Increase In Plasma Renin Activity Research Articles

Effects of peripherally and centrally applied ghrelin on the oxidative stress induced by renin angiotensin system in a rat model of renovascular hypertension.

Renovascular hypertension (RVH) is a result of renal artery stenosis, which is commonly due to astherosclerosis. In this study, we aimed to clarify the central and peripheral effects of ghrelin on the renin-angiotensin system (RAS) in a rat model of RVH. RVH was induced in rats by partial subdiaphragmatic aortic constriction. Experiment A was designed to assess the central effect of ghrelin via the intracerebroventricular (ICV) injection of ghrelin (5 μg/kg) or losartan (0.01 mg/kg) in RVH rats. Experiment B was designed to assess the peripheral effect of ghrelin via the subcutaneous (SC) injection of ghrelin (150 μg/kg) or losartan (10 mg/kg) for 7 consecutive days. Mean arterial blood pressure (MAP), heart rate, plasma renin activity (PRA), and oxidative stress markers were measured in all rats. In addition, angiotensin II receptor type 1 (AT1R) concentration was measured in the hypothalamus of rats in Experiment B. RVH significantly increased brain AT1R, PRA, as well as the brain and plasma oxidative stress. Either SC or ICV ghrelin or losartan caused a significant decrease in MAP with no change in the heart rate. Central ghrelin or losartan caused a significant decrease in brain AT1R with significant alleviation of the brain oxidative stress. Central ghrelin caused a significant decrease in PRA, whereas central losartan caused a significant increase in PRA. SC ghrelin significantly decreased PRA and plasma oxidative stress, whereas SC losartan significantly increased PRA and decreased plasma oxidative stress. The hypotensive effect of ghrelin is mediated through the amelioration of oxidative stress, which is induced by RAS centrally and peripherally.

Increased Aldosterone Release During Head-Up Tilt in Early Primary Hypertension.

Hyperaldosteronism is well known cause of secondary hypertension. However, the importance of aldosterone for the much larger group of patients with primary hypertension is less clear. We hypothesized that in young subjects with primary hypertension, the rise of plasma aldosterone levels in response to head-up tilt testing as a stress stimulus is exaggerated. Hemodynamics (blood pressure (BP), heart rate (HR), cardiac index (CI), and total peripheral vascular resistance index (TPRI), all by TaskForce monitor) and hormones (plasma renin activity (PRA), angiotensin II (Ang II), aldosterone) were measured before and during 30 minutes of head-up tilt in 45 young hypertensive and 45 normotensive subjects. BP, HR, CI, and TPRI all increased in response to head-up tilt, with no difference between groups. There was no difference in baseline PRA, Ang II, and aldosterone between groups. During head-up tilt, PRA, and Ang II levels increased similarly. However, aldosterone levels increased to a greater extent in the hypertensive vs. normotensive subjects (P = 0.0021). Our data suggest that an increased release of aldosterone in response to orthostatic stress is a feature of early primary hypertension. The similar increase in PRA and Ang II suggests a potential role for secretagogues of aldosterone other than Ang II in this response. In addition to its established role in secondary hypertension, dysregulation of aldosterone release might contribute to the development of primary arterial hypertension.

Glucocorticoid-induced leucine zipper protein regulates sodium and potassium balance in the distal nephron

Glucocorticoid induced leucine zipper protein (GILZ) is analdosterone-regulated protein that controls sodium transport in cultured kidney epithelial cells. Mice lacking GILZ have been reported previously to have electrolyte abnormalities. However, the mechanistic basis has not been explored. Here we provide evidence supporting a role for GILZ in modulating the balance of renal sodium and potassium excretion by regulating the sodium-chloride cotransporter (NCC) activity in the distal nephron. Gilz-/- mice have a higher plasma potassium concentration and lower fractional excretion of potassium than wild type mice. Furthermore, knockout mice are more sensitive to NCC inhibition by thiazides than are the wild type mice, and their phosphorylated NCC expression is higher. Despite increased NCC activity, knockout mice do not have higher blood pressure than wild type mice. However, during sodium deprivation, knockout mice come into sodium balance more quickly, than do the wild type, without a significant increase in plasma renin activity. Upon prolonged sodium restriction, knockout mice develop frank hyperkalemia. Finally, in HEK293T cells, exogenous GILZ inhibits NCC activity at least in part by inhibiting SPAK phosphorylation. Thus, GILZ promotes potassium secretion by inhibiting NCC and enhancing distal sodium delivery to the epithelial sodium channel. Additionally, Gilz-/- mice have features resembling familial hyperkalemic hypertension, a human disorder that manifests with hyperkalemia associated variably with hypertension.

