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BACKGROUND New onset resistant hypertension in a previously stable patient with chronic hypertension should lead to consideration of secondary causes. Electrolyte abnormalities are useful clues for identifying some common causes, especially mineralocorticoid excess. CASE PRESENTATION We report the case of a 69-year-old man who developed severe resistant hypertension despite the use of 6 antihypertensive medications, including diuretics. He had metabolic alkalosis and hypokalemia with suppressed plasma renin activity and serum aldosterone. Concurrently, he was diagnosed with small cell neuroendocrine carcinoma of the prostate gland, a rare form of prostate cancer. Despite absence of typical Cushingoid features, investigation confirmed the diagnosis of ectopic adrenocorticotropic hormone (ACTH) syndrome from neuroendocrine prostate cancer. Because of the severity of his hypercortisolism, he underwent urgent bilateral adrenalectomy for hormonal and symptomatic control. Blood pressure improved significantly and he was dismissed with a single antihypertensive agent. Unfortunately, the patient died from his cancer 1 month later. CONCLUSION Primary and secondary hyperaldosteronism are usually diagnosed based on measurements of aldosterone and plasma renin activity. However, if plasma renin activity and aldosterone are both low, rare causes of mineralocorticoid excess such as ectopic ACTH syndrome should be entertained.

BACKGROUND Activation of beta-1 adrenoreceptor (β1-AR) in the kidney releases renin that plays a major role in the maintenance of blood pressure. Genetic variation in β1-AR could therefore alter the physiological and clinical effects of this hormone. We tested this hypothesis in patients from a primary care cohort being screened for primary hyperaldosteronism (n = 467). METHODS Demographic and hemodynamic data were measured and plasma renin was determined by a standard immunoassay. Subjects were genotyped for the 2 common single-nucleotide polymorphisms Arg389Gly (rs1801253) and Ser49Gly (rs1801252), and thus the 4 possible haplotypes in β1-AR gene. RESULTS In patients being screened for hyperaldosteronism, plasma renin was significantly elevated in Ser49 homozygotes (49SS) compared with Gly49 (49G) allele carriers (0.307 ± 0.03 vs. 0.164 ± 0.05; P = 0.01). However, this did not translate into differences in either blood pressure or heart rate. On the other hand, the Arg389Gly polymorphism did not affect either plasma renin or blood pressure in this group. There was also no evidence that the 2 loci were linked in this group of patients. CONCLUSION These data suggest that in this cohort the Ser49 variant of the Ser49Gly β1-AR gene polymorphism associates with higher renin levels. However, these common β1-AR gene polymorphisms do not affect blood pressure in the same cohort.

BACKGROUND Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood. METHODS Using systematic-phased approach, PRA’s clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed. RESULTS EAs with PRA < 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by –15.9 mm Hg, adjusted P < 0.0001), whereas those with PRA ≥ 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA ≥ 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%. CONCLUSIONS PRA at the previously established 0.60–0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs. TRIAL REGISTRATION NCT01203852, NCT00246519, NCT00005520.

BACKGROUND Understanding the interactions between genetics, sodium (Na+) intake, and blood pressure (BP) will help overcome the lack of individual specificity in our current treatment of hypertension. This study had 3 goals: expand on the relationship between striatin gene (STRN) status and salt-sensitivity of BP (SSBP); evaluate the status of Na+ and volume regulating systems by striatin risk allele status; evaluate potential SSBP mechanisms. METHODS We assessed the relationship between STRN status in humans (HyperPATH cohort) and SSBP and on volume regulated systems in humans and a striatin knockout mouse (STRN+/−). RESULTS The previously identified association between a striatin risk allele and systolic SSBP was demonstrated in a new cohort (P = 0.01). The STRN–SSBP association was significant for the combined cohort (P = 0.003; β = +5.35 mm Hg systolic BP/risk allele) and in the following subgroups: normotensives, hypertensives, men, and older subjects. Additionally, we observed a lower epinephrine level in risk allele carriers (P = 0.014) and decreased adrenal medulla phenylethanolamine N-methyltransferase (PNMT) in STRN+/− mice. No significant associations were observed with other volume regulated systems. CONCLUSIONS These results support the association between a variant of striatin and SSBP and extend the findings to normotensive individuals and other subsets. In contrast to most salt-sensitive hypertensives, striatin-associated SSBP is associated with normal plasma renin activity and reduced epinephrine levels. These data provide clues to the underlying cause and a potential pathway to achieve, specific, personalized treatment, and prevention.

Background Prenatal lipopolysaccharide (LPS) exposure causes hypertension in rat offspring through an unknown mechanism. Here, we investigated the role of the intrarenal renin-angiotensin system (RAS) in hypertension induced by prenatal LPS exposure and also explored whether adipose tissue-derived mesenchymal stem cells (ADSCs) can ameliorate the effects of prenatal LPS exposure in rat offspring. Methods Sixty-four pregnant rats were randomly divided into 4 groups (n = 16 in each), namely, a control group and an LPS group, which were intraperitoneally injected with vehicle and 0.79 mg/kg LPS, respectively, on the 8th, 10th, and 12th days of gestation; an ADSCs group, which was intravenously injected with 1.8 × 107 ADSCs on the 8th, 10th, and 12th days of gestation; and an LPS + ADSCs group, which received a combination of the treatments administered to the LPS and ADSCs groups. Results Prenatal LPS exposure increased blood pressure, Ang II expression, Ang II-positive, monocyte and lymphocyte, apoptotic cells in the kidney, and induced renal histological changes in offspring; however, the LPS and control groups did not differ significantly with respect to plasma renin activity levels, Ang II levels, or renal function. ADSCs treatment attenuated the blood pressure and also ameliorated the other effects of LPS-treated adult offspring. Conclusions Prenatal exposure to LPS activates the intrarenal RAS but not the circulating RAS and thus induces increases in blood pressure in adult offspring; however, ADSCs treatment attenuates the blood pressure increases resulting from LPS exposure and also ameliorates the other phenotypic changes induced by LPS treatment by inhibiting intrarenal RAS activation.

OBJECTIVES African and African American hypertensives tend to retain salt and water, with lower levels of plasma renin and more resistant hypertension. We tested the hypothesis that physiological phenotyping with plasma renin and aldosterone would improve blood pressure control in uncontrolled hypertensives in Africa. METHODS Patients at hypertension clinics in Nigeria, Kenya, and South Africa with a systolic blood pressure >140 mm Hg or diastolic pressure > 90 mm Hg despite treatment were allocated to usual care (UC) vs. physiologically individualized care (PhysRx). Plasma renin activity and aldosterone were measured using ELISA kits. Patients were followed for 1 year; the primary outcome was the percentage of patients achieving blood pressure RESULTS Results are presented for the 94/105 participants who completed the study (42 UC, 52 PhysRx). Control of both systolic and diastolic pressures was obtained in 11.1% of UC vs. 50.0% of PhysRx (P = 0.0001). Systolic control was achieved in 13.9% of UC vs. 60.3% of PhysRx (P = 0.0001); diastolic control in 36.1% of UC vs. 67.2% of PhysRx, vs. (P = 0.003). Number of visits and total number of medications were not significantly different between treatment groups, but there were differences across the sites. There were important differences in prescription of amiloride as specified in the PhysRx algorithm. CONCLUSIONS Physiologically individualized therapy based on renin/aldosterone phenotyping significantly improved blood pressure control in a sample of African patients with uncontrolled hypertension. This approach should be tested in African American and other patients with resistant hypertension. Registered as ISRCTN69440037

