions was 21.30, 20.70, and 21.30 mcg/dL. Midnight cortisol was 17.8 mcg/dL, and 24-hour urine free cortisol on two occasions was 163 mcg (urine volume 3.4L with creatinine 1.14) and 99.2 mcg (urine volume 1.15L). After 1mg dexamethasone her AM ACTH and cortisol were <5 and 18.70 mcg/dL, respectively. Preoperative AVS was performed and 8mg of dexamethasone was administered the night prior to ensure ACTH suppression during the procedure, and epinephrine was measured to ascertain adequate adrenal vein cannulation. Cortisol levels (in mcg/dL) from the common iliac, right and left adrenal veins were 14.7, 61.5, and 23.5 at 0 minute and 15.2, 61.0, and 22.7 at 2 minutes, respectively. Epinephrine levels (in pg/dL) from the common iliac, right and left adrenal veins were 42, 577, and 3225 at 0 minutes, and 46, 718, and 2989 at 2 minutes. Despite higher epinephrine levels from the left adrenal, the cortisol ratio of the right adrenal vein to peripheral vein was 4.18 with the right-to-left ratio of 2.59 and 2.68 at 0 and 2 minutes, suggesting hypersecretion of cortisol from the right adrenal gland. Unilateral right adrenalectomy revealed a 5.6 cm adrenal adenoma arising in a background of adrenal cortical hyperplasia. Morning postoperative cortisol was 2.2 mcg/dL. She was placed on hydrocortisone and tapered over a 10-month period with remission maintained for more than 3.5 years post-operatively. Conclusion This case demonstrates the safety, usefulness, and necessity, of AVS in localizing cortisol production when bilateral adrenal masses are present. In addition, this case suggests that the use of high dose dexamethasone and measurement of catecholamines may be helpful for more accurate interpretation. More data on AVS in CS patients with bilateral adrenal masses is needed so a well-validated and standardized CS-specific ACS protocol can be developed.

SAT-219 Allgrove Syndrome: How to Suspect a Problem?

Background: Allgrove syndrome (triple A syndrome) is a rare autosomal recessive multisystem disease characterized by adrenal insufficiency, alacrimia and achalasia. It is caused by a mutation in the AAAS gene (12q13) encoding the protein ALADIN (1). This syndrome is often associated with neurological dysfunction disorders, amyotrophy, in such cases, it is named 4A and 5A syndrome, but sometimes there is also 2A syndrome. Prevalence:<1/1000000. The first description was in 1978. Clinical case: A 18-year patient A. complained of fatigue, weakness, darkening of the skin. From anamnesis of life: born from the first pregnancy without complications, weight 3200g. Parents often turned to the pediatrician with complaints: lethargy, frequent regurgitation, ARVI up to 6–7 times a year. Slow weight gain, dyspeptic syndrome (nausea, vomiting) was noted objectively. At the age of 3, the boy entered the surgical department with acute abdomen, fever, vomiting. Achalasia was revealed, reconstructive surgery was carried out. In the diagnostic search for the causes of body weight loss he was directed to the endocrinologist. There were an increase in ACTH 470 pg/ml (0,0-46 pg/ml), cortisol 0.05 µg/DL. Diagnosis: primary chronic adrenal insufficiency; the dose of hydrocortisone 10 mg/day did not change with age. An in-depth anamnesis found: the patient never cried with tears. Objectively: asthenic body type, BMI 16.5 kg/m2, hyperpigmentation of the palms, armpits; weakness in the proximal muscles of the limbs. Laboratory studies: ACTH 95 PG/ml, cortisol 0.1 µg/DL (3.7–19.4 µg/DL). The secretion of mineralocorticoids was evaluated: plasma aldosterone and renin levels were within the reference values. Ophthalmologist: injected conjunctiva, sclera. Schirmer’s test: mild alacrimia. It allowed to make the diagnosis: “Primary chronic adrenal insufficiency. Condition after surgery for achalasia (1997). Alacrimia. Allgrove Syndrome.” The dose of hydrocortisone was increased to 17.5 mg/day. In 2019, the patient complained of a sharp deterioration of health, darkening of the skin. The dose of hydrocortisone was increased to 25 mg/day (15 mg at 8.00, 10 mg in the afternoon). The ophthalmologist noted an increase in the severity of alacrimia, artificial tear drops was recommended. The diagnosis was confirmed by pathogenic mutation c.43C>T of the AAAS gene. Discussion: Despite the full clinical picture, the right diagnosis was made only after 14 years. We shown the difficulty of diagnosis is due to the lack of awareness of clinicians about the disease, the importance of interdisciplinary interaction, as well as the need for follow-up of such patients. Reference: (1) Handschug K, Sperling S, Yoon SJ, et al. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Human Molecular Genetics. 2001;10:283–290.