Angiotensin-Converting Enzyme Inhibition and Parathyroid Hormone Secretion.

Background Prior studies suggest that renin-angiotensin-aldosterone system (RAAS) inhibitors decrease parathyroid hormone (PTH) secretion. Objective To evaluate the effect of angiotensin-converting enzyme inhibitors (ACEi) on serum PTH in participants with and without primary hyperparathyroidism (P-HPT). Methods An open-label, single-arm, pilot study whereby participants with and without P-HPT had PTH were evaluated before and after 1 week of maximally tolerated lisinopril therapy. Results A total of 12 participants with, and 15 participants without, P-HPT successfully completed the protocol. Following 1 week of lisinopril, participants with P-HPT had a decrease in systolic blood pressure (SBP) (−6.4 mmHg, P < 0.01), an increase in plasma renin activity (PRA) (+1.50 ng/mL/h, P = 0.06), and a decrease in PTH (79.5 (21.6) to 70.9 (19.6) pg/mL, ∆ = −8.6 pg/mL, P = 0.049); however, serum and urine calcium did not change. In contrast, although 1 week of lisinopril significantly decreased SBP and increased PRA among participants without P-HPT, there were no changes in PTH or calcium. Conclusion In this short pilot investigation, 1 week of maximally titrated ACEi did not impact PTH in participants without P-HPT, but resulted in a modest and marginally significant reduction of PTH but not calcium, among participants with P-HPT. This trial is registered with ClinicalTrials.gov NCT01691781.

Urinary Angiotensinogen Could Be a Prognostic Marker of the Renoprotection of Olmesartan in Metabolic Syndrome Patients.

This study was performed to demonstrate urinary angiotensinogen as a potential prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome. In 24 patients (eight women, 57.88 ± 2.00 years), 5–40 mg/day of olmesartan were given. Urinary concentrations of albumin and angiotensinogen (normalized by urinary concentrations of creatinine) and plasma renin activity were measured before and after the 12- and 24-week marks of olmesartan treatment. Olmesartan treatment increased plasma renin activity and decreased urinary albumin and urinary angiotensinogen significantly (p < 0.05). Based on the % change in urinary albumin, patients were divided into two groups, responders (<−50%) and non-responders (≥−50%), and a logistic analysis of urinary angiotensinogen before treatment showed the area under the curve as 0.694. When the cutoff value of urinary angiotensinogen before the treatment of 13.9 µg/g Cr was used, the maximum Youden index (0.500, specificity: 11/12 = 91.7% and sensitivity: 7/12 = 58.3%) was obtained. When all patients were re-divided into two groups, those with higher values of urinary angiotensinogen before the treatment (Group H, n = 16) and those with lower values, Group H showed significantly decreased urinary albumin (p < 0.05). Therefore, urinary angiotensinogen could be a prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome.

OS 31-03 CLINICAL EFFECTIVENESS OF ANTI-HYPERTENSIVE THERAPY WITH ACEI OR ARB ASSESSED BY PLASMA RENIN ACTIVITY/PLASMA ALDOSTERONE CONCENTRATION RATIO