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

BACKGROUND Aldosterone has been linked with obesity, metabolic syndrome (MetS), pro-inflammatory, and prothrombotic states; however, most studies relate these indicators with primary aldosteronism (PA), excluding non-PA patients. OBJECTIVE To determine whether aldosterone, renin, or the plasma aldosterone/renin ratio (ARR) are associated with metabolic disorders and inflammatory/vascular biomarkers in a non-PA population. METHODS We studied 275 patients including adolescents and adults of both genders and measured plasma and urinary aldosterone and determined the plasma renin activity. In all subjects, the presence of MetS was determined according to Adult Treatment Panel III. Renal, vascular, inflammatory, and mineralocorticoid activity biomarkers were evaluated. RESULTS The ARR correlated with the number of variables of MetS (r = 0.191, P = 0.002), body mass index (BMI; r = 0.136, P = 0.026), systolic blood pressure (r = 0.183, P = 0.002), diastolic blood pressure (r = 0.1917, P = 0.0014), potassium excreted fraction (r = 0.174, P = 0.004), low-density lipoprotein (r = 0.156, P = 0.01), plasminogen activator inhibitor type 1 (r = 0.158, P = 0.009), microalbuminuria (r = 0.136, P = 0.029), and leptin (r = 0.142, P = 0.019). In a linear regression model adjusted by age, BMI, and gender, only the ARR was still significant (r = 0.108, P = 0.05). In a logistic regression analysis, the ARR predicted MetS index (odds ratio (OR) = 1.07 [95% confidence interval (CI) = 1.011–1.131], P= 0.02) even after adjusting for age, BMI, and gender. On the other hand, aldosterone showed no association with MetS or inflammatory markers. CONCLUSION These results suggest a continuum of cardiometabolic risk beyond the classic PA threshold screening. The ARR could be a more sensitive marker of obesity, MetS, and endothelial damage in non-PA patients than aldosterone or renin alone. Prospective studies are needed to develop future screening cutoff values.

BACKGROUND Several approaches to initiation of antihypertensive therapy have been suggested. These include thiazide diuretics (TDs) as the first drug in all patients, initial drug selection based on age and race criteria, or therapy selection based on measures of plasma renin activity (PRA). It is uncertain which of these strategies achieves the highest control rate with monotherapy in Stage-I hypertension. We sought to compare control rates among these strategies. METHODS We used data from the Pharmacogenomic Evaluation of Antihypertensive Responses study (PEAR) to estimate control rates for each strategy: (i) TD for all, (ii) age- and race-based strategy: Hydrochlorothiazide (HCTZ) for all blacks and for whites ≥50 years and a renin-angiotensin system inhibitor (atenolol) for whites

Background To study the correlation between blood pressure variability (BPV) and plasma renin activity (PRA), angiotensin II (AngII), aldosterone levels in patients with essential hypertension. Methods A total of 300 patients with mild to moderate essential hypertension were analyzed retrospectively. The subjects were divided into 3 age groups: 100 patients aged 18–44 years (young group), 110 patients aged 45–64 years (middle-aged group), and 90 patients aged over 65 years (elderly group). PRA, AngII, and aldosterone levels were assessed. Blood pressure (BP) was measured by 24-hour ambulatory BP monitoring. The relationships between BP variability and the PRA, AngII, aldosterone levels were compared among the 3 groups. Results Supine and upright PRA and aldosterone levels were significantly higher in the young group than those in the middle-aged and elderly groups. The coefficient of variation (CV) of 24-hour systolic (24hSBPCV), diastolic BP (24hDBPCV), CV of daytime systolic (dSBPCV), diastolic (dDBPCV), and nighttime systolic BP (nSBPCV) in the elderly group was higher than those in the young group and the middle-aged group (all P < 0.05). Spearman correlation analysis showed that in the young and middle-aged groups, BPV was significantly correlated with the levels of PRA, AngII, and aldosterone (all P < 0.05). In the elderly group however, only 24hDBPCV, nDBPCV, and nSBPCV were correlated with AngII and aldosterone levels (all P < 0.05). Conclusions BPV is correlated with plasma renin–angiotensin–aldosterone levels in young and middle-aged patients with mild to moderate essential hypertension.

BACKGROUND Higher fibroblast growth factor-23 (FGF23) concentrations have been found to be associated with incident heart failure (HF). Experimental data suggest FGF23 directly stimulates myocardial hypertrophy. FGF23 may also enhance renin–angiotensin–aldosterone system activity. Whether FGF23 is associated with increased HF risk in populations with hypertension and whether this association is weaker in the presence of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy is unknown. METHODS We studied 2,858 adults with hypertension free of cardiovascular disease at baseline (65.6 ± 9.5 years, 46.2% male) participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We investigated the association of baseline serum intact FGF23 with incident HF over a 14-year median follow-up and whether ACEI/ARB therapy modified this risk. We also investigated the relationship of FGF23 with aldosterone and plasma renin activity in a random subgroup of the entire MESA cohort with available assays (N = 1,642). RESULTS In adjusted Cox regression models, higher FGF23 was associated with a 63% greater hazard of incident HF (hazard ratio: 1.63, 95% confidence interval: [1.13–2.36] per 1-unit increase in log-transformed FGF23), which persisted after exclusion of participants with chronic kidney disease (hazard ratio: 1.94 [1.10–3.43]). There was no heterogeneity by ACEI/ARB use (Pinteraction = 0.438). FGF23 improved model fit over covariables (likelihood ratio χ2 = 6.67, P = 0.010). In multivariable linear regression models, there was no association between FGF23 and aldosterone or plasma renin activity. CONCLUSIONS Higher FGF23 concentrations are associated with a significantly increased risk of HF in hypertension but this risk did not differ by ACEI/ARB treatment status. FGF23 may be a useful biomarker for HF risk in hypertensive populations.

BACKGROUND Mounting evidence has associated high sodium (HS) intake with hypertension, cardiovascular disease, and stroke. We investigated whether HS intake modulates the parameters of endothelial damage, inflammation, and oxidative stress. METHODS We used a cross-sectional study design including 223 Chilean subjects (6.9–65.0 years old). We measured aldosterone, renin activity, cortisol, cortisone, adiponectin, leptin, hsCRP, interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor type 1 (PAI-1), metalloproteinase (MMP)-9 and MMP-2 activity, and malondialdehyde. Sodium and creatinine were measured in 24-hour urine samples. The subjects were divided by sodium intake, high sodium (HS): ≥150 mEq/day, n = 118, and adequate sodium (AS): RESULTS We observed a positive correlation between urinary sodium excretion and blood pressure (r = 0.1669, P = 0.0124 for systolic and r = 0.2416, P = 0.0003 for diastolic), glycemia (r = 0.2660, P < 0.0001), and triglycerides (r = 0.1604, P = 0.0175) and a highly significant correlation between sodium excretion and PAI-1 (r = 0.2701, P < 0.0001). An inverse correlation was observed between urinary sodium and HDL-cholesterol (r = −0.2093, P = 0.0018) and adiponectin (r = −0.2679, P < 0.0001). In a linear regression model, urinary sodium excretion remained significantly associated with PAI-1 values even after adjusting for age, gender, and BMI. The HS group had higher blood pressure, glycemia, HOMA-IR, atherogenic index of plasma, and PAI-1 values than the group with AS intake. CONCLUSIONS HS intake is associated with endothelial damage (high PAI-1) and metabolic dysregulation. On the other hand, inflammation and oxidative stress parameters are not modified by sodium intake.