SAT-220 A Misdiagnosis Causing a Feared Complication

Adrenal incidentalomas are being increasingly found with the widespread use of thoracic and abdominal imaging. Clinicians must determine the nature of the mass to decide what treatment, if any, is needed. All patients should undergo biochemical testing to rule out hypercortisolism, pheochromocytoma and if hypertension is present, primary hyperaldosteronism. These patients should ideally be evaluated by endocrinologists as misdiagnosis can lead to complications.A 60-year-old African American female with a history of hypertension and type 2 diabetes, was admitted to the internal medicine ward with intractable vomiting, abdominal pain and hypotension. Two weeks prior to admission, she had undergone a left sided adrenalectomy for a diagnosis of primary hyperaldosteronism. An adrenal adenoma was incidentally found 1 year before surgery during abdominal imaging done for diverticulitis. She was immediately referred to a surgeon for further work up and evaluation. The work up done for the adrenal incidentaloma included renin, aldosterone and plasma fractionated metanephrines. Plasma renin was low (0.2 ng/mL/hr, n: 0.5-4.0 ng/mL/hr), and Aldosterone was normal (8.1 ng/dL, n<16 ng/dL) and the Aldosterone/ Renin ratio was elevated. No confirmatory test was done and no evaluation for hypercortisolism was done either. Plasma fractionated metanephrines were normal.During current hospitalization, an AM cortisol was 1.5 mcg/dL (n: 6-28 mcg/dL). An ACTH stimulation test was done which showed an inadequate response. She was subsequently started on stress dose steroids with rapid improvement in her symptoms. She was discharged with hydrocortisone and has been followed in our endocrinology clinic. She has yet to fully recover HPA axis but is currently on low dose Hydrocortisone and doing well.This patient was misdiagnosed with primary hyperaldosterenism when she most likely had subclinical hypercortisolism. Patients with primary hyperaldosteronism typically have plasma aldosterone > 15 ng/dL and low levels of plasma renin, with a ratio of plasma aldosterone to plasma renin activity > 20. Low levels of both plasma renin activity and aldosterone suggest nonaldosterone mineralocorticoid excess. Cushing syndrome can cause similar findings. Confirmatory tests should be done, and most patients require bilateral catheterization of the adrenal veins to measure cortisol and aldosterone levels to confirm whether the aldosterone excess is unilateral or bilateral. A 1 mg overnight dexamethasone suppression test is recommended for all adrenal incidentaloma patients to exclude asymptomatic hypercortisolism.

Actualization of the problem and understanding of «cute overdrive». Preparations for the regulation of heart rate

The key role in the pathogenesis of cardiovascular diseases is played by sympathetic overdrive - chronic hyperactivation of the sympathoadrenal system, which ultimately leads to its depletion. Heart rate, blood pressure, and plasma renin levels are markers of hypersympathicotonia. In large-scale clinical studies, it was proved that an increased resting heart rate is an independent risk factor for cardiovascular diseases and is associated with an increased risk of death, and the most effective treatment strategy is to prescribe beta-blockers that affect all parts of the sympathetic overdrive, exhibiting additional metabolic effects.

Surgical approach to patients with primary aldosteronism.