ACE inhibitors and angiotensin receptor blockers (ARB) modulate the renin-angiotensin system (RAS) leading to an increase in plasma renin activity (PRA) together with a reduction of plasma aldosterone concentration (PAC), likely proportional to the pharmacological effect. Aim: to evaluate the efficacy of therapy based on ACEI or ARB, using PRA/PAC ratio values in real-life clinical-practice. We studied 184 essential hypertensives (59.2 ± 11.9 years, 63% males) in stable treatment for at least three months with an ACEI or ARB as part of the treatment. PRA was expressed as ng/ml and PAC as ng/dl, and then the ratio was multiplied by 100. Tertiles of PRA/PAC ratio were considered for the analysis. ABPM was performed to evaluate the BP control. Tertiles of PRA/PAC: 1st 0.2 to 5.7; 2nd 5.9 to 28.4; 3rd 29.4 to 509.8. There was no difference by age, sex, BMI and eGFR between PRA/PAC tertiles. A significant reduction in 24hour, daytime and night-time BP values was associated with increasing PRA/PAC tertiles (all p < 0.05). An increase of PRA/PAC tertiles was associated with a higher prevalence of controlled patients during the night-time period (1st: 14.5%; 2nd: 43.3%; 3rd: 45.9%; p < 0.001). PRA/PAC ratio was also a predictor of night-time BP control, as shown by ROC curve (AUC: 0.664, 95% CI: 0.582–0.745; p < 0.001). An increasing PRA/PAC ratio reflects reduced values of PAC despite higher values of PRA as expression of a more effective RAS blockade by ACEIs or ARBs. These findings are associated with lower BP values and better BP control, especially in night-time period, highlighting the effectiveness and compliance to the anti-hypertensive therapy with ACEI or ARB. Therefore, PRA/PAC ratio may be not only a useful biomarker of effective treatment based on ACEI or ARB, but also can be used an indirect index of drug intake and therapy compliance.

Effects of repeated freeze–thaw cycles on endocrine parameters in plasma and serum

Background Repeated freezing and thawing of plasma (or serum) may influence the stability of plasma (or serum) constituents. Despite the alarming warnings from commercial manuals that freeze-thaw cycles affect the stability of hormones in plasma (or serum), surprisingly little, consistent information about this concept is available in literature. Methods We studied the stability of 15 endocrine parameters (adrenocorticotropic hormone, osteocalcin, plasma renin activity, α-subunits, cortisol binding globulin, glucagon, inhibin B, fT4, TT4, TT3, rT3, TBG, TSH, chromogranin A and thyroglobulin upon repeated freeze-thaw cycles in plasma (or serum) samples from 10 volunteers. Blood was collected by venipuncture and after centrifugation and aliquoting, all samples were frozen at -20℃. Aliquots were thawed up to four times and changes in concentrations of endocrine parameters were compared to baseline condition. Results Repeated freeze-thaw cycling resulted in significant and relevant increases of plasma renin activity and a small decrease of adrenocorticotropic hormone. Conclusions For most of the analysed endocrine parameters, we found no effects of multiple freeze-thaw cycles despite alarming notifications in assay manuals. Plasma renin activity was the only endocrine parameter that showed significant and relevant changes following repeated freeze-thaw cycling.

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Aliskiren update

Effect of benazepril, robenacoxib and their combination on glomerular filtration rate in cats.

BackgroundCombined use of angiotensin-converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs may induce acute kidney injury in humans, especially when combined with diuretics. The objective of this investigation was to evaluate the effects of benazepril, robenacoxib and their combination in healthy cats.In each of two studies (study 1 followed by study 2), 32 healthy cats were randomised to one of four groups (n = 4 male and 4 female cats per group) in a parallel-group design. The groups received orally once daily for 7 days either placebo (control group), benazepril, robenacoxib or benazepril plus robenacoxib. In study 2, all groups received in addition 0.5 mg/kg furosemide twice daily by subcutaneous injection for 7 days.ResultsBenazepril, robenacoxib and their combination were well tolerated as evidenced from lack of clinical signs and no negative effects on body weight, feed consumption and clinical chemistry, haematology and urinalysis variables.The primary endpoint of the study was the glomerular filtration rate (GFR), which was estimated from the plasma clearance of iohexol. In the absence of furosemide, GFR was significantly higher in cats receiving the combination of benazepril plus robenacoxib compared to the other three groups, and was also significantly higher in females receiving only benazepril compared to the control.Administration of furosemide induced diuresis, reduced GFR and activated the renin-aldosterone-angiotensin system, evidenced from increased plasma renin activity and plasma aldosterone concentrations. Compared to the control group in cats treated with furosemide, GFR was increased by benazepril (females only) but decreased by robenacoxib (males only). Benazepril, robenacoxib and their combination significantly inhibited the increase in plasma aldosterone induced by furosemide.ConclusionsThe combination of benazepril and robenacoxib was well tolerated and either increased or had a neutral effect on GFR in healthy cats without or with concomitant furosemide. The combination of benazepril and robenacoxib reduced plasma aldosterone concentrations increased by furosemide. It is recommended to test the efficacy and safety of the combined use of benazepril and robenacoxib in cats with clinical disease, notably proteinuric chronic kidney disease.