BACKGROUND We herein report on a 20 years old woman with stage I hypertension, who was found to carry a renin-producing tumor (RPT). METHODS Due to her young age, the patient underwent screening measurement of plasma renin and aldosterone, abdominal computed tomography (CT) angiography, and selective renal vein renin assessment to identify secondary hypertension. RESULTS The patient was screened for secondary causes of hypertension and was diagnosed with secondary aldosteronism. Therefore, she underwent an abdominal computed tomography (CT) angiography that was reported as unremarkable. Selective renal vein renin studies showed overproduction of renin in the right kidney and a re-evaluation of her CT allowed detection of an 8-mm mass in her right kidney, suggesting the presence of a RPT. Considering the technical difficulty of renal sparing surgery a CT-guided cryoablation was undertaken, which provided long-term cure of arterial hypertension and normalization of plasma active renin concentration. CONCLUSIONS RPTs usually present with a clinical phenotype featuring stage III and/or malignant hypertension and are held to be exceptionally rare. This case is unique in that it presented with stage I hypertension and a mild clinical phenotype. Moreover, to our knowledge this is the first case of RPTs shown to be safely treated with CT-guided cryoablation and found to be cured at long-term.

Background Parathyroid hormone (PTH) stimulates aldosterone secretion in human adrenocortex and is regulated by the renin-angiotensin-aldosterone system. We speculated that measurement of PTH may be a valuable aid in the diagnosis of aldosterone-producing adenoma (APA). Methods To test this hypothesis, we recruited 142 patients with adrenal adenoma, of whom 84 had an APA and 58 had a nonfunctioning adrenal adenoma (NFA). Plasma levels of intact PTH, serum potassium, sodium, calcium, phosphate, 25(OH) vitamin D, plasma aldosterone concentration (PAC), plasma renin activity (PRA), and aldosterone to renin ratio (ARR) were measured in every patient. Computed tomography (CT) scanning of the adrenal gland and adrenal hormone levels was used to evaluate the function of the adrenal adenoma. We also evaluated the impact of renin-angiotensin-aldosterone system (RAAS) components on PTH from the recumbent-upright test in 15 patients with APA and 30 patients with NFA. Results Compared with NFA, PTH levels were significantly increased in patients with APA, and serum calcium and phosphate were significantly decreased. When position was changed from supine to upright, the variation in PTH levels was significantly higher in APA patients compared with NFA patients. Receiver operator characteristic (ROC) curves identified the Youden index, which corresponded to the best tradeoff of combined marker (ARR and PTH) with a sensitivity and specificity of 89.3% and 93.1%, respectively. Conclusions The baseline and positional variation of serum PTH levels were significant in APA, thus PTH may be a promising auxiliary index for the clinical diagnosis of APA.

BACKGROUND Although angiotensin II (Ang II) is essential to the development of renovascular hypertension, aldosterone plays a role as well. Recent studies have demonstrated a cross-talk between Ang II type 1 and mineralocorticoid receptors in the brain and kidneys. However, the role of aldosterone in the autonomic and renal dysfunction of renovascular hypertension is not well understood. AIM The current study evaluated whether aldosterone contributes to cardiovascular and renal dysfunction in the 2 kidney-1 clip (2K1C) model. METHODS Mean arterial pressure (MAP) and baroreceptor reflex for control of the heart rate were evaluated in 2K1C treated or not treated with spironolactone (200mg/kg/day, 7 days). Tonic and reflex control of renal sympathetic nerve activity (rSNA) were assessed in urethane-anaesthetized rats. Plasma renin activity (PRA), kidney renin protein expression, renal injury, and central AT1 receptor protein expression were assessed. RESULTS Spiro reduced MAP (198±4 vs. 170±9mm Hg; P < 0.05), normalized rSNA (147±9 vs. 96±10 pps; P < 0.05), and increased renal baroreceptor reflex sensitivity in the 2K1C rats. Spiro reduced α-smooth muscle actin expression in the nonclipped kidney in the 2K1C group (5±0.6 vs. 1.1±0.2%; P < 0.05). There was no change in PRA; however, a decrease in renin protein expression in the nonclipped kidney was found in the 2K1C treated group (217±30 vs. 160±19%; P < 0.05). Spiro treatment decreased AT1 receptor in the central nervous system (CNS) only in 2K1C rats (138±10 vs. 84±12%; P < 0.05). CONCLUSION Aldosterone contributes to autonomic dysfunction and intrarenal injury in 2K1C, these effects are mediated by the CNS.

BACKGROUND Heart rate is a strong predictor of mortality and development of obesity and diabetes. The renin-angiotensin-aldosterone system plays an important role in blood pressure control and volume homeostasis. Although many studies have indicated the association between aldosterone and hypertension or insulin resistance, epidemiological evidence of the association of heart rate with plasma renin activity (PRA) remains scant. Therefore, we investigated whether heart rate is associated with PRA. METHODS A total of 1,943 subjects were enrolled, who underwent a health examination in Tanushimaru in 2009. Plasma renin and aldosterone concentrations were measured by radioimmunoassay. PRA and the homeostasis model assessment (HOMA) were used by natural-log transformed. Resting heart rate was measured using electrocardiography. RESULTS We divided the subjects into four groups by heart rate (

BACKGROUND Left ventricular (LV) diastolic dysfunction characterizes heart failure with a preserved ejection fraction. Although it is recognized that the renin–angiotensin–aldosterone system (RAAS) decreases LV diastolic function, whether systemic angiotensinogen (AGT) contributes to these effects is uncertain. Hence, the aim was to determine the relationship between systemic AGT concentrations and LV diastolic function. METHODS LV diastolic function was determined from the mean of the lateral and septal wall myocardial tissue lengthening at the mitral annulus (average e’) and from the ratio of early transmitral blood flow velocity (E) to average e’ (E/e’) in 445 Black African participants from a community sample. RESULTS In multivariate regression models with adjustments for age, sex, waist circumference diabetes mellitus, alcohol and tobacco use, hypertension treatment, systolic blood pressure (BP), and relative wall thickness, the square root of serum AGT concentrations was independently associated with E/e’ (partial r (95% confidence interval [CI]) = 0.11 (0.02–0.21), P = 0.04), but not with average e’ (partial r (95% CI) = −0.06 (−0.15 to 0.04), P = 0.25). There was no association between plasma renin concentrations and markers of diastolic function (all P > 0.05). CONCLUSION Circulating AGT concentrations are associated with LV diastolic function beyond BP and other confounders in an African population. Hence, through circulating AGT, the systemic RAAS may play an important role in contributing to LV diastolic function in Black Africans.

BACKGROUND About one-half of all hypertensive adults do not have their blood pressure controlled. They are often prescribed medications that conform to national guidelines but they continue to have elevated blood pressure. This public health problem might be improved by applying plasma renin guided therapy. RESULTS A contributor to the public health problem of unsuccessfully treated hypertension is that the circulating renin–angiotensin system (RAS) is not recognized in treatment guidelines as clinically relevant for the treatment of hypertension or as important as the body salt status for determining blood pressure levels. Another contributor to the problem is the lack of specificity in the package inserts for antihypertensive drugs. They do not specifically state under the heading “Indications” that RAS blockers are primarily most effective in hypertensive subjects with medium and high plasma renin levels; by contrast, natriuretic drugs are most effective in those with low plasma renin levels. METHODS Literature review. CONCLUSIONS To address the problem of unsuccessfully treated hypertension, we recommend that the “Indications” section of package inserts for antihypertensive drugs be more specific. The primary indication for RAS blockers ought to be hypertension with medium and high plasma renin levels, and natriuretic agents for those with low plasma renin levels. Similar language ought to be added to treatment guidelines. Additionally, 3 other reasons for lack of blood pressure control also need to be addressed—failure to prescribe antihypertensive drugs to hypertensive subjects, failure of patients to fill prescriptions, and low drug adherence.

