Changes In Plasma Aldosterone Research Articles

Abstract 57: Macrolides for KCNJ5–mutated Aldosterone-Producing Adenoma (MAPA): a Study for Personalized Management of Primary Aldosteronism

Background: Somatic mutations in the KCNJ5 potassium channel involve up to 70% of the patients presenting with primary aldosteronism (PA) caused by an aldosterone-producing adenoma (APA). Macrolides corrected the altered function of the two common mutations G151R and L168R, in vitro suggesting their potential usefulness for personalized management of patients with KCNJ5-mutated APA. Hence, we investigated if the macrolide roxithromycin that restored the KCNJ5 channel function could lower plasma aldosterone and blood pressure (BP) in KCNJ5-mutated APA patients. Methods and Design: In a within-patient study we assessed changes of plasma aldosterone, active renin, cortisol and BP induced by an oral roxithromycin (150-300 mg) challenge, in consenting consecutive hypertensive patients. In parallel, we investigated the vascular and BP effects of macrolides ex vivo and in vivo in mice. Results: We recruited 425 consecutive patients: 19 had G151R - or L168R - mutated APA, 27 KCNJ5 wild-type APA, and the rest had no identifiable cause of hypertension. Roxithromycin lowered the plasma aldosterone concentration (p<0.001), not BP, in the G151R- and L168R-mutated APA patients, but not in the wild-type. However, an aldosterone-independent BP decrease was seen in the much larger cohort of hypertensive patients without PA. In mice experiments, studies showed that this was accounted far by a significant anti-hypertensive effect of macrolides that involved an endothelium-NO-dependent vasodilatory action. Conclusions: The roxithromycin-induced fall of plasma aldosterone concentration might be a marker of the presence of KCNJ5-mutated APA. Moreover, our studies unveiled an anti-hypertensive effect of macrolides that involves endothelium- and NO-dependent vasodilation.

A four-in-one first-in-human study to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and concentration-QTc relationship of HRS-1780, a selective non-steroidal mineralocorticoid receptor antagonist, in healthy men.

This first-in-human study evaluated HRS-1780, an oral selective non-steroidal mineralocorticoid receptor antagonist, in healthy men. In single ascending dose (SAD) part, 10 participants for each dose cohort (5, 10, 20, 40, 60, and 80 mg) were randomized (8:2) to HRS-1780 or placebo. In multiple ascending dose part, 12 participants for each dose (10, 20, and 40 mg) were randomized (9:3) to HRS-1780 or placebo once daily for 7 days. The primary endpoint was safety and tolerability. HRS-1780 was well tolerated with all adverse events being mild. In the steady state, the median time to maximum concentration (Tmax) was 0.750 h and mean half-life was 1.76-1.96 h. High-fat/high-calorie meal prolonged Tmax but did not affect exposure. Multiple dosing of HRS-1780 at 40 mg showed a decreasing trend in systolic blood pressure compared with placebo. Changes in plasma aldosterone and norepinephrine with HRS-1780 were higher compared to placebo. Upper bounds of two-sided 90% confidence interval of placebo-adjusted change-from-baseline QTcF were below 10 msec at the maximum concentration in SAD. The trial had limited sample size and short study duration. HRS-1780 had favorable safety and pharmacokinetic profiles and did not cause clinically meaningful QTcF prolongation. ClinicalTrials.gov (NCT05638126).

Efficacy and safety of adrenal arterial embolization for primary aldosteronism: a systematic review and meta-analysis.

Primary aldosteronism (PA) is related with resistant hypertension and cardiovascular events. Adrenal artery embolization (AAE) is a choice for patients who refused surgery and medical therapy. However, whether AAE can effectively and safely treat PA is unclear. We performed this meta-analysis to determine the efficacy and safety of AAE for patients with PA. Databases including Cochrane Library, Embase, PubMed and Web of Science were used to obtain relevant articles published before July 30, 2023. The primary outcome was blood pressure before and after AAE. The second outcomes included changes in plasma aldosterone level, serum potassium level, and plasma cortisol level. Finally, 7 prospective studies with 222 patients were included. The results showed that systolic and diastolic blood pressure was reduced by 21.68 mmHg (P<0.001) and 10.54 mmHg (P=0.007) respectively after AAE. The change in plasma aldosterone and serum potassium level was -11.52 ng/dL and 0.61 mmol/L respectively (P<0.001), whereas the reduction in cortisol level was not apparent. Moreover, AAE is a relatively safe procedure which only causes some minor complications such as back pain and fever. This meta-analysis indicated that AAE could effectively and safely treat PA. It is a good choice for patients that are not suitable for adrenalectomy or drug therapy.