Primary hyperaldosteronism (PA) is one of the most common causes of hypertension that is amenable to surgical cure. Once a patient has a biochemical diagnosis of PA, workup should proceed with tumor lateralization to determine whether the patient has unilateral or bilateral disease. Tumor lateralization can be done with noninvasive imaging such as a CT or MRI. However, in older patients or in patients with non-lateralizing imaging, arteriovenous sampling (AVS) should be considered. If the patient has confirmed unilateral disease, options for surgical intervention include laparoscopic or, less commonly, open. Laparoscopic adrenalectomy for PA has been shown to be a safe and effective procedure that is associated with less morbidity compared to open adrenalectomy. Patients can either undergo a laparoscopic transabdominal adrenalectomy via a lateral (most common) or anterior approach or a retroperitoneoscopic adrenalectomy via a posterior approach. The majority of patients have complete biochemical success, defined as normalization of plasma aldosterone, renin and potassium levels and appropriate suppression with stimulation tests. Less than half of patients have complete clinical success, defined as normotensive with no antihypertensive medications. However, the majority of patients who do not have complete clinical success will have some improvement in their blood pressure and/or are able to decrease the number of antihypertensive medications that they require.

Late-onset renal hypertrophy and dysfunction in mice lacking CTRP1.

Local and systemic factors that influence renal structure and function in aging are not well understood. The secretory protein C1q/TNF-related protein 1 (CTRP1) regulates systemic metabolism and cardiovascular function. We provide evidence here that CTRP1 also modulates renal physiology in an age- and sex-dependent manner. In mice lacking CTRP1, we observed significantly increased kidney weight and glomerular hypertrophy in aged male but not female or young mice. Although glomerular filtration rate, plasma renin and aldosterone levels, and renal response to water restriction did not differ between genotypes, CTRP1-deficient male mice had elevated blood pressure. Echocardiogram and pulse wave velocity measurements indicated normal heart function and vascular stiffness in CTRP1-deficient animals, and increased blood pressure was not due to greater salt retention. Paradoxically, CTRP1-deficient mice had elevated urinary sodium and potassium excretion, partially resulting from reduced expression of genes involved in renal sodium and potassium reabsorption. Despite renal hypertrophy, markers of inflammation, fibrosis, and oxidative stress were reduced in CTRP1-deficient mice. RNA sequencing revealed alterations and enrichments of genes in metabolic processes in CTRP1-deficient animals. These results highlight novel contributions of CTRP1 to aging-associated changes in renal physiology.

Clinical features, genetic background, and outcome in infants with urinary tract infection and type IV renal tubular acidosis.

Type IV renal tubular acidosis (RTA) is a severe complication of urinary tract infection (UTI) in infants. A detailed clinical and molecular analysis is still lacking. Infants with UTI who exhibited features of type IV RTA were prospectively enrolled. Clinical, laboratory, and image characteristics and sequencing of genes responsible for phenotype were determined with follow-up. The study cohort included 12 infants (9 males, age 1-8 months). All exhibited typical type IV RTA such as hyperkalemia with low transtubular potassium gradient, hyperchloremic metabolic acidosis with positive urine anion gap, hypovolemic hyponatremia with renal salt wasting, and high plasma renin and aldosterone levels. Seven had hyperkalemia-related arrhythmia and two of them developed life-threatening ventricular tachycardia. With prompt therapy, all clinical and biochemical abnormalities resolved within 1 week. Five had normal urinary tract anatomy, and three of them carried genetic variants on NR3C2. Three variants, c.1645T>G (S549A), c.538G>A (V180I), and c.1-2C>G, on NR3C2 were identified in four patients. During follow-up, none of them had recurrent type IV RTA, but four developed renal scaring. Genetic mutation on NR3C2 may contribute to the development of type IV RTA as a complication of UTI in infants without identifiable risk factors, such as urinary tract anomalies.