Background: A paradoxical pressor systolic response to initial antihypertensive monotherapy has been observed in 8% of hypertensive patients. The long-term consequences of this finding are unknown. Methods: We included 945 hypertensive patients with baseline systolic blood pressure (SBP) ≥140mm Hg. A 4-week washout period free of antihypertensive drugs was allowed for those already on treatment at entry. Mortality outcomes were ascertained from the National Death Index. Subjects were categorized by SBP response into depressor (≥10mm Hg fall), nonresponder, and pressor (≥10mm Hg rise) categories. Results: There were 268 fatalities. Of these, 100 (37%) were from cardiovascular disease (CVD), of which 70 (70%) were due to coronary artery disease (CAD). A pressor response was associated with higher SBP at 1 year compared with the nonresponder or depressor response (141 vs. 136 vs. 136mm Hg). CVD mortality was greater in pressors than depressors (hazard ratio (HR) = 3.0; 95% confidence interval (CI) = 1.4-6.4; P = 0.004], as was CAD (HR = 3.1; 95% CI = 1.4-6.8; P < 0.01) and all-cause mortality (HR = 1.7; 95% CI = 1.1-2.6; P = 0.02), after adjusting for 1-year SBP and other possible confounders. Conclusions: We found the incidence of a pressor response to monotherapy at 3 months was significantly, specifically, and independently associated with higher subsequent cardiovascular mortality.

Animal studies suggest that the renin–angiotensin–aldosterone system (RAAS) is involved in many central nervous system processes in hypertension, including cognitive function and cerebral hemodynamic control.1–3 Angiotensin II infusion into rats’ brains is associated with impaired memory,4 neurovascular uncoupling, and hypoperfusion.5 In transgenic mice, activation of brain RAAS impairs cognitive function by decreasing cerebral blood flow.6 In humans, the evidence supporting a role of RAAS in brain function is derived indirectly from the observation that drugs that inhibit RAAS may be associated with cognitive preservation.7 To our knowledge, studies showing a relationship between RAAS activity and neurocognitive function in hypertensive older adults are nonexistent. Aldosterone is the major contributor to the negative cardiovascular effects of RAAS. Higher circulating aldosterone predicts greater increase in blood pressure and incident hypertension with aging.8 In the Framingham cohort, higher aldosterone levels were associated with shorter leukocyte telomere length, suggesting a high inflammation and oxidative stress load.9 Aldosterone has multiple binding sites in the brain.10 However, its role in cognitive and cerebrovascular function has not been fully explored. On the vascular side, higher aldosterone levels are linked with endothelial dysfunction,11,12 which in turn may negatively affect cognitive function.13 While local brain endothelial function is difficult to assess, reactivity to changes in end-tidal CO2 may be an indirect marker of the central endothelium.14 Therefore, we hypothesized that in humans markers of elevated RAAS activity, higher aldosterone levels will be associated with lower scores on measures of cognition (memory and executive function) and impaired cerebral hemodynamics (autoregulation and vasoreactivity). Prior studies suggest that there is a genetic basis for the individual heterogeneity of vascular response to antihypertensive therapy.15 We previously reported that polymorphisms in the angiotensinogen gene that are associated with higher RAAS activity16 predicted a better cognitive outcome with antihypertensive therapy.17 It is not known if these observations are related to the class of antihypertensive used, such as those that modulate RAAS, or are related to lowering blood pressure control. We therefore wanted to investigate this difference (class effect vs. blood pressure–lowering effect) in a recently completed clinical trial. Our objective was to assess the association of circulating aldosterone and plasma renin activity (PRA) with cognitive function (memory and executive domains) and cerebral hemodynamics in hypertensive individuals off antihypertensive therapy. Our second objective was to investigate the impact of baseline RAAS markers on the cognitive/hemodynamic responses to antihypertensive therapy and/or controlling blood pressure to

In cross-sectional studies, the aldosterone-to-renin ratio (ARR) has been reported to be associated with hypertension under conditions of higher sodium intake. The objective of this prospective study was to investigate the association between ARR and the development of hypertension in community residents stratified by dietary sodium intake.From the general population of Ohasama, we obtained plasma renin activity (PRA) and plasma aldosterone concentrations (PACs) for 608 participants (mean age = 57.6 years; 71.4% women) without hypertension at baseline. Using the Cox model, we computed the adjusted hazard ratio (HR) of natural log-transformed ARR (lnARR) for the development of hypertension, defined as blood pressure ≥140/90mm Hg or start of treatment with antihypertensive drugs during follow-up.During a mean follow-up of 6.8 years, 298 participants developed hypertension. The median PRA, PAC, and ARR were 1.2ng/ml/hour, 6.6ng/dl, and 5.5ng/dl per ng/ml/hour, respectively. Each 1 SD increase in lnARR was associated with an increased risk for the development of hypertension in participants overall (HR = 1.18; P = 0.007). In participants with higher sodium intake (median ≥4,102mg/day), a significant association of lnARR with hypertension remained (HR = 1.25; P = 0.009), whereas no significant association was observed in participants with lower sodium intake (P = 0.18). Participants who developed hypertension had significantly lower PRA than those who did not (P = 0.003), despite no differences in PAC (P = 0.91).These results raise the hypothesis that relative aldosterone excess may have a deleterious effect on the development of hypertension by contributing to salt/volume-related hypertension.

BACKGROUND Obstructive sleep apnea (OSA) is associated with hypertension and the progression of chronic kidney disease (CKD). Renal sympathetic innervation contributes to either condition. METHODS We investigated the effect of renal sympathetic denervation (RDN) on blood pressure (BP), renal perfusion, and neurohumoral responses during and after repetitive obstructive apneas in a pig model for OSA. BP, femoral artery, and renal artery flow were measured in 29 spontaneously breathing urethane-chloralose-anesthetized pigs. The effect of RDN (n = 14) and irbesartan (n = 3) was investigated. Repetitive tracheal occlusions for 2 minutes with applied negative tracheal pressure at -80 mbar were performed over 4 hours. RESULTS Spontaneous breathing attempts during tracheal occlusion caused an intra-apneic breathing synchronous oscillating pattern of renal flow. Renal flow oscillations were > 2-fold higher compared with femoral flow that almost showed changes proportional to the BP alterations (2.9%/mm Hg vs. 1.3%/mm Hg; P < 0.0001). A marked postapneic BP rise from 102 ± 3 to 172 ± 8 mm Hg (P < 0.00001) was associated with renal hypoperfusion (from 190 ± 24 to 70 ± 20 ml/min; P < 0.00001) occurring after application of obstructive respiratory events. RDN, but not irbesartan, inhibited postapneic BP rises and renal hypoperfusion and attenuated increased plasma renin activity and aldosterone concentration induced by repetitive tracheal occlusions. Additionally, increased urinary protein/creatinine ratio was significantly reduced by RDN, whereas intra-apneic hemodynamic changes or blood gases were not modified by RDN. CONCLUSIONS Repetitive obstructive respiratory events result in postapneic BP rises and renal hypoperfusion, as well as neurohumoral responses and increased protein/creatinine ratio. These changes are mainly sympathetically driven because they could be attenuated by RDN.

