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Background: Renin–angiotensin–aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) is the cornerstone of antihypertensive treatment in patients with chronic kidney disease (CKD) and diabetes mellitus. Mineralocorticoid receptor antagonists (MRA) on top of conventional RAAS blockade confer cardio- and renoprotective effects. Yet, the detailed effects of this therapeutic approach on key RAAS effectors have not been elucidated to date. Methods: In this exploratory placebo-controlled study, 15 patients with CKD stages 2–3 and albuminuria due to diabetic kidney disease (DKD) were randomized to receive the MRA eplerenone or placebo in addition to ACEi therapy. Employing mass-spectrometry, we quantified plasma angiotensin levels [Ang I, Ang II, Ang-(1–7), Ang-(1–5), Ang III, Ang IV], renin and aldosterone in patients before and after 8 weeks of MRA treatment. Results: While blood pressure and kidney function were similar in the placebo and eplerenone treatment group during the study period, distinct differences in RAAS regulation occurred: eplerenone treatment resulted in an increase in plasma renin activity, Ang I and aldosterone concentrations, indicating global RAAS activation. In addition, eplerenone on top of ACEi profoundly upregulated the alternative RAAS effector Ang-(1–7). Conclusions: Combined eplerenone and ACEi therapy increases Ang-(1–7) levels in patients with CKD indicating a unique nephroprotective RAAS pattern with considerable therapeutic implications. [ABSTRACT FROM AUTHOR]

Background Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, atrasentan. Objective We performed longitudinal assessments of thoracic bioimpedance in patients with type 2 diabetes mellitus and nephropathy to determine whether a decrease in bioimpedance accurately reflected fluid retention during treatment with atrasentan. Study Design We conducted a randomized, double-blind, placebo-controlled study in 48 patients with type 2 diabetes mellitus and nephropathy who were receiving stable doses of renin angiotensin system inhibitors and diuretics. Methods Patients were randomized 1:1:1 to placebo, atrasentan 0.5 mg, or atrasentan 1.25 mg once daily for 8 weeks. Thoracic bioimpedance, vital signs, clinical exams, and serologies were taken at weeks 1, 2, 4, 6, and 8, with the exception of serum hemoglobin, which was not taken at week 1, and serum brain natriuretic peptide, which was only taken at baseline, week 4, and week 8. Results Alterations in bioimpedance were more often present in those who received atrasentan than in those who received placebo, though overall differences were not statistically significant. Transient declines in thoracic bioimpedance during the first 2 weeks of atrasentan exposure occurred before or during peak increases in body weight and hemodilution (decreased serum hemoglobin). [ABSTRACT FROM AUTHOR]

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensives. Recently, these drugs have been associated with a protective effect against pancreatic cancer, but data on this putative association remain limited. Thus, the objective of this study was to determine whether the use of ACEIs and/or ARBs is associated with a decreased risk of pancreatic cancer.Methods: We conducted a population-based cohort study, using a nested case-control analysis within the UK Clinical Practice Research Datalink population. The cohort consisted of all patients newly treated with antihypertensive drugs between 1 January 1995 and 31 December 2009, with follow-up until 31 December 2010. Cases were patients with newly diagnosed pancreatic cancer, which were matched with up to 10 controls on age, sex, calendar year of cohort entry, and duration of follow-up. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of pancreatic cancer incidence associated with ever use of ACEIs and ARBs. A secondary analysis was conducted to assess whether the incidence of pancreatic cancer varied with cumulative duration of use of these drugs.Results: A cohort of 547 566 was assembled. During 3 040 332 person-years of follow-up, a total of 866 patients were newly diagnosed with pancreatic cancer (rate: 3/10 000 per year) and matched to 8636 controls. Overall, when compared with other antihypertensive drugs, the use of ACEIs was not associated with a decreased risk of pancreatic cancer overall (OR: 1.01, 95% CI: 0.86-1.17) or according to cumulative duration of use. The use of ARBs was not associated with a decreased risk of pancreatic cancer overall (OR: 0.93, 95% CI: 0.75-1.15), whereas a cumulative duration of use of 1-3 years was associated with a 38% decrease (OR: 0.62, 95% CI: 0.41-0.94), which returned to the null after >3 years of use (OR: 1.04, 95% CI: 0.74-1.46).Conclusions: The use of ARBs and ACEIs was not associated with an overall decreased risk of pancreatic cancer when compared with patients using other antihypertensive drugs. Additional research is needed to determine whether ARBs may confer a short-term protective effect. [ABSTRACT FROM AUTHOR]