Short- and long-term effects of lipoprotein apheresis on plasma hormones in patients with therapy-resistant dyslipidemia

Background and aimsLipoprotein apheresis (LA) is a highly effective method to improve the clinical and metabolic situation in patients with therapy-resistant disorders of lipid metabolism. Cholesterol is the substrate for the synthesis of all steroid hormones. If repeated massive reduction of LDL-cholesterol may interfere with human adrenal steroidogenesis, and could become clinically relevant is unknown, so far. Thus, the aim of this study was to determine possible short- and long-term effects of LA on blood plasma levels of ACTH, cortisol, aldosterone, DHEAS, renin and testosterone. MethodsIn total, 39 patients, treated with one of four LA techniques were studied: 1. Lipid Filtration (LF; n = 7), 2. Dextran Sulfate Adsorption (DSA; n = 7), 3. Membrane Filtration Optimised Novel Extracorporeal Treatment (MONET; n = 8), and 4. Direct Absorption of Lipoproteins (DALI; n = 15). Hormone levels were analyzed before and after five LA sessions with an interval of 20 weeks covering a total observation time of two years. In addition patients were comprehensively characterized by clinical and laboratory data. ResultsPatients treated with LA revealed an acute reduction of steroid hormones and ACTH, independent of apheresis technology but no long-term insufficiency in steroidogenesis was observed. Plasma renin levels were stable in LF patients and were highly elevated in patients under DSA, MONET and DALI apheresis throughout the observation period. ConclusionsIn summary, these data suggest that although different LA techniques considerably differ in their acute effects on hormone levels during LA, they did not alter long-term hormone levels sustainably.

Liddle syndrome due to a novel mutation in the \u03b3 subunit of the epithelial sodium channel (ENaC) in family from Russia: a case report

BackgroundLiddle syndrome is a monogenic disease with autosomal dominant inheritance. Basic characteristics of this disease are hypertension, reduced concentration of aldosterone and renin activity, as well as increased excretion of potassium leading to low level of potassium in serum and metabolic alkalosis. The cause of Liddle syndrome is missense or frameshift mutations in SCNN1A, SCNN1B, or SCNN1G genes that encode epithelial sodium channel subunits.Case presentationWe describe a family with Liddle syndrome from Russia. 15-year-old proband has arterial hypertension, hypokalemia, hyporeninemia, metabolic alkalosis, but aldosterone level is within the normal range. At 12 years of age, arterial hypertension was noticed for the first time. We identified novel frameshift mutation c.1769delG (p.Gly590Alafs) in SCNN1G, which encodes the γ subunit of ENaC in vertebrates. The father and younger sister also harbor this heterozygous deletion. Treatment with amiloride of proband and his sister did not normalize the blood pressure, but normalized level of plasma renin activity.ConclusionsOur results expand the mutational spectrum of Liddle syndrome and provide further proof that the conserved PY motif is crucial to control of ENaC activity. Genetic analysis has implications for the management of hypertension, specific treatment with amiloride and counselling in families with Liddle syndrome.

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.

ENDOTHELIAL DYSFUNCTION AND NEUROHUMORAL REGULATION OF BLOOD PRESSURE IN PATIENTS WITH SYSTEMIC SCLEROSIS

Objective: to investigate the effect of endothelial dysfunction, catecholamines, and renin on the diurnal blood pressure (BP) profile in patients with systemic sclerosis (SS).Subjects and methods. Twenty-five patients with SS underwent determination of the blood count of desquamated endotheliocytes by the method described by J. Hladovec (1978), the plasma levels of endothelin-1 (ET-1), adrenaline, norepinephrine, and renin by enzyme immunoassay. All the patients underwent 24-hour BP monitoring with calculating the time index, daily index, the magnitude and rate of a morning rise in BP, as well as its daily variability.Results and discussion. Hypertension was detected in 8 (32%) patients with SS. All the patients with SS showed signs of endothelial dysfunction, as evidenced by considerable differences in endothelial activation measures compared with the control group: the mean level of ET-1 was 5.8±2.3 and 0.48±0.21 fmol/ml (p&lt;0.05); the number of desquamated endotheliocytes was 4.50 [3.00; 7.00] and 2.10 [1.00; 3.20] • 104/l, respectively (p&lt;0.05). The levels of adrenaline and norepinephrine in SS were significantly higher than those in the control. There were positive correlations between endothelial dysfunction and the degree of an increase in BP. Endothelial dysfunction was found to have a negative impact on the diurnal BP profile in the presence of pathological types of night-peaker and non-dipper. Conclusion. Two mechanisms, such as endothelial dysfunction and sympathoadrenal activation, are responsible for the pathogenesis of clinical symptoms of SS, including hypertension.