Systematic review/meta-analysis and a cross-sectional study to assess effects of potassium supplementation on the renin-angiotensin-aldosterone system (RAAS) and blood pressure

Abstract Introduction Nutritional medicine plays a key role in disease prevention and treatment, and we pharmacists must consider our contribution beyond our role in dispensing. Apart from the Dietary Approaches to Stop Hypertension (DASH) diet1, there is a paucity of data on the benefits of nutritional interventions in hypertension with no clear recommendation on potassium in the NICE guidelines. Potassium has been an area of interest in clinical medicine over the decades because of its effect on cardiovascular disease. However, its mechanism of action is poorly understood, and it is unclear it differs between different ethnic groups. Dietary potassium decreases blood pressure (BP) but can also stimulate aldosterone production2. However, the magnitude of potassium-dependent regulation of aldosterone secretion in humans is not fully characterised and it is not clear whether this is mediated by activation of the renin-angiotensin-aldosterone system (RAAS) as a result of a reduction in BP or other mechanisms. Aim To perform a (1) systematic review and meta-analysis of clinical trials assessing effects of potassium on plasma aldosterone and renin in adult individuals alongside a (2) cross-sectional multi-ethnic study to explore the relationship between potassium intake and aldosterone in hypertension. Methods (1) This study was carried out in accordance with PRISMA guidelines3. The full protocol can be found on the PROSPERO database. (2) Self-defined black or white hypertensives were recruited from the hypertension outpatient clinic at St. Thomas’ Hospital and had aldosterone, renin and a 24-hour urinary potassium collected. The systematic review and meta-analysis on already approved clinical trials and did not require ethnical approval. The cross-sectional study was approved by the local Research Ethics Committee in the UK and written informed consent was obtained from all patients. Results 6395 articles were retrieved, and 124 full-text articles were assessed for eligibility. 36 met the prespecified inclusion/exclusion criteria. Potassium supplementation caused a significant decrease in systolic BP (- 3.69 mmHg [-4.91, -2.46], P&amp;lt;0.001) and increase in serum potassium (+0.37 [0.23, 0.52] mmol/L, P&amp;lt;0.001). There was an increase in plasma aldosterone (standardised difference 0.414 [0.291, 0.537], P&amp;lt;0.001) but no effect on plasma renin activity (+0.033 [-0.07, 0.14], P=0.538]. Meta-regression showed a significant positive correlation between change in plasma aldosterone and change in serum potassium (P&amp;lt;0.001). (2) In 469 subjects (72% black), there was a positive association between the measured 24-hour potassium excretion and aldosterone in black (β = 0.200, P = 0.014) but not in white individuals (P = 0.531). Discussion/Conclusion Potassium supplementation increases plasma aldosterone but not renin. The increase in aldosterone correlates with the raise in serum potassium. In subjects with hypertension, potassium intake is related with aldosterone concentration only in black subjects. Overall, the data supports a RAAS-independent potassium regulation of aldosterone which could be particularly relevant in African origin subjects. Limitations: 1. the systematic review results could not be stratified by ethnicity because most of the studies were performed in Caucasian subjects, 2. Use of background therapy in some studies, variable doses of potassium supplementation and duration of supplementation.

Very-low-calorie ketogenic diet vs hypocaloric balanced diet in the prevention of high-frequency episodic migraine: the EMIKETO randomized, controlled trial