Effects of the Water Extracts of Mantidis Ootheca, Rosa Laevigata, and Imperata Cylindrica on Blood Pressure in Renovascular Hypertension Induced by 2K 1C

The aim of the present study is to investigate the hypotensive effect of Mantidis ootheca (WMO), Rosa laevigata (WIC), and Imperata cylindrica (WRL) in renovascular hypertension rats. Experimental hypertension model is 2-kidney and 1-clip (2K1C) induced rats. 2K1C rats were treated with WMO, WIC, and WRL at dose of 100 mg/kg/day orally for 3 weeks, respectively. Treatment groups with WMO, WIC, and WRL significantly lowered blood pressure. Interestingly, WMO, WIC, and WRL ameliorated endothelium-dependent and independent vascular relaxation in the phenylephrine-precontracted thoracic aorta in hypertension models. In addition, 2K1C-induced hypertension model increased plasma renin activity, however, WMO, WIC, and WRL attenuated those activities. These results suggest that WMO, WIC, and WRL ameliorates vascular dysfunction in 2K1C-induced hypertension models via the regulation of nitric oxide and renin-angiotensin-aldosterone system.

Fixed-dose combination therapy of nebivolol and valsartan for the treatment of hypertension

ABSTRACTRecent large clinical trials have refuted earlier suggestions from the Joint National Committee 8 committee that less aggressive targets for blood pressure control were all that could be justified in most hypertensive patients. It now does appear that in fact “lower is better,” with blood pressure targets < 120/80 mm Hg appropriate for many hypertensive patients. Two drug combinations are often indicated as initial therapy if a 20/10 mm Hg or greater blood pressure reduction is necessary to reach target. Combinations consisting of β-blockers and renin-angiotensin-aldosterone system inhibitors have previously been deemed “less effective,” based on partially overlapping mechanisms of action and limited clinical trial evidence. Nebivolol is a vasodilating β1-selective blocker and β3- adrenoceptor agonist; β3-adrenoceptor activation increases nitric oxide concentrations and thus explains the vasodilatory effect. A recent 8-week randomized trial (N=4,161) in individuals with stage 1-2 hypertension demonstrated that single-pill fixed dose combinations (FDC) of nebivolol and valsartan, an angiotensin II subtype 1 receptor blocker, were more effective in reducing blood pressure than the corresponding monotherapies, with comparable tolerability. In addition, an ABPM-biomarkers substudy from that trial (n=805) demonstrated that the FDC prevented a valsartan-induced increase in plasma renin activity, and that the nebivolol/valsartan 20/320 mg/day dose reduced plasma aldosterone concentration significantly more than valsartan 320 mg/day. This article will describe the properties of nebivolol that make it unique and separate it from other β-blockers, and will further support the pharmacological advantages of this particular combination.

Evaluation of the clinical effectiveness of ACEI or ARB in hypertension using plasma renin activity/plasma aldosterone concentration ratio

Renin-angiotensin system (RAS) modulation is considered a cornerstone of hypertension therapy and ACE inhibitors and angiotensin receptor (AR) blockers are among the most widely used anti-hypertensive drugs. The expected effects on the RAS are an increase in plasma renin activity (PRA) together with a reduction of plasma aldosterone concentration (PAC), proportional to the efficacy of ACE or AR blockade. Aim: evaluation of real-life clinical-practice efficacy of stable therapies based on ACE or AR blockers, using PRA / PAC ratio values. We studied 184 essential hypertensives (59.2 11.9 years, 63% males) in stable treatment for at least three months with an ACEI or ARB as part of the treatment. PRA was expressed as ng/ml and PAC as ng/dl, then the ratio was multiplied by 100. Tertiles of PRA/PAC ratio were considered for the analysis. ABPM was performed to evaluate the BP control. Tertiles of PRA/PAC: 1st 0.2 to 5.7; 2nd 5.9 to 28.4; 3rd 29.4 to 509.8. There was no difference by age, sex, BMI and eGFR between PRA/PAC tertiles. A significant reduction in 24hour, daytime and nighttime BP values was associated with increasing PRA/PAC tertiles (all p<0.05). An increase of PRA/ PAC tertiles was associated with a higher prevalence of controlled patients during the nighttime period (1st: 14.5%; 2nd: 43.3%; 3rd: 45.9%; p<0.001 for trend). PRA/PAC ratio was also a predictor of nighttime BP control, as shown by ROC curve (AUC: 0.664, 95% CI: 0.582-0.745; p<0.001). An increasing PRA/PAC ratio reflects, in most cases, reduced values of PAC despite higher values of PRA as expression of a more effective RAS blockade by ACEIs or ARBs. These findings are associated with lower BP values and better BP control, especially in nighttime period, highlighting the effectiveness and compliance to the anti-hypertensive therapy with ACEI or ARB. Therefore, PRA/PAC ratio may be not only a useful biomarker of effective treatment based on ACEI or ARB, but also it can be used as an indirect index of drug intake and therapy compliance.