Abstract 096: Renal-Specific Deletion of (Pro)Renin Receptor in Mice Induces Hyperkalemia During High Potassium Intake

We have previously shown that systemic administration of (pro)renin receptor (PRR) decoy inhibitor PRO20 impaired kaliuretic response to high K + (HK) intake (5% KCl in diet). The present study extends this observation by examining the phenotype of inducible renal tubule-specific PRR knockout (RT PRR KO) mice fed a HK diet. The null mice were generated by breeding Floxed PRR mice with mice transgenic for Pax8-rtTA and LC-1 transgene. To induce RT PRR KO, mice with homozygous for Floxed PRR gene and hemizygous for the Pax8-rtTA and the LC-1 transgene were given 2 mg/ml doxycycline in 5% sucrose drinking water for 14 days followed by 4-wk off doxycycline. Following 1-wk HK intake, RT PRR KO mice had decreased urinary K + (by 33.6%) excretion and elevated plasma K + level (KO+HK: 5.38 ± 0.21 vs. Floxed+HK: 3.98 ± 0.03 mM, P &lt;0.001), accompanied with a reduction of urinary prorenin/renin content (by 56.5%), urinary renin activity (by 69.6%), urinary free and total Aldo excretion (by 41.2% and 25.3%, respectively), and kidney cortical and medullary Aldo levels (by 62.0% and 64.2%, respectively), without affecting plasma Aldo or renin levels. HK upregulated renal protein expression of fPRR (cortical: 170.4%, medullary: 195.0%), sPRR (cortical: 138.0%, medullary: 180.1%), prorenin (cortical: 217.5%, medullary: 164.0%), renin (cortical: 183.2%, medullary: 153.1%), Aldo synthase CYP11B2 (cortical: 321.6%, medullary: 243.8%), ROMK (165.4%), α-BK (161.4%), α-Na + -K + -ATPase (160.3%), β-ENaC (130.2%), and cleaved-γ-ENaC (542.0%), and downregulated phosphorylated NCC-T53 (pNCC-T53) protein expression, all of which were significantly blunted in RT PRR KO mice (by 25-80%). In Flp-In T-REX 293 NCC cell line (stably expressing NCC), PRR siRNA significantly increased pNCC-T53 (by 72.3%) and partially reversed prorenin (100 nM)-induced inhibition of pNCC-T53 (by 38.2%). sPRR-His (10 nM) inhibited pNCC-T53 (by 48.9%), which were significantly reversed by losartan or angiotensin II receptor type 1 (AT1R) siRNA, without affecting total NCC expression. Together, these results suggest that PRR/sPRR contributes to the kaliuretic response through an impact on the intrarenal RAAS and the K + secretory machinery in the distal nephron.

Abstract P2031: Control Of Antihypertensive Effect Of Small Interfering RNA Targeting Angiotensinogen