The renin-angiotensin-aldosterone system (RAAS) maintains extracellular volume in the setting of salt or volume loss through vasoconstriction and sodium retention. Although this system maintains blood pressure (BP) in pathologic states of effective volume depletion, renin and aldosterone are also believed to be major contributors to hypertension, atherosclerosis, and heart failure.1 Classically, renin release stimulates angiotensin activation and aldosterone release and is therefore considered to stimulate higher blood pressure. Despite this, several prior studies in community-living, nonhypertensive populations have demonstrated inverse relationships of plasma renin activity (PRA) and systolic BP (SBP). In addition, it is well recognized that there are forms of low-renin hypertension where aldosterone is elevated out of proportion to renin levels. Among hypertensives, this low-renin state is approximately twice as common in blacks versus whites;2–4 in these conditions, high aldosterone levels portend greater treatment resistance and end-organ damage.5 Although these hormones have been extensively studied in whites and blacks, little is known about variations in hormone levels for nonwhite, nonblack races/ethnicities. The Multi-Ethnic Study of Atherosclerosis (MESA), a study of cardiovascular disease risk factors in whites, Chinese, blacks, and Hispanics, provides a unique opportunity to compare renin and aldosterone levels in individuals across these 4 races/ethnicities. Therefore, we investigated differences in PRA and aldosterone between races/ethnicities in individuals not treated for hypertension. Given the physiologic role of RAAS to maintain BP, we also examined the associations of PRA and aldosterone with BP in all races/ethnicities together and separately in each race/ethnicity. We hypothesized that among those not taking antihypertensive medications, PRA would be lower among blacks vs. other races/ethnicities and that Hispanics and Chinese would have similar patterns to whites in this regard.

background A plasma renin activity (PRA)–guided strategy is more effective than standard care in treating hypertension (HTN). However, its clinical implementation has been slow, presumably due in part to economic concerns. We estimated the cost effectiveness of a PRA-guided treat ment strategy compared with standard care in a treated but uncontrolled HTN population. methods We estimated costs, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) of PRA-guided therapy compared to standard care using a state-transition simulation model with alternate patient characteristic scenarios and sensitivity analyses. Patient-specific inputs for the base case scenario, males average age 63 years, reflected best available data from a recent clinical trial of PRA-guided therapy. Transition probabilities were estimated using Framingham risk equations or derived from the literature; costs and utilities were derived from the literature. results In the base case scenario for males, the lifetime discounted costs and QALYs were $23,648 and 12.727 for PRA-guided therapy and $22,077 and 12.618 for standard care, respectively. The base case ICER was $14,497/QALY gained. In alternative scenario analyses varying patient input parameters, the results were sensitive to age, gender, baseline systolic blood pressure, and the addition of cardiovascular risk factors. Univariate sensitivity analyses demonstrated that results were most sensitive to varying the treatment effect of PRA-guided therapy and the cost of the PRA test. conclusions Our results suggest that PRA-guided therapy compared with standard care increases QALYs and medical costs in most scenarios. PRA-guided therapy appears to be most cost effective in younger persons and those with more cardiovascular risk factors.

Two kidney–1 clip (2K1C) Goldblatt hypertension is an excellent experimental model to study renal vascular hypertension, a serious and prevalent cardiovascular disease. Animals with 2K1C hypertension exhibit substantial elevations in plasma renin activity (PRA) and circulating angiotensin II (ANG II) levels that reach peak levels around 4 weeks after clipping.1,2 In contrast with 2K1C hypertension, several other forms of hypertension are characterized by low renin3 concomitant with endothelial dysfunction.4,5 One of the most devastating consequences of hypertension and high salt (HS) diet is stroke. Dysregulation of cerebral vascular relaxation can have other disastrous consequences, and vascular-related factors (including oxidant stress) have been proposed to contribute to several varieties of cognitive dysfunction and dementia, including Alzheimer’s disease.6 Importantly, endothelial dysfunction has been shown to be a powerful prognostic indicator of adverse cardiovascular events, including stroke, independent of blood pressure.7 Although the ability of supraphysiological levels of ANG II to cause endothelial dysfunction and increase vascular oxidant stress is well known,8 there is increasing evidence that salt-induced suppression of plasma ANG II also leads to endothelial dysfunction, vascular oxidant stress, and impaired vascular relaxation.9–12 Dahl salt-sensitive (SS) rats, a rodent model of chronically lowered renin-angiotensin system (RAS) activity,13 exhibit a similar vascular phenotype, even when they are normotensive and maintained on a normal salt (NS) diet.14 In light of these disparate observations, this study addressed the following questions: (i) what is the effect of short-term exposure to HS diet on cerebral vascular function in rats with 2K1C Goldblatt hypertension; and (ii) do the elevated PRA and increased circulating ANG II levels in 2K1C hypertension exacerbate or ameliorate salt-induced vascular dysfunction in cerebral arteries?

Background Renin is synthesized in the collecting duct and is regulated differently than renin in the juxtaglomerular apparatus. However, the physiological relevance of collecting duct renin remains unknown, particularly with regard to its ability to regulate blood pressure. Methods We used gene targeting to generate mice with overexpression of renin in the collecting duct. A conditional mutant mouse line was created with the mouse renin transcript distal to a "transcriptional stop sequence" such that gene expression only occurred when the stop sequence was excised. These mice were bred with mice transgenic for the aquaporin-2 promoter driving Cre recombinase in order to achieve collecting duct-specific overexpression of renin. Results RNA analysis confirmed kidney-specific recombination, and medullary renin mRNA levels were increased 5-fold in collecting duct renin mice. Blood pressure was recorded by telemetry and plasma and urine was collected in 24-hour metabolic cages on normal, high-, and low-Na+ diets. Although no significant differences in 24-hour urinary Na+ excretion between targeted and control mice were detected, renin overexpresser mice had elevated blood pressure compared with controls on a high-Na+ diet. Urinary renin excretion was 2-fold higher in targeted mice as compared with controls on normal and low-Na+ diets. Plasma renin concentration was significantly suppressed in targeted mice as compared with controls on normal and high-Na+ diets. Conclusion Taken together, these results suggest that collecting duct-derived renin has the potential to modulate blood pressure independent of the systemic renin-angiotensin system.

Strategies for initial drug therapy of hypertension are a thiazide diuretic for all or drug selection based on age/race criteria or on plasma renin activity (PRA). It is uncertain which of these strategies will achieve the highest control rate among patients with stage 1 essential hypertension. We sought to compare control rates among 3 drug selection strategies: (i) thiazide diuretic for all, (ii) thiazide diuretic for all black subjects and white subjects aged ≥50 years and a renin-angiotensin system blocker for white subjects aged50 years, or (iii) thiazide diuretic for PRA0.6ng/ml/h (suppressed PRA) and a renin-angiotensin system blocker for PRA ≥ 0.6ng/ml/h (nonsuppressed PRA).Blood pressure responses from the Genetic Epidemiology of Responses to Antihypertensives (GERA) study were used to determine control rates for each of the 3 strategies. In GERA, hypertensive adults were treated with hydrochlorothiazide (n = 286 black subjects and 284 white subjects) or with candesartan (n = 248 black subjects and 278 white subjects).In the overall sample, the PRA strategy was associated with the highest control rate of 69.4% vs. 61.3% with the age/race strategy (P0.001) and 53.8% with the thiazide for all strategy (P0.001). This was also true in each racial subgroup (in black subjects: 62.1% vs. 55.2% for the other 2 strategies, P = 0.02; in white subjects: 76.3% vs. 67.1% with the age/race strategy (P0.001) and 52.4% with the thiazide for all strategy (P0.001)).This exploratory analysis suggests that choice of initial therapy for hypertension using a PRA strategy may be associated with higher control rates than alternative strategies recommended in current guidelines.