BackgroundMigraine is the second world’s cause of disability. Among non-pharmacological treatments, nutritional intervention, particularly ketogenic diet, represents one of the most promising approaches.MethodsThis a prospective, single center, randomized, controlled study aimed at evaluating the efficacy of a very low-calorie ketogenic diet (VLCKD) compared to a hypocaloric balanced diet (HBD) in migraine prophylaxis in patients affected by high-frequency episodic migraine (HFEM) with a Body Mass Index (BMI) > 27 kg/m2. Fifty-seven patients were randomly assigned to a VLCKD (group 1) or HBD (group 2). Group 1 patients followed a VLCKD for 8 weeks, followed by a low calorie diet (LCD, weeks 9–12), and a HBD (weeks 13–24), whereas group 2 patients followed a HBD from week 0 to 24. Anthropometric indexes, urine and blood chemistry were assessed at enrollment, baseline, weeks 4, 8, 12, and 24. Migraine characteristics were evaluated at baseline, weeks 8, 12 and 24. Change in monthly migraine days (MMDs) at weeks 5–8 compared to baseline was the primary endpoint. Secondary endpoints encompassed changes in visual analogue scale (VAS), Headache Impact Test-6 (HIT-6) and Short Form Health Survey-36 (SF-36) scores. We also studied effects on circulating lymphocytes and markers of inflammation, changes in plasma aldosterone and renin levels before and after VLCKD or HBD treatment.ResultsReduction from baseline in MMDs was greater in VLCKD compared to HBD group at week 8 (p = 0.008), at week 12 (p = 0.007), when ketosis had been interrupted by carbohydrates reintroduction, and at week 24 (p = 0.042), when all patients were following the same dietary regimen. Quality of life scores (SF-36) were improved in VLCKD group at week 8 and 12, and were also improved in HBD group, but only at week 12. Weight-loss was significantly higher in VLCKD group at week 8 (p = 0.002) and week 12 (p = 0.020). At the end of the study weight loss was maintained in VLCKD group whereas a slight weight regain was observed in HBD group. Inflammatory indexes, namely C reactive protein (CRP), neutrophil to lymphocyte ratio (NLR) and total white blood cell count (WBC) were significantly reduced (p < 0.05) in VLCKD group at week 12. Aldosterone plasma level were significantly increased in both groups at week 8, particularly in VLCKD group. However, electrolytes and renin plasma levels were never altered throughout the study in both groups.ConclusionsVLCKD is more effective than HBD in reducing MMD in patients with HFEM and represents an effective prophylaxis in patients with overweight/obesity.Trial registration ClinicalTrials.gov identifier: NCT04360148.

Renal and Endocrine Responses to Arm Exercise in Persons with Cervical Spinal Cord Injury

The aim of this study was to assess renal functions and endocrine responses to arm exercise in persons with cervical spinal cord injury (CSCI) under euhydrated conditions (free drinking of water), and to determine the physiological effects of exercise on renal function in these subjects. Eleven CSCI individuals (spinal lesions between C6 and C8, American Spinal Injury Association impairment scale A) and nine able-bodied (AB) persons rested for 30 min before performing 30 min arm-crank ergometer exercises at 50% of their maximum oxygen consumption, followed by 60-min of rest/recovery. Urine and blood samples were collected before and immediately after the exercise and recovery period. The CSCI patients showed no increase in plasma adrenaline and plasma renin activity compared with the AB controls, but showed similar changes in plasma aldosterone and the plasma antidiuretic hormone in response to the exercise. Creatinine clearance, osmolal clearance, free water clearance, and the fractional excretion of Na+ did not change during exercise in both groups of subjects, however free water clearance in the CSCI group was higher than in the AB group throughout the study. These findings suggested that activated plasma aldosterone without an increase in adrenaline or renin activity during exercise in CSCI individuals may reflect an adaptation to the disturbance of the sympathetic nervous system to compensate for renal function. As a result, no adverse effects of exercise on renal function in CSCI patients were observed.

Changes of plasma aldosterone and angiotensin II levels in patients with ischemic cardiomyopathy combined with Type-2 diabetes mellitus and their clinical significance.

To analyze the changes of plasma aldosterone (ALD) and angiotensin II (Ang II) levels in patients with ischemic cardiomyopathy (ICM) combined with Type-2 diabetes mellitus (T2DM) and their clinical significance. Sixty-eight patients with ICM combined with T2DM and fifty-two patients with simple ICM treated in the People's Hospital of Three Gorges University/the First People's Hospital of Yichang from February 2018 to February 2021 were selected as observation group and control group, respectively. All the patients had intervention with the same neuroendocrine hormone regime. The plasma ALD and Ang II and left ventricular function indexes (left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD)] were measured and compared between the two groups before and after treatment. The correlations of plasma ALD and Ang-II with left ventricular function before treatment were analyzed using Pearson's correlation analysis. The diagnostic efficacy of plasma ALD and Ang-II in ICM and T2DM was evaluated by the receiver operating characteristic (ROC) curve. Before treatment, the plasma ALD and Ang II levels in the observation group were (184.42 ± 56.75) ng/L and (46.68 ± 12.16) ng/L, respectively, which were significantly higher than those in the control group [(165.03 ± 45.67) ng/L and (39.70 ± 10.69) ng/L, p< 0.05]. Compared with before treatment, ALD level increased significantly in the observation group while decreased significantly in the control group after treatment (p< 0.05). After treatment, Ang-II level reduced significantly while LVEF increased significantly in both groups (p< 0.05). After treatment, plasma ALD and LVESD in the observation group were significantly higher than those in the control group (p< 0.05), but plasma Ang II level, LVEF and LVEDD showed no statistically significant differences between the two groups (p> 0.05). Before treatment, plasma ALD and Ang II were negatively correlated with LVEF (p< 0.05). Before treatment, the area under the curve (AUC) of plasma ALD and Ang II levels in diagnosing ICM combined with T2DM were 0.689 and 0.704, respectively. The plasma levels of ALD and Ang-II in patients with ICM combined with T2DM increase significantly, and their diagnostic value is not high. Compared with patients with simple ICM, the decrease in plasma ALD and Ang- II levels is less obvious after the same intervention, but it is still conducive to the improvement of cardiac function.