Trends in antihypertensive medication use among persons with resistant hypertension in the U.S. from 2008-2013

Renin-angiotensin system (RAS) modulation is considered a cornerstone of hypertension therapy and ACE inhibitors and angiotensin receptor (AR) blockers are among the most widely used anti-hypertensive drugs. The expected effects on the RAS are an increase in plasma renin activity (PRA) together with a reduction of plasma aldosterone concentration (PAC), proportional to the efficacy of ACE or AR blockade. Aim: evaluation of real-life clinical-practice efficacy of stable therapies based on ACE or AR blockers, using PRA / PAC ratio values. We studied 184 essential hypertensives (59.2 11.9 years, 63% males) in stable treatment for at least three months with an ACEI or ARB as part of the treatment. PRA was expressed as ng/ml and PAC as ng/dl, then the ratio was multiplied by 100. Tertiles of PRA/PAC ratio were considered for the analysis. ABPM was performed to evaluate the BP control. Tertiles of PRA/PAC: 1st 0.2 to 5.7; 2nd 5.9 to 28.4; 3rd 29.4 to 509.8. There was no difference by age, sex, BMI and eGFR between PRA/PAC tertiles. A significant reduction in 24hour, daytime and nighttime BP values was associated with increasing PRA/PAC tertiles (all p<0.05). An increase of PRA/ PAC tertiles was associated with a higher prevalence of controlled patients during the nighttime period (1st: 14.5%; 2nd: 43.3%; 3rd: 45.9%; p<0.001 for trend). PRA/PAC ratio was also a predictor of nighttime BP control, as shown by ROC curve (AUC: 0.664, 95% CI: 0.582-0.745; p<0.001). An increasing PRA/PAC ratio reflects, in most cases, reduced values of PAC despite higher values of PRA as expression of a more effective RAS blockade by ACEIs or ARBs. These findings are associated with lower BP values and better BP control, especially in nighttime period, highlighting the effectiveness and compliance to the anti-hypertensive therapy with ACEI or ARB. Therefore, PRA/PAC ratio may be not only a useful biomarker of effective treatment based on ACEI or ARB, but also it can be used as an indirect index of drug intake and therapy compliance.

Neural Control of Blood Pressure in Chronic Intermittent Hypoxia.

Sleep apnea (SA) is increasing in prevalence and is commonly comorbid with hypertension. Chronic intermittent hypoxia is used to model the arterial hypoxemia seen in SA, and through this paradigm, the mechanisms that underlie SA-induced hypertension are becoming clear. Cyclic hypoxic exposure during sleep chronically stimulates the carotid chemoreflexes, inducing sensory long-term facilitation, and drives sympathetic outflow from the hindbrain. The elevated sympathetic tone drives hypertension and renal sympathetic activity to the kidneys resulting in increased plasma renin activity and eventually angiotensin II (Ang II) peripherally. Upon waking, when respiration is normalized, the sympathetic activity does not diminish. This is partially because of adaptations leading to overactivation of the hindbrain regions controlling sympathetic outflow such as the nucleus tractus solitarius (NTS), and rostral ventrolateral medulla (RVLM). The sustained sympathetic activity is also due to enhanced synaptic signaling from the forebrain through the paraventricular nucleus (PVN). During the waking hours, when the chemoreceptors are not exposed to hypoxia, the forebrain circumventricular organs (CVOs) are stimulated by peripherally circulating Ang II from the elevated plasma renin activity. The CVOs and median preoptic nucleus chronically activate the PVN due to the Ang II signaling. All together, this leads to elevated nocturnal mean arterial pressure (MAP) as a response to hypoxemia, as well as inappropriately elevated diurnal MAP in response to maladaptations.