Background Four recent reports revealed differences in survival rates among treated cardiovascular patients taking renin-angiotensin system–blocking drugs. Patients with higher on-treatment plasma renin activity (PRA) levels died sooner of cardiovascular mortality than those with lower levels. We investigated whether excessive sodium depletion might have induced the higher PRA levels and contributed to the greater morbidity and mortality. Methods Using published data, ranges of PRA, blood pressures, drug usage, and biochemical parameters were compared among various groups of cardiovascular patients. Results We showed (i) that PRA levels are usually medium to low in treated cardiovascular patients, but are sometimes abnormally high, (ii) that excessive sodium depletion can induce such high PRA levels, (iii) that the higher PRA patients exhibited evidence of sodium depletion: lower blood pressures, more frequent natriuretic drug usage, lower N-terminal pro b-type natriuretic peptide (NT-proBNP), and higher blood urea nitrogen and uric acid levels, with similar usage of renin-angiotensin blocking drugs. Conclusions We hypothesize that patients with high on-treatment PRA levels die sooner of cardiovascular events because they are excessively sodiumvolume depleted. Moreover, renin-angiotensin system–blocking drugs may be harmful in such patients because they can functionally interfere with the effects of reactive rises in PRA that are triggered to prevent potentially dangerous falls in blood pressure, increases in plasma potassium, and falls in glomerular filtration rate. Careful liber alization of salt intake and subtraction of natriuretic drugs, sufficient to reduce reactive hyperreninemia without inducing unacceptable increases in blood pressure, might benefit such patients and decrease risk of adverse effects from drugs that block the renin-angiotensin system.

Although the mechanism of action of angiotensin II (Ang II) receptor (AT1-R) blockers (ARBs) is well established, data suggest that their antihypertensive effects may be limited in part by the overriding effect of compensatory increases in plasma renin activity (PRA) and Ang II.1 Contrasting with the mechanism of action of other ARBs, Agata et al. 2 reported that the antihypertensive and cardiac antihypertrophic actions of 4-week olmesartan medoxomil administration were not associated with the expected increases in circulating Ang II in adult stroke-prone spontaneously hypertensive rats (SHR). Agata et al. 2 speculated that the failure of plasma Ang II to rise in response to blockade of AT1-R could be explained by angiotensin-(1–7) [Ang-(1–7)]–induced inhibition of angiotensin converting enzyme (ACE) activity, given previous observations of increased Ang-(1–7) after treatment with ARBs,3,4 as well as an inhibitory role of the heptapeptide at the C- and N-terminus catalytic activity of the enzyme.5,6 The intriguing possibility of a differential effect of olmesartan on plasma Ang II levels compared with other ARBs was also consistent with 2 other studies in human essential hypertensive subjects in whom prolonged therapy with olmesartan was accompanied by either decreases or no changes in plasma Ang II levels.7,8 The effects of olmesartan on Ang II levels may also result from increased conversion of the octapeptide to Ang-(1–7) because ACE2 has been shown to be upregulated by AT1-R blockade.4,9,10 This has been demonstrated in vivo by recent work showing that the infusion of soluble human recombinant ACE2 efficiently lowered plasma Ang II while increasing Ang-(1–7).10 Furthermore, in isolated cardiac myocytes, ACE2 messenger RNA expression and activity were not affected by Ang-(1–7); however, the inhibitory effects of Ang II on ACE2 were blocked by Ang-(1–7).11 The heptapeptide modulatory effect was prevented by the Ang-(1–7) mas receptor antagonist [D-ALA7]-Ang-(1–7) (A-779), indicating that the Ang-(1–7) response was mediated by a specific Ang-(1–7) receptor. A-779 is a selective blocker of the mas receptor that has been identified to mediate vasodilatory, antitrophic, and antiproliferative effects of Ang-(1–7).12–14 The long-term effects of Ang-(1–7) antagonism in the presence of concomitant Ang II receptor blockade have not been determined. With this in mind, we investigated the Ang-(1–7)–mediated effects of olmesartan on blood pressure, plasma, renal, and cardiac Ang II as well as ACE2 in mRen2.Lewis congenic hypertensive rats. This monogenetic hypertensive rat strain was developed in our laboratory through a backcross of the hypertensive (mRen2)27 transgenic rats with normotensive Lewis rats. The aim of this backcross was to offset the heterogeneity of the parent strain that contributed to the genetic variability found within the original transgenic strain.15,16 Because the malignant phase of hypertension is not observed in mRen2.Lewis rats, the longer life span of this experimental model provides a better opportunity to investigate the function and regulation of tissue renin–angiotensin system (RAS) and its contribution to the etiology of hypertension and target organ damage.

Background Angiotensinogen (AGT) is synthesized in the liver and proximal tubule. AGT overexpression at either site might increase blood pressure (BP). We used transgenic mice with AGT overexpression in proximal tubule (K), liver (L), or both sites (KL) to determine the relative contributions of hepatic- and proximal tubule–derived AGT in modulating BP. Methods Hepatic AGT overexpression was obtained using the albumin enhancer promoter; the kidney androgen protein gene was used for proximal tubule AGT overexpression. BP and renin angiotensin system parameters were examined in male KL, K, L, and wild-type mice on normal and high-sodium diets. results Compared with wild-type mice, K and KL mice had higher BP on normal and high-sodium diets. L mice had similar BP to wild-type mice on a normal-sodium diet, but high sodium intake caused hypertension. There were no differences in plasma AGT, plasma renin concentration, urine volume, or urine sodium excretion between the groups. Urine AGT and angiotensin II (Ang II) excretion were higher in KL and K mice than in L or wild-type mice on a normal-sodium diet and increased with high sodium intake. During high sodium intake, urine AGT and Ang II were higher in all transgenic mice vs wild-type mice. conclusions Mice with liver AGT overexpression manifest salt-sensitive hypertension, whereas mice with renal AGT overexpression are hypertensive regardless of salt intake. Systemic AGT may stimulate endogenous renal AGT synthesis during high sodium intake, leading to hypertension in L mice. This suggests that systemic and renal AGT may interact to modulate BP.

BACKGROUND: Aldosterone acts to restrain the extracellular potassium (K+) concentration. Blacks have on average lower plasma aldosterone concentrations (PACs) than Whites. Whether this ethnic difference is associated with similar changes in the concentration of K+ is unclear. METHODS: Subjects were Blacks and Whites from an observational study of blood pressure regulation. PAC was known to be significantly lower in Blacks than Whites. We sought to test the hypothesis that the concentration of K+ remains constant despite variability in PAC. Initial enrollment took place in childhood in 1986. Some of the original enrollees were studied again in adulthood: 160 healthy Blacks and 271 healthy Whites (ages 5 to 39 years; all were studied as children and as adults). RESULTS: Plasma renin activity [a biomarker of angiotensin II and, more proximally, extracellular fluid volume (ECFV)] and PAC were lower in Blacks (P < 0.0354 and P < 0.001, respectively, for all ages). At the same time no ethnic difference in levels of K+ was observed regardless of age. Plasma K+ concentration and PAC associated differently based on ethnicity: PAC increased in Blacks by 1.5-2.0 and in Whites by 2.3-3.0 ng/dl per mmol/l increase in K+ (P < 0.001). CONCLUSIONS: Lower aldosterone levels in Blacks did not translate into higher K+ concentrations. We speculate that reaching the right concentration of K+ was an endpoint of aldosterone production in the presence of varying levels of ECFV and angiotensin II.