Effect of diuretics on plasma aldosterone and potassium in primary hypertension: A systematic review and meta-analysis.

By contrast with drugs inhibiting the renin-angiotensin-aldosterone system (RAAS), diuretics stimulate renin release by the kidneys. Although plasma aldosterone (PA) is thought to be mainly regulated by RAAS activity, serum potassium has been shown to be an important factor in animal models and humans. Here we perform a systematic review and meta-analysis of randomised controlled trials (RCT) in hypertension investigating the effects of diuretic therapy on PA and the correlation of change in PA with that of potassium and blood pressure (BP). Three databases were searched: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). Titles were first screened by title and abstract for relevance before full-text articles were assessed for eligibility according to a predefined inclusion/exclusion criteria. A total of 1139 articles were retrieved, of which 42 met the prespecified inclusion/exclusion criteria. The average standardised difference in mean PA was similar for all classes of diuretic: thiazide/thiazide-like 0.299 (95% confidence interval [CI] 0.150, 0.447), loop 0.927 (0.37, 1.49), MRA/potassium-sparing 0.265 (0.173, 0.357) and combination 0.466 (0.137, 0.796), Q = 6.33, P = .097. In subjects untreated with another antihypertensive, there was a significant relationship between change in PA and change in systolic BP but no relationship with the change in potassium. In RCTs of diuretic therapy in hypertension, there is an increase in PA with all classes of diuretic and no significant between-class heterogeneity. Change in PA is not related with potassium but correlates with the change in BP in subjects untreated with another antihypertensive medication.

Chronic Metabolic Acidosis Elicits Hypertension via Upregulation of Intrarenal Angiotensin II and Induction of Oxidative Stress

Chronic metabolic acidosis (CMA) can be a consequence of persistent hypertension but could potentially play a role in invoking hypertension. Currently, there is a scarcity of studies examining the outcome of induced chronic acidosis on blood pressure regulation. This study investigates CMA as a cause of hypertension. Chronic acidosis was induced in Sprague Dawley rats (100–150 g) by providing a weak acid solution of 0.28 M ammonium chloride (NH4Cl) in tap water for 8 weeks. To determine whether the rats were acidotic, blood pH was measured, while blood pressure (BP) was monitored by tail-cuff plethysmography weekly. Rats were divided into five groups: control, CMA, CMA ± spironolactone, captopril, and tempol. Serum sodium and potassium; renal interstitial fluid (for Angiotensin II concentration); and kidney proximal tubules (for Na+/K+ ATPase- α1 concentration) were analyzed. Reactive oxygen species (ROS) were detected in renal cortical homogenates using electron paramagnetic resonance (EPR). In the CMA rats, a sustained elevation in mean arterial pressure (MAP) associated with a significant decrease in blood pH was observed compared to that of control over the 8 weeks. A significant decrease in MAP was observed in acidotic rats treated with captopril/tempol, whereas spironolactone treatment caused no decrease in MAP as compared to that of the CMA group. The interstitial angiotensin II was increased in the CMA group but decreased in the CMA with captopril and tempol groups. In addition, the urinary sodium was decreased, and the serum sodium levels increased significantly in the CMA groups as compared to that of control. However, the acidotic groups with captopril and tempol showed reduced levels of serum sodium and an elevation in urinary sodium as compared to that of the CMA group. In addition, there was a significant increase in plasma renin and no change in plasma aldosterone in the CMA group with no significant differences in plasma renin or aldosterone observed during spironolactone, captopril, or tempol treatments. The increased expression of Na+/K+ ATPase-α1 in the CMA group suggests that active transport of Na+ to the blood could be causative of the observed hypertension. Furthermore, the EPR analysis confirmed an elevation in superoxide (O2-) radical levels in the CMA group, but the tempol/captopril treated acidotic groups showed less (O2-) compared to that of either the CMA group or control. Taken together, our data suggest that induction of CMA could potentially be causative of hypertension, while the mechanisms underlying the increased BP could be through the activation of intrarenal Ang II and induction of oxidative stress.

Normalizing Plasma Renin Activity in Experimental Dilated Cardiomyopathy: Effects on Edema, Cachexia, and Survival.