Chronic Metabolic Acidosis Activates Renal Tubular Sodium Chloride Cotransporter through Angiotension II-dependent WNK4-SPAK Phosphorylation Pathway

The mechanism by which chronic metabolic acidosis (CMA) regulates sodium (Na+)-chloride (Cl−) cotransporter (NCC) in the renal distal convoluted tubules remains unexplored. We examined the role of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and with-no-lysine kinase 4 (WNK4) on expression of NCC in mouse models of CMA. CMA was induced by NH4Cl in wild type mice (WTA mice), SPAK, and WNK4 knockout mice. The quantities of Ncc mRNA, expression of total NCC, phosphorylated (p)-NCC, SPAK and WNK4 in the kidneys as well as NCC inhibition with hydrochlorothiazide and Na+ balance were evaluated. Relative to WT mice, WTA mice had similar levels of Ncc mRNA, but increased expression of total and p-NCC, SPAK, and WNK4 and an exaggerated response to hydrochlorothiazide which could not be observed in SPAK or WNK4 knockout mice with CMA. In WTA mice, increased plasma renin activity, aldosterone and angiotensin II concentrations accompanied by a significantly negative Na+ balance. High Na+ diet abolished the enhanced NCC expression in WTA mice. Furthermore, an angiotensin II type 1 receptor blocker rather than a mineralocorticoid receptor antagonist exerted a marked inhibition on Na+ reabsorption and NCC phosphorylation in WTA mice. CMA increases WNK4-SPAK-dependent NCC phosphorylation and appears to be secondary to previous natriuresis with volume-dependent angiotensin II activation.

The ethanol metabolite acetaldehyde induces water and salt intake via two distinct pathways in the central nervous system of rats

The sensation of thirst experienced after heavy alcohol drinking is widely regarded as a consequence of ethanol (EtOH)-induced diuresis, but EtOH in high doses actually induces anti-diuresis. The present study was designed to investigate the introduction mechanism of water and salt intake after heavy alcohol drinking, focusing on action of acetaldehyde, a metabolite of EtOH and a toxic substance, using rats. The aldehyde dehydrogenase (ALDH) inhibitor cyanamide was used to mimic the effect of prolonged acetaldehyde exposure because acetaldehyde is quickly degraded by ALDH. Systemic administration of a high-dose of EtOH at 2.5 g/kg induced water and salt intake with anti-diuresis. Cyanamide enhanced the fluid intake following EtOH and acetaldehyde administration. Systemic administration of acetaldehyde with cyanamide suppressed blood pressure and increased plasma renin activity. Blockade of central angiotensin receptor AT1R suppressed the acetaldehyde-induced fluid intake and c-Fos expression in the circumventricular organs (CVOs), which form part of dipsogenic mechanism in the brain. In addition, central administration of acetaldehyde together with cyanamide selectively induced water but not salt intake without changes in blood pressure. In electrophysiological recordings from slice preparations, acetaldehyde specifically excited angiotensin-sensitive neurons in the CVO. These results suggest that acetaldehyde evokes the thirst sensation following heavy alcohol drinking, by two distinct and previously unsuspected mechanisms, independent of diuresis. First acetaldehyde indirectly activates AT1R in the dipsogenic centers via the peripheral renin-angiotensin system following the depressor response and induces both water and salt intake. Secondly acetaldehyde directly activates neurons in the dipsogenic centers and induces only water intake.