BACKGROUND Renovascular hypertension (2-kidney 1-clip model (2K1C)) is characterized by renin-angiotensin system (RAS) activation. Increased Angiotensin II (AngII) leads to sympathoexcitation, oxidative stress, and alterations in sodium and water balance. AIM The aim of this study was to evaluate whether a discrete increase in sodium chloride intake in 2K1C rats leads to changes in cardiovascular and autonomic function, oxidative stress, and renin angiotensin aldosterone system. METHODS After 4 weeks of induction of hypertension, rats were fed a normal sodium diet (0.4% NaCl) or a high-sodium diet (2% NaCl) for 2 consecutive weeks. Experiments were carried out for 6 weeks after clipping. Mean arterial pressure (MAP), renal sympathetic nerve activity (rSNA), arterial baroreflex control of rSNA, and heart rate (HR) were assessed. Thiobarbituric acid reactive substances and glutathione were measured as indicators of systemic oxidative stress. Angiostensin-converting enzyme (ACE), ACE2, and angiotensinogen were evaluated in clipped and unclipped kidneys as also urinary angiotensinogen and plasma renin activity. Angiotensinogen, plasma renin activity (PRA) and angiotensin-converting enzyme (ACE) and ACE2 in clipped and unclipped kidneys were evaluated. RESULTS High-sodium diet did not change systemic oxidative stress, and basal values of MAP, HR, or rSNA; however, increased renal (-0.7±0.2 vs. -1.5±0.1 spikes/s/mm Hg) and cardiac (-0.9±0.14 vs. -1.5±0.14 bpm/mm Hg) baroreceptor reflex sensitivity in 2K1C rats. Although there was no alteration in PRA, a high-salt diet significantly decreased urinary angiotensinogen, ACE, and ACE2 expressions in the clipped and unclipped kidneys. CONCLUSIONS Increased arterial baroreceptor control associated with a suppression of the intrarenal RAS in the 2K1C rats on high-salt diet provide a salt-resistant effect on hypertension and sympathoexcitation in renovascular hypertensive rats.

BACKGROUND The aim of this study was to evaluate whether body mass index (BMI) is independently correlated with plasma aldosterone concentration (PAC) in treated essential hypertensive patients, and whether the relationship between BMI and high blood pressure (BP) can be partially mediated by PAC despite renin-angiotensin-aldosterone system blockade. METHODS This study used a cross-sectional design and included 295 consecutive essential hypertensive patients referred to our centre for uncontrolled BP despite stable antihypertensive treatment for at least 6 months. The main exclusion criteria were age >65 years; glomerular filtration rate

BACKGROUND Aldosterone is thought to have deleterious effects on the cardiovascular system. The aldosterone-to-renin ratio (ARR) is more reproducible than aldosterone levels alone and could be an index for inappropriate aldosterone secretion or activity. We previously reported the apparent relation between ARR and hypertension in subjects with high sodium intake. This prospective study investigated the risk of ARR for a first stroke in a general population stratified by sodium intake. METHODS We obtained plasma renin activity (PRA) and plasma aldosterone concentrations (PAC) for 883 participants aged ≥ 35 years not receiving antihypertensive treatment in the general population of Ohasama (mean age: 59.0 ± 11.3 years; 65.6% women). RESULTS Over a mean of 10.9 follow-up years, 45 strokes occurred. The median PRA, PAC, and ARR were 1.2 ng/ml/h, 6.4 ng/dl, and 5.3 ng/dl per ng/ml/h, respectively. Using Cox regression, we computed hazard ratios adjusted for sex, age, body mass index (BMI), and systolic blood pressure. No association between logARR and stroke was observed in subjects overall. However, in subjects with high sodium intake (≥ median of 4,058 mg/day (salt equivalent, 10.5 g/day)), each 1 s.d. increase in logARR was associated with an increased hazard ratio for stroke (hazard ratio: 1.49, P = 0.04). No significant association was observed in subjects with low sodium intake (P = 0.7). When we repeated all the analyses using logPRA or logPAC, no significant associations were found. CONCLUSION These results suggest that high ARR, that is, relative aldosterone excess, is a predictor for stroke under conditions of high sodium intake.

BACKGROUND It is highly likely that the rise in plasma prorenin and plasma renin during renin inhibitor treatment is induced at least as much by the fall in blood pressure (BP) as it is by the negative feedback of angiotensin II. This could potentially be harmful because high levels of renin and prorenin may stimulate the (pro)renin receptor, thus inducing profibrotic effects. To further understand this relationship, the influence of aliskiren on the urinary excretion of transforming growth factor-β1 (TGF-β1) and procollagen III N-terminal propeptide (PIIINP) was evaluated in patients with nondiabetic kidney diseases. METHODS Aliskiren 300 mg and perindopril 10 mg, were each individually administered for 12 weeks separated by a placebo period in a cross-over, randomized, double-blinded pilot study. RESULTS A 1,131% (P < 0.001) and 628% (P < 0.001) increase in plasma renin concentration was observed after the aliskiren and perindopril therapies, respectively, as compared to the placebo. Aliskiren and perindopril increased prorenin concentrations as compared to the placebo by 100% (P < 0.01) and 52.4% (P = 0.53), respectively. The TGF-β1 excretion was lower after tested therapies compared to the placebo (55.0 ± 7.56 vs. 56.21 ± 8.56 vs. 85.79 ± 14.11 pg/mg creatinine; P = 0.016); without differences between aliskiren and perindopril. PIIINP excretion did not differ between treatments. CONCLUSIONS The study shows that both aliskiren and perindopril suppress TGF-β1 in patients with chronic kidney diseases. This effect was observed despite significant increases in the renin and prorenin concentrations. Further studies involving histological assessments are required to elucidate the exact impact of these agents on renal fibrosis.

Background Plasma renin activity (PRA) has been associated with cardiovascular disease mortality (CVD) events among hypertensive patients. We now report a long-term follow-up to assess the enduring association of PRA to CVD and all-cause mortality. methodS Participants (3,791) in a systematic hypertension treatment study had entry systolic blood pressure (BP) ≥140 mm Hg and mean age 52. CVD and all-cause mortality was ascertained for mean of 16 years. Pretreatment PRA was analyzed as a continuous variable, and by tertiles. The 10-year Framingham score was similarly examined. Hazard ratios (HRs) were estimated from multivariate Cox proportional hazard models. reSult S There were 804 deaths, and 360 (45%) were CVD. PRA was associated with all-cause mortality and CVD, but not cancer or non-CVD. Although T3 had lower mean baseline and follow-up systolic BP than T1, (146 vs. 152 mm Hg (P < 0.001) and 135 vs. 139 mm Hg (P < 0.001), respectively), T3 had 37% higher all-cause mortality (HR: 1.37, 95% confidence interval (CI): 1.15–1.63, P < 0.001) and 70% higher CVD mortality (HR: 1.70, 95% CI: 1.29–2.23, P < 0.001) after adjustment. The difference between T3 and T1 in mortality from coronary artery disease and myocardial infarction was more pronounced than for all CVD. PRA also significantly improved CVD risk estimation provided by Framingham. concluSionS These findings extend and reinforce previous evidence that pretreatment PRA has a significant, independent, specific, and direct long-term association with CVD mortality. Moreover, PRA adds significantly to risk identified by the Framingham score.