Heart failure (HF) patients frequently have elevated plasma renin activity. We examined the significance of elevated plasma renin activity in a translationally-relevant model of dilated cardiomyopathy (DCM), which replicates the progressive stages (A–D) of human HF. Female mice with DCM and elevated plasma renin activity concentrations were treated with a direct renin inhibitor (aliskiren) in a randomized, blinded fashion beginning at Stage B HF. By comparison to controls, aliskiren treatment normalized pathologically elevated plasma renin activity (p < 0.001) and neprilysin levels (p < 0.001), but did not significantly alter pathological changes in plasma aldosterone, angiotensin II, atrial natriuretic peptide, or corin levels. Aliskiren improved cardiac systolic function (ejection fraction, p < 0.05; cardiac output, p < 0.01) and significantly reduced the longitudinal development of edema (extracellular water, p < 0.0001), retarding the transition from Stage B to Stage C HF. The normalization of elevated plasma renin activity reduced the loss of body fat and lean mass (cachexia/sarcopenia), p < 0.001) and prolonged survival (p < 0.05). In summary, the normalization of plasma renin activity retards the progression of experimental HF by improving cardiac systolic function, reducing the development of systemic edema, cachexia/sarcopenia, and mortality. These data suggest that targeting pathologically elevated plasma renin activity may be beneficial in appropriately selected HF patients.

Role of the Renin Angiotensin System in Blood Pressure Allostasis-induced by Severe Food Restriction in Female Fischer rats

Severe food restriction (FR) is associated with blood pressure (BP) and cardiovascular dysfunction. The renin-angiotensin system (RAS) regulates BP and its dysregulation contributes to impaired cardiovascular function. Female Fischer rats were maintained on a control (CT) or severe FR (40% of CT) diet for 14 days. In response to severe FR, BP allostasis was achieved by up-regulating circulating Ang-[1–8] by 1.3-fold through increased angiotensin converting enzyme (ACE) activity and by increasing the expression of AT1Rs 1.7-fold in mesenteric vessels. Activation of the RAS countered the depressor effect of the severe plasma volume reduction (≥30%). The RAS, however, still underperformed as evidenced by reduced pressor responses to Ang-[1–8] even though AT1Rs were still responsive to the depressor effects of an AT1R antagonist. The aldosterone (ALDO) response was also inadequate as no changes in plasma ALDO were observed after the large fall in plasma volume. These findings have implications for individuals who have experienced a period(s) of severe FR (e.g., anorexia nervosa, dieters, natural disasters) and suggests increased activity of the RAS in order to achieve allostasis contributes to the cardiovascular dysfunction associated with inadequate food intake.

Changes in plasma aldosterone and electrolytes levels, kidney epithelial sodium channel (ENaC) and blood pressure in normotensive WKY and hypertensive SHR rats following gonadectomy and chronic testosterone treatment

We hypothesized that testosterone-induced increase in blood pressure involve changes in aldosterone levels and expression of epithelial sodium channel (ENaC) in the kidneys. MethodsOvariectomized female normotensive Wistar Kyoto (WKY) and Spontaneous hypertensive (SHR) rats were given six weeks treatment with testosterone via subcutaneous silastic implant. The rats were anesthetized and mean arterial pressure (MAP) was measured via direct cannulation of the carotid artery. Animals were sacrificed and kidneys were removed and subjected for α, β and γ-ENaC protein and mRNA expression analyses by Western blotting and Real-time polymerase chain reaction (qPCR), respectively. Distributions of α, β and γ-ENaC proteins in kidneys were observed by immunofluorescence. Plasma testosterone, aldosterone, electrolytes, osmolality, urea and creatinine levels were determined by biochemical assays. Analysis were also performed in non-testosterone treated orchidectomized and sham-operated male WKY and SHR rats. ResultsTreatment of ovariectomized female WKY and SHR rats with testosterone causes increased in MAP but decreased in plasma aldosterone, sodium (Na+), osmolality and expression and distribution of α, β and γ-ENaC subunits in the kidneys. Orchidectomy decreased the MAP but increased plasma aldosterone, Na+, osmolality and α, β and γ-ENaC expression and distribution in the kidneys of male WKY and SHR rats. ConclusionsDecreased in plasma aldosterone, Na+ and ENaC levels in kidneys under testosterone influence indicated that testosterone-induced increased in MAP were not due to increased plasma aldosterone and ENaC levels in kidneys, and thus the testosterone effect on MAP likely involve other mechanisms.