A single dose of small interfering ribonucleic acids (siRNA) targeting angiotensinogen (AGT) provides a strong and sustained antihypertensive effect, lasting weeks to months in preclinical models. It is not known whether conventional vasopressors are effective to reverse RNAi-mediated blood pressure lowering. Here, we investigated whether conventional vasopressors can elevate arterial pressure under conditions of AGT depletion. Spontaneously hypertensive rats on a low-salt diet (&lt;0.03% NaCl) were treated for 4 weeks with siRNA (10 mg/kg fortnightly; s.c.), supplemented with fludrocortisone (6 mg/kg/day; s.c.), midodrine (4 mg/kg/day; s.c.) or a high-salt diet (4% NaCl) during the final 2 weeks (all groups n=6-7). Before and after 2 weeks of siRNA, blood pressure responses to intravenous bolus injections of angiotensin II (0.05; 0.5 and 5 μg/kg) and noradrenalin (0.1; 1.0 and 10 μg/kg) were examined in anesthetized rats, via radiotelemetry. Baseline mean arterial pressure (MAP; 136±3 mmHg) was lowered by 19±1 mmHg by AGT siRNA combined with a low-salt diet. Acute pressor responses to angiotensin II and noradrenalin were identical before and after siRNA. Fludrocortisone restored MAP to baseline levels (137±3 mmHg), as did replacing the low-salt diet with a high-salt diet (139±4 mmHg). Midodrine had no effect. Under low salt conditions, siRNA virtually abolished plasma AGT by 99.2±0.1% to 6±1 nM, and increased active plasma renin concentrations. AGT was not altered by midodrine, only marginally increased by high sodium intake, but increased to 20±5% of pre-siRNA treatment levels by fludrocortisone, paralleled by near-elimination of plasma renin levels by 97.6±0.9% to 2.1±0.9 ng angiotensin I/mL.h. Collectively, these data indicate that the efficacy of angiotensin II and noradrenaline to raise blood pressure is not affected by RNAi-mediated AGT suppression. Increased sodium intake or fludrocortisone may represent chronic, less invasive alternatives for controlling blood pressure during AGT depletion, of which the latter seems to be facilitated by amplification of AGT production.

RAA System and Exercise Relationship

In this review, it is aimed to discuss the possible interactions between renin-angiotensin-aldosterone system and exercise for health and performance and to present new literature on this subject. From this point of view, an analysis of the experimental and clinical studies on this subject has been made. Physical exercise leads to a number of changes in the plasma levels of renin, angiotensin, and aldosterone, which represent the adaptation of the human body to a new biological environment. Significant (P <0.05) increases occur in the levels of plasma renin, angiotensin and aldosterone especially in submaximal and maximal exercise intensity. Hormone levels return to normal with the end of the exercise. Factors such as age and gender, menstrual cycle, salt intake, posture, thermal tension, elevation, training, type of exercise have a major impact on the response of the RAA system to exercise. A relationship between physical activity and permanent endocrine changes could not be demonstrated.

Perioperative hypertension associated neurohumoral stress response in craniotomy patients: Effects of β-blocker and angiotensin converting enzyme inhibitor

BackgroundDevelopment of perioperative hypertension in craniotomy procedures is commonly associated with activation of sympathetic events through renin-angiotensin-aldosterone system (RAAS). Preemptive therapy with β-blockers or angiotensin converting enzyme (ACE) inhibitors may attenuate this hypertensive response. We conducted a randomized, double blind; placebo controlled study to compare the effect of β-blocker (atenolol) and an ACE inhibitor (Lisinopril) on perioperative hypertension in patients undergoing for the craniotomy and also studied biochemical markers of these two systems. MethodsEighty five patients undergoing craniotomy for supratentorial tumor removal were screened and randomized into three groups to receive either (atenolol; lisinopril or placebo). Blood analysis of renin, aldosterone, norepinephrine and sodium levels was drawn 12 h prior to surgery, at the time of dural opening, and at the time of extubation. Differences in mean arterial pressure (MAP), hear rate (HR) and biochemical markers between three groups were analyzed using one-way ANOVA. ResultsPerioperative hemodynamic changes were highly associated with biochemical markers in all the three groups. Specifically, HR was significantly attenuated by atenolol in the immediate extubation period (p < 0.01) persisted till 12 h postoperatively and this was associated with low plasma renin levels at the extubation. MAP was lowered by lisinopril and both aldosterone and norepinephrine levels were significantly lower (p < 0.01) at dural incision and extubation periods. ConclusionsPretreatment with atenolol or lisinopril significantly attenuated perioperative hypertension in patients undergoing craniotomy procedures. Lisinopril was better in lowering perioperative MAP while atenolol attenuated HR changes. RAAS inhibition may be the possible mechanism responsible for this hypertension effect in craniotomy procedures.