Catheter-based renal nerve ablation (CBRNA) is a promising new approach to reducing blood pressure in human patients with drug-resistant hypertension.1 The concept behind the method was derived from many decades of work in laboratory animals that showed the significant effect of renal nerves on blood pressure regulation in experimental hypertension and the physiological mechanisms underlying that effect.2 Early indications of efficacy of CBRNA in human trials, however, led to an explosion of interest in the procedure and its rapid application to thousands of patients worldwide.3 Most studies have appropriately focused on the clinical efficacy and safety of the procedure. On the other hand, comparatively little attention has been paid to identifying the specific physiological mechanisms responsible for the persistent fall in blood pressure seen in some (but not all) patients. A highly publicized recent report4 on the first prospective, double-blind, randomized, sham-controlled trial in patients with severe resistant hypertension (Symplicity HTN-3) showed that CBRNA failed to lower blood pressure significantly more than a sham procedure. The report has re-energized consideration of the physiological conditions under which the renal nerves are most likely to affect blood pressure in hypertension and the mechanisms responsible. It also has brought to the foreground questions about precisely how much renal nerve damage is necessary to meaningfully affect blood pressure in hypertensive subjects. Two articles appearing in this issue of the Journal, one by Henegar et al. 5 and one by Linz et al.,6 report data from experimental animal studies that shed significant new light on these issues. The most directly germane is the study by Henegar et al.5 These investigators used a well-characterized dog model of hypertension and a catheter device designed for human applications (St. Jude Medical EnligHTN system) to investigate the acute and chronic effects of renal denervation on blood pressure and other relevant physiological variables. Several valuable features of the study design deserve mention. First, renal denervation was performed in dogs with established hypertension. In most previous work on renal denervation in laboratory animals, denervation was done before the onset of hypertension. The approach used by Henegar et al. is more clinically relevant and recognizes the well-known fact that many interventions that mitigate hypertension development have little or no effect on blood pressure once hypertension is established. Second, the dogs were made hypertensive by high-fat feeding; this has clinical relevance because many patients with drug-resistant hypertension are overweight.7 Third, the investigators did a thorough job of quantifying the damage to the renal nerves caused by the ablation procedure using both histology and measurement of renal content of norepinephrine. This is important because at present it is not clear how much damage to the renal nerves is necessary to affect blood pressure, and similar quantification is not possible on a routine basis in the clinical setting. Last, but not least, blood pressure measurements were performed using repeated sampling for 18 hours a day for the duration of the study. This kind of recording (roughly equivalent to ambulatory measurements in humans) is critical to detect the small changes in blood pressure typically seen after renal denervation. The main findings of the Henegar et al. study were that CBRNA lowered BP significantly and persistently in obese hypertensive dogs without a major change in renal function and that this was associated with relatively modest damage to the renal nerves (approximately 42% loss as assessed by histology or norepinephrine content). Although the experiments were not designed specifically to explore the mechanisms responsible for the fall in blood pressure, some of the data collected are informative. No significant changes in heart rate, glomerular filtration rate, plasma renin activity, extracellular fluid volume, plasma volume (estimated from plasma protein concentration), plasma aldosterone, or plasma cortisol were found after CBRNA. Interestingly, the fall in blood pressure did not reach a peak steady-state value until several days after the procedure, suggesting the involvement of more slowly acting blood pressure control mechanisms. Similarly detailed time-course data are virtually absent from clinical studies. It is of substantial importance that only partial loss of renal nerve integrity was required to significantly reduce blood pressure in this study. Moreover, there was a trend (although not statistically significant) for the antihypertensive effect of CBRNA to correlate with the degree of denervation. A noteworthy limitation of all human trials of CBRNA to date (including Symplicity HTN-3) is a lack of data on the completeness of denervation. The little evidence we have in human patients indicates that denervation is far from complete, even when the procedure is performed by experts.8 This could be a major factor in explaining why blood pressure responses vary widely between patients. A logical (although not necessarily correct) assumption is that the magnitude of fall in blood pressure after CBRNA in any given subject will depend on the degree to which their blood pressure is being controlled by physiological mechanisms responsive to renal sympathetic nerve activity (RSNA) (e.g., renin release, sodium reabsorption, and renal vascular resistance). Elegant investigations in human subjects by Esler and colleagues reveal that RSNA is increased in some, but not all, patients with essential hypertension.9 To our knowledge there is no direct evidence for renal sympathetic overactivity in drug-resistant hypertension, but such patients often are obese, and many obese individuals have elevated RSNA.10 One clear link between obesity, sympathetic overactivity, and hypertension is obstructive sleep apnea (OSA),11 a prevalent condition in patients with drug-resistant hypertension.12 Therefore it is important to determine the impact of the renal sympathetic nerves on physiological responses to OSA, including systemic blood pressure. This was the goal of a paper by Linz et al. 6 They used an acute model of OSA in anesthetized pigs that involved repetitive obstruction of the trachea with negative pressure (NTP) every 15 minutes for 4 hours. They continuously recorded blood pressure and renal and femoral blood flow and determined plasma renin activity, plasma aldosterone, urinary protein/creatinine ratio, and glomerular filtration rate several times during the 4-hour protocol. In a subgroup of pigs, the effects of NTP were investigated after renal denervation was performed using the standard surgical approach of stripping away visible nerves and applying a phenol solution to the perivascular region. Another group of pigs was pretreated with the angiotensin receptor blocker irbesartan before being subjected to NTP. The results were striking: although the interapneic values of the measured variables were not affected by renal denervation, the marked postapneic increases in blood pressure and renal vascular resistance seen in untreated pigs were significantly attenuated by renal denervation (but not by irbesartan). Likewise, the gradual increments in plasma renin activity, plasma aldosterone, and urinary protein/creatinine ratio seen in control pigs during repetitive NTP were nearly eliminated in pigs with renal denervation. Although this was an acute protocol and renal denervation was surgical rather than by catheter, the results highlight some important issues discussed earlier. First, the findings support the common-sense view that the magnitude of any physiological response to renal denervation will depend on the level of renal sympathetic activity at the time of denervation. Accordingly, identification of patients likely to respond to CBRNA should include consideration of other pathologies (such as obesity and OSA) that are associated with increased RSNA. Second, it is notable that a large component of the systemic blood pressure response to NTP appears to depend on neurogenic changes in renal vascular resistance (femoral resistance changed very little). This suggests that under some conditions the mechanism of the antihypertensive response to CBRNA may simply be a reduced contribution of the renal vasculature to total peripheral resistance. Of course the impact of renal denervation on hormones and renal injury in this study also identify other potential mechanisms by which renal nerves could influence long-term blood pressure regulation. Collectively these articles show that well-designed, animal-based experimental physiology can importantly complement the results of clinical trials and clinical research in our efforts to establish the clinical utility (if any) of CBRNA in treating hypertension.

Since thiazide diuretics were introduced in the late 1950s for treatment of hypertension, interpatient variation has been documented for blood pressure responses to agents from all classes of antihypertensive drugs.1,2 For any single agent given as monotherapy, ~50% of patients achieve blood pressure levels

Background Reduction of renal blood flow (RBF) due to a renal artery stenosis (RAS) can lead to renal ischemia and atrophy. However in pigs, there are no data describing the relationship between the degree of RAS, the reduction of RBF, and the increase of systemic plasma renin activity (PRA). Therefore, we conducted a study in order to measure the effect of acute and gradual RAS on RBF, mean arterial pressure (MAP), and systemic PRA in pigs. Methods RAS was induced experimentally in six pigs using an occluder placed around the renal artery downstream of an ultrasound flow probe. The vascular occluder was inflated gradually to reduce RBF. At each inflation step, percentage of RAS was measured by digital subtraction angiography (DSA) with simultaneous measurements of RBF, MAP, and PRA. Data were normalized to baseline values obtained before RAS induction. Piecewise regression analysis was performed between percentage of RAS and relative RBF, MAP, and PRA, respectively. Results In all pigs, the relationship between the degree of RAS and RBF was similar. RBF decreased over a threshold of 42% of RAS, with a rapid drop in RBF when RAS reached 70%. PRA increased dramatically over a threshold of 58% of RAS (+1,300% before occlusion). MAP increased slightly (+15% before occlusion) without identifiable threshold. Conclusions This study emphasizes that the relation between the degree of RAS and RBF and systemic PRA is not linear and that a high degree of RAS must be reached before the occurrence of significant hemodynamic and humoral effects.