PP.17.24] THE RESPONSE OF PLASMA ALDOSTERONE TO SALINE INFUSION IS UNDER THE INFLUENCE OF AGE IN PRIMARY HYPERTENSION

Objective: In patients with primary hypertension, plasma aldosterone (PA) levels are significantly decreased by an intravenous saline load (IVSL), but this response is variable among patients and related to the ability of salt to modulate aldosterone production. Previous studies have reported that the activity of the renin-angiotensin-aldosterone system is related with age. The aim of this study was to investigate whether age might affect the aldosterone response to an IVSL. Design and method: In 124 hypertensive patients (48 ± 13 y, 71 males) who were washed-out of antihypertensive drugs for 2 weeks, we measured renin and PA levels before and after an IVSL (2 lt. saline in 4 h). In all patients secondary causes of hypertension were excluded. For statistical purposes patients were subdivided into two groups based on age (< or > 60 y). Results: Twenty-three of 124 patients (18%) were had 60 y of age or more (range 61–77) and the remaining were younger than 60 y (19–60 y). No differences were found between the two groups for gender, body mass index, serum potassium and creatinine clearance. Urinary sodium excretion was comparable in patients older (159 ± 83) or younger (159 ± 66) than 60 y. Baseline PA (76 [49–121] pg/ml) and renin (5.0 [1.9–9.8] mcIU/ml) levels were significantly lower in patients older than 60 y than in those younger than 60 y (115 [77–162] pg/ml, P = 0.019; 10.7 [5.1–20.8] mcIU/ml, P = 0.026). As expected IVSL decreased significantly (P < 0.001) both plasma renin and aldosterone levels. Post IVSL renin was 3.0 [1.1–4.9] mcIU/ml in patients older than 60 y and 6.2 [3.0–12.5] mcIU/ml younger than 60 y. Following IVSL, PA decreased by 87% (10 [10–13] pg/ml) in patients older than 60 y and by 76% (28 [10–49] pg/ml; P = 0.003) in patients younger than 60 y. The change in PA induced by IVSL was significantly and inversely related to age (r = -0.185, P = 0.039). Conclusions: PA levels are lower in hypertensive patients older than 60 y. This difference becomes more relevant after IVSL suggesting greater response of the renin-angiotensin system to volume expansion. This should be taken into account in the diagnostic work-up of hypertensive patients.

Clinical Experience With IV Angiotensin II Administration: A Systematic Review of Safety.

Angiotensin II is an endogenous hormone with vasopressor and endocrine activities. This is a systematic review of the safety of IV angiotensin II. PubMed, Medline, Scopus, and Cochrane. Studies in which human subjects received IV angiotensin II were selected whether or not safety was discussed. In total, 18,468 studies were screened by two reviewers and one arbiter. One thousand one hundred twenty-four studies, in which 31,281 participants received angiotensin II (0.5-3,780 ng/kg/min), were selected. Data recorded included number of subjects, comorbidities, angiotensin II dose and duration, pressor effects, other physiologic and side effects, and adverse events. The most common nonpressor effects included changes in plasma aldosterone, renal function, cardiac variables, and electrolytes. Adverse events were infrequent and included headache, chest pressure, and orthostatic symptoms. The most serious side effects were exacerbation of left ventricular failure in patients with congestive heart failure and bronchoconstriction. One patient with congestive heart failure died from refractory left ventricular failure. Refractory hypotensive shock was fatal in 55 of 115 patients treated with angiotensin II in case studies, cohort studies, and one placebo-controlled study. One healthy subject died after a pressor dose of angiotensin II was infused continuously for 6 days. No other serious adverse events attributable to angiotensin II were reported. Heterogeneity in study design prevented meta-analysis. Adverse events associated with angiotensin II were infrequent; however, exacerbation of asthma and congestive heart failure and one fatal cerebral hemorrhage were reported. This systematic review supports the notion that angiotensin II has an acceptable safety profile for use in humans.

Changes in Plasma Aldosterone and Electrolytes Following High-Volume and High-Intensity Resistance Exercise Protocols in Trained Men.