A case of Bartter's syndrome associated with nephrocalcinosis presenting with tetany

A 10-year-old boy was admitted to hospital with a 3 month history of intermittent spasms of the wrists and ankles, and twitching of the eyelids. He also had polyuria, polydipsia, nocturnal enuresis, fatigue and constipation since he was a toddler. Physical examination revealed normal blood pressure, myokymia on the right eyelid and bilateral carpopedal spasms. Laboratory investigation revealed hypocalcemia, hypokalemia, increased plasma renin and aldosterone , hypercalciuria, metabolic alkalosis, and bilateral medullary nephrocalcinosis. Cranial computed tomography was normal. Based on the clinical and laboratory findings he was diagnosed as having Bartter’s syndrome, which is characterized by hypochloremia, hypokalaemia and metabolic alkalosis associated with potassium renal leakage, with normal blood pressure despite increased plasma renin activity. It is well known that tetany is not uncommon in the neonatal form of Bartter’s syndrome and nephrocalcinosis is usually not present in the classic form. Interestingly, our patient had both the clinical manifestations of the neonatal form and of the classic form of Bartter’s syndrome. In conclusion, we would like to emphasize that both the clinical manifestations of neonatal and classic forms of Bartter’s syndrome (as an overlapping syndrome) might be seen in children and that Bartter’s syndrome should also be considered in children with tetany as in our case. (J Pediatr Neurol 2004; 2 (1): 45-47).

Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion.

Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 μg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry-based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and α- and γ-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal γENaC[112-122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and αENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal γENaC[112-122] concentration may provide a useful biomarker of ENaC activation in future clinical studies.

Short-term dietary salt supplementation blunts telmisartan induced increases in plasma renin activity in hypertensive patients with type2 diabetes mellitus.

Current guidelines recommend low dietary salt intake (LDS) in patients with diabetes to reduce blood pressure (BP). However, low salt intake has been associated with higher mortality rates in people with diabetes. Our aim is to examine the effect of angiotensin II receptor blocker (ARB), telmisartan, with and without dietary sodium chloride (NaCl) supplementation, on BP [mean arterial pressure (MAP)], plasma renin activity (PRA), serum aldosterone level and estimated glomerular filtration rate (eGFR) in hypertensive patients with type2 diabetes. In a randomized, double-blind, placebo-controlled study (RCT), 28 patients with type2 diabetes, treated with telmisartan (40mg daily), received 2weeks of placebo or NaCl capsules (100mmol/24h). Following a 6-week washout, the protocol was repeated in reverse. Twenty-four-hour urinary sodium excretion (24hUNa), ambulatory BP (ABP) monitoring and blood tests were performed before and after each study phase. The telmisartan-associated increase in PRA was blunted by approximately 50% during salt supplementation compared with placebo; median PRA was 2.3μg/l/h with placebo compared with 1.7μg/l/h with salt (P<0.001). A trend towards blunting of ARB induced increases in serum aldosterone was also demonstrated. Salt supplementation significantly reduced the MAP lowering effects of telmisartan (P<0.05). The present study demonstrates that salt supplementation blunts the telmisartan induced increase in PRA in patients with type2 diabetes.

Angiotensin type 1 receptor mediates chronic ethanol consumption-induced hypertension and vascular oxidative stress

ObjectivesWe hypothesized that chronic ethanol intake enhances vascular oxidative stress and induces hypertension through renin–angiotensin system (RAS) activation. Methods and resultsMale Wistar rats were treated with ethanol (20% v/v). The increase in blood pressure induced by ethanol was prevented by losartan (10mg/kg/day; p.o. gavage), a selective AT1 receptor antagonist. Chronic ethanol intake increased plasma renin activity (PRA), angiotensin converting enzyme (ACE) activity, plasma angiotensin I (ANG I) and angiotensin II (ANG II) levels and serum aldosterone levels. No differences on plasma osmolality and sodium or potassium levels were detected after treatment with ethanol. Ethanol consumption did not alter ACE activity, as well as the levels of ANG I and ANG II in the rat aorta or mesenteric arterial bed (MAB). Ethanol induced systemic and vascular oxidative stress (aorta and MAB) and these effects were prevented by losartan. The decrease on plasma and vascular nitrate/nitrite (NOx) levels induced by ethanol was prevented by losartan. Ethanol intake did not alter protein expression of ACE, AT1 or AT2 receptors in both aorta and MAB. Aortas from ethanol-treated rats displayed decreased ERK1/2 phosphorylation and increased protein expression of SAPK/JNK. These responses were prevented by losartan. MAB from ethanol-treated rats displayed reduced phosphorylation of p38MAPK and ERK1/2 and losartan did not prevent these responses. ConclusionsOur study provides novel evidence that chronic ethanol intake increases blood pressure, induces vascular oxidative stress and decreases nitric oxide (NO) bioavailability through AT1-dependent mechanisms.