Effects of Hibiscus Sabdariffa Calyces Aqueous Extract on the Antihypertensive Potency of Captopril in the Two-Kidney-One-Clip Rat Hypertension Model.

Hibiscus sabdariffa aqueous extract (HS) is often used as complementary therapy for hypertension. However, some studies have shown that coadministration with a conventional antihypertensive drug can affect drug potency. We compared the effects of HS plus captopril (CAP) coadministration to HS and CAP administration alone on blood pressure and renin-angiotensin-aldosterone system (RAAS) biomarkers in the rat two-kidney-one-clip (2K1C) model of hypertension. Male Sprague Dawley rats were randomly divided into seven groups (n=6/group), a normal control (SHAM) group, and six 2K1C groups. In 2K1C animals, hypertension was induced using a stainless microclip (inner diameter of 0.20 mm). Four weeks after 2K1C surgery, blood pressure was significantly higher than in the SHAM group. Then, model rats were randomly divided into negative control (2K1C, no treatment), positive control (4.5 mg captopril/200 g body weight [BW] orally [p.o.]), HS alone (30 mg/200 g BW; p.o.), and 3 co-treatment groups receiving HS (15, 30, or 60 mg/200 g BW; p.o.) plus 4.5 mg/200 g BW captopril. The treatments were performed for two weeks. Blood pressure was significantly reduced by all the drug treatments to near the level of SHAM controls. Plasma renin level, serum angiotensin converting enzyme (ACE) activity, and plasma angiotensin II level were also significantly elevated in the 2K1C group compared to the SHAM group. Both serum ACE activity and plasma angiotensin II level were significantly reduced to near SHAM group levels by all the drug treatments. Hibiscus sabdariffa aqueous extract alone can reduce blood pressure. This extract appears could be used as a supplement with captopril but may not provide any additional benefit.

Plasma renin levels are associated with cardiac function in primary adrenal insufficiency

BackgroundDespite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, primary adrenal insufficiency (AI) is associated with an increased mortality, mainly due to cardiovascular disease. The role of MC replacement is not known. Therefore, we assessed whether renin concentrations during routine GC and MC substitution therapy are associated with heart function and morphology.MethodsThirty two patients with primary AI were included in a cross-sectional case–control study. In total, 17 patients and 34 healthy controls (age: 48 ± 12 vs. 46 ± 18 years; BMI: 23 ± 3 vs. 24 ± 3 kg/m2) underwent magnetic resonance spectroscopy and imaging measurements to assess cardiac function, morphology, ectopic lipids, and visceral/subcutaneous fat mass. Patients were divided according to their actual plasma renin concentration at the study visit (Actual-Reninlow vs. Actual-Reninhigh) and their median plasma renin concentration of previous visits (Median-Reninlow vs. Median-Reninhigh).ResultsEjection fraction was higher (67 ± 5 vs. 55 ± 3%; p = 0.001) and left ventricular mass was lower (60 ± 9 vs. 73 ± 10 g/m2; p = 0.025) in Actual-Reninhigh. Median-Reninhigh was associated with lower cardiac mass (64 ± 9 vs. 76 ± 11 g/m2; p = 0.029). Blood pressure, glucose, and lipid metabolism, as well as ectopic lipid content, pericardial fat mass, and visceral/subcutaneous fat were not different between the groups. Compared with controls, ejection fraction was significantly lower in patients with AI (56 ± 4 vs. 63 ± 8%; p = 0.019). No differences were found in patients with ≤20 mg compared with >20 mg of hydrocortisone per day.ConclusionsHigher renin concentrations are associated with more favorable cardiac function and morphology in patients with primary AI.