Boone, CH, Hoffman, JR, Gonzalez, AM, Jajtner, AR, Townsend, JR, Baker, KM, Fukuda, DH, and Stout, JR. Changes in plasma aldosterone and electrolytes following high-volume and high-intensity resistance exercise protocols in trained men. J Strength Cond Res 30(7): 1917-1923, 2016-Program variables such as training intensity, volume, and rest interval length are known to elicit distinct hormonal, metabolic, and physical responses. However, little is known regarding resistance exercise (RE) program design and the fluid regulatory response. This investigation aimed to compare the plasma aldosterone (ALD), electrolyte, plasma volume (PV), and osmolality (Posm) responses following high-volume (HV; 4-6 × 10-12 reps, 70% 1 repetition maximum [1RM], 60-s rest) and high-intensity (HI; 6 × 3-5 reps, 90% 1RM, 180-second rest) RE protocols. Ten experienced, resistance-trained men (24.7 ± 3.4 years; 90.1 ± 11.3 kg; 176.0 ± 4.9 cm) performed each protocol in a random, counterbalanced order. Blood samples were obtained at baseline (BL), immediately (IP), 30 minutes (30P), and 1 hour (1H) postexercise. Significant trial × time interactions (p < 0.01) were observed in Posm, sodium (Na), and potassium (K), whereas a trend (p = 0.06) was observed for ALD. The PV shift from BL-30P was greater than BL-IP and BL-1H (p ≤ 0.05), but no significant between-trial differences were noted. Comparisons between RE protocols revealed significantly greater (p ≤ 0.05) elevations during HV vs. HI in Posm at IP, 30P, and 1H; and Na at IP and 30P. During HV, significant reductions (p ≤ 0.05) were noted in K at IP compared with HI. Area under the curve analysis indicates a trend (p = 0.07) toward a higher ALD response following HV compared with HI. Results of this study indicate that high-volume, moderate-intensity resistance exercise seems to augment the fluid regulatory response to a greater extent than low-volume, high-intensity training.

GPR30, Mineralocorticoid Receptors, and the Rapid Vascular Effects of Aldosterone

See related article, pp 442–451 It is now generally accepted that in common with other steroid hormones aldosterone has rapid nongenomic effects, in addition to those mediated via DNA-directed, RNA-mediated protein synthesis. The currently accepted physiology of aldosterone was primarily charted by nephrologists, who understandably focused on the epithelial (and genomic) effects of aldosterone on urinary electrolytes, and the homeostatic changes in aldosterone secretion in response to sodium deficiency or potassium loading. The most acute physiological stimulus to aldosterone secretion, however, is assumption of the upright posture. Given this, it is not inappropriate to seek responses, similarly acute, to this rapid change in plasma aldosterone levels. In the paper by Gros et al,1 the authors conclusively show that aldosterone at low picomolar concentrations can act rapidly via both GPR30 (originally an “orphan” G protein–coupled receptor, subsequently an erstwhile membrane estrogen receptor) and classic mineralocorticoid receptors (MR) over a range of parameters. These include extracellular signal-regulated kinase (ERK) 1/2 activation and myosin light chain phosphorylation in rat aortic vascular smooth muscle cells (VSMC) in vitro; for ERK activation, aldosterone has equivalent action via both receptors at low picomolar concentrations. The effects on GPR30 appear mineralocorticoid specific: in rat aortic endothelial cells, with MR expression below detection levels by Western blotting, aldosterone increased ERK activation with an EC50 < 10 pM, an action abrogated by the GPR30 antagonist G15. In contrast, the effect of estradiol on inhibition of ERK activation was unaffected by G15 but blocked by the estrogen receptor α (ERα) antagonist ICI-182780. The first point to be made is that these studies firmly establish GPR30 as a bona fide receptor for aldosterone, given the low picomolar concentrations used (except for myosin light chain phosphorylation, where inexplicably 10 nmol/L aldosterone was used, and Figures 8 and 9 point in …

Pituitary Peptides other than ACTH may not be Aldosterone Secretagogue in Primary Aldosteronism

In order to elucidate whether pituitary peptides other than ACTH which are derived from the proopiomelanocortin (POMC) are involved for aldosterone secretion in primary aldosteronism, we administered ovine corticotropin releasing factor (CRF), beta-endorphin and naloxone to seven patients with aldosterone producing adenoma. One hundred micrograms of CRF produced an augmented aldosterone response in patients with aldosteronism, while 500 micrograms of beta-endorphin infusion failed to cause any significant changes in neither normal subjects nor patients. An opioid antagonist, naloxone (10 mg, iv) produced no noticeable change in plasma aldosterone in normal subjects, while it caused a slight increase in patients with primary aldosteronism. Plasma cortisol increased to a similar degree in response to CRF and naloxone in normal subjects and patients. In three patients with isolated ACTH deficiency, neither aldosterone nor cortisol responded to these stimuli. The present results indicate that POMC-derived pituitary peptides other than ACTH are unlikely to participate in the aldosterone secretion in normal subjects or in patients with primary aldosteronism.

Relaxin-induced changes in renal sodium excretion in the anesthetized male rat

Pregnancy is associated with profound changes in renal hemodynamics and electrolyte handling. Relaxin, a hormone secreted by the corpus luteum, has been shown to induce pregnancy-like increases in renal blood flow and glomerular filtration rate (GFR) and alter osmoregulation in nonpregnant female and male rats. However, its effects on renal electrolyte handling are unknown. Accordingly, the influence of short (2 h)- and long-term (7 day) infusion of relaxin on renal function was determined in the male rat. Short term infusion of recombinant human relaxin (rhRLX) at 4 microg.h(-1).100 g body wt(-1) induced a significant increase in effective renal blood flow (ERBF) within 45 min, which peaked at 2 h of infusion (vehicle, n = 6, 2.1 +/- 0.4 vs. rhRLX, n = 7, 8.1 +/- 1.1 ml.min(-1).100 g body wt(-1), P < 0.01). GFR and urinary excretion of electrolytes were unaffected. After a 7-day infusion of rhRLX at 4 microg/h, ERBF (1.4 +/- 0.2 vs. 2.5 +/- 0.4 ml.min(-1).100 g body wt(-1), P < 0.05), urine flow rate (3.1 +/- 0.3 vs. 4.3 +/- 0.4 microl.min(-1).100 g body wt(-1), P < 0.05) and urinary sodium excretion (0.8 +/- 0.1 vs. 1.2 +/- 0.1 micromol.min(-1).100 g body wt(-1), P < 0.05) were significantly higher; plasma osmolality and sodium concentrations were lower in rhRLX-treated rats. These data show that long-term relaxin infusion induces a natriuresis and diuresis in the male rat. The mechanisms involved are unclear, but they do not involve changes in plasma aldosterone or atrial natriuretic peptide concentrations.

Low plasma aldosterone despite normal plasma renin activity in uncomplicated type 1 diabetes mellitus: effects of RAAS stimulation.

Data on levels and responsiveness of PRA and aldosterone in type 1 diabetes mellitus are conflicting. Earlier studies were not standardized with respect to the type of diabetes mellitus, the presence of diabetic complications or sodium intake. Therefore, we studied plasma renin activity and plasma aldosterone in uncomplicated type 1 diabetes mellitus by evaluating the effects of endogenous (sodium restriction) and exogenous (angiotensin I infusion) stimulation. Twenty-four type 1 diabetic patients and 24 matched healthy subjects were studied after 1 week of liberal sodium diet (200 mmol 24 h-1) and 1 week of low sodium diet (50 mmol 24 h-1). Angiotensin (Ang)I was infused at 4 and 8 ng kg-1 min-1 during both study days. During liberal and low sodium intake, plasma aldosterone was lower in type 1 diabetic patients compared with healthy subjects both at 08:00 h (P < 0.05) and after a 2-h euglycaemic clamp (P < 0.05), despite similar PRA levels. The correlations between changes in PRA and changes in plasma aldosterone when shifting sodium intake were similar in both groups. During liberal sodium intake, the aldosterone levels after AngI infusion were lower in type 1 diabetic patients, whereas during low sodium they were not different. Plasma aldosterone was deceased relative to PRA in uncomplicated type 1 diabetic patients, irrespective sodium intake. The responsiveness to sodium restriction was adequate and sodium restriction was able to overcome the decreased plasma aldosterone response to exogenous AngI, which was observed during liberal sodium in diabetic patients. The lower aldosterone is not secondary to diabetic complications and does not depend on the level of sodium intake.

Circadian variations of plasma renin activity (PRA), aldosterone and electrolyte concentrations in plasma in pregnant and non-pregnant goats

The aim of this study was to estimate and analyse circadian variations of the renin–angiotensin–aldosterone system (RAA) activity in blood of goats and the influence of late pregnancy on the circadian variations of RAA system. The study was carried out on a group of 17 non-pregnant and 9 pregnant goats. The animals were kept in uniform environmental conditions, (9 h light/15 h darkness). Blood samples were collected seven times over a period of 24 h, every 4 h. Plasma renin activity (PRA), plasma aldosterone (PA), sodium, potassium and chloride concentrations were determined. PRA and PA of both groups changed during 24 h, with the highest values in the dark phase and with higher RAA system activity (especially during the night) in the pregnant goats. In the non-pregnant goats, no circadian changes in PRA and PA were observed. The circadian changes in PRA and PA found in pregnant goats had acrophases at 06:27 h and 01:13 h, respectively. Plasma electrolyte concentrations in both groups of goats also changed during 24 h. These results suggest that circadian changes of potassium concentration in plasma of goats during late pregnancy may be one of the main factors affecting the RAA system.