Obesity-related hypertension is associated with increased activity of the renin-angiotensin-aldosterone system (RAAS), increasing arterial stiffness. Aerobic exercise decreases pulse wave velocity (PWV), therefore a treatment option for hypertension and obesity. Assess RAAS activity and PWV before and after 4 weeks of aerobic training in unmedicated, pre-to-stage-1 hypertensives. Ten obese subjects (52±3.2 years, body mass index=33.5±1.4) performed 30 min of aerobic exercise on a treadmill 3 days per week at 65% of peak oxygen consumption (VO2peak). Descriptive characteristics, systolic and diastolic blood pressure (SBP and DBP), PWV, and a blood draw was performed at baseline, following the 4-week control and training interventions. No differences in descriptive characteristics during the control period were observed, however, a significant decrease in plasma aldosterone (ALDO) (255.4±75 to 215.8±66 pg ml−1, P=0.001), SBP (140±12 to 136±10.4 mm Hg; P=0.02), DBP (89±4.2 to 85±6.3 mm Hg; P=0.03) and central PWV (11.2±0.6 to 9.8±0.8 m s−1; P=0.04) was shown pre-to-post exercise training. Four weeks of moderate-intensity aerobic training in obese, hypertensives decreases plasma ALDO independently of body weight and is significantly correlated to decreases in PWV reductions. [ABSTRACT FROM AUTHOR]

Events mediating transformation from the pre-malignant monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are unknown. We analyzed gene expression data sets generated on the Affymetrix U133 platform from 22 MGUS and 101 MM patients using gene-set enrichment analysis. Genes overexpressed in MM were enriched for cell cycle, proliferation and MYC activation gene sets. Upon dissecting the relationship between MYC and cell-cycle gene sets, we identified and validated an MYC activation signature dissociated from proliferation. Applying this signature, MYC is activated in 67% of myeloma, but not in MGUS. This was further confirmed by immunohistochemistry (IHC) using membrane CD138 and nuclear MYC double staining. We also showed that almost all tumors with RAS mutations expressed the MYC activation signature, and multiple mechanisms may be involved in activating MYC. MYC activation, whether assessed by gene-expression signature or IHC, is associated with hyperdiploid MM and shorter survival even in tumors that are not proliferative. Bortezomib treatment is able to overcome the survival disadvantage in patients with MYC activation. [ABSTRACT FROM AUTHOR]

Metabolic syndrome, a cluster of risk factors that increase the risk of cardiovascular morbidity and mortality, is common in patients with hypertension. Chronic renin-angiotensin-aldosterone system (RAAS) activation, shown by elevated plasma renin activity (PRA), is implicated in many of the features of metabolic syndrome. The direct renin inhibitor aliskiren may be of benefit in this patient group as aliskiren targets the RAAS at the rate-limiting step. In this double-blind study, 141 patients with hypertension (mean baseline BP 155/93 mm Hg) and metabolic syndrome (modified National Cholesterol Education Program ATP III criteria) were randomized to aliskiren 300 mg or irbesartan 300 mg once daily. Patients treated with aliskiren 300 mg had their mean sitting blood pressure (BP) lowered by 13.8/7.1 mm Hg after 12 weeks, significantly greater (P0.001) than the 5.8/2.8 mm Hg reduction observed in patients treated with irbesartan 300 mg. A significantly greater proportion of patients treated with aliskiren achieved BP control to <135/85 mm Hg (29.2 vs 16.7% with irbesartan; P=0.019). Aliskiren treatment led to a 60% decrease in PRA from baseline, whereas irbesartan increased PRA by 99% (both P<0.001). Aliskiren and irbesartan had similar effects on glucose and lipid profiles and on a panel of biomarkers of inflammation and cardiovascular risk. Both aliskiren and irbesartan were well tolerated. Collectively, these results suggest that aliskiren 300 mg may offer treatment benefits compared with irbesartan 300 mg for BP reduction in patients with hypertension and metabolic syndrome. [ABSTRACT FROM AUTHOR]

AbstractAim:The aim of the present study was to explore whether renin angiotensin system (RAS) inhibitor can reduce the production of vascular endothelium growth factor (VEGF). Further, we sought to elucidate the correlation between VEGF level and certain clinical parameters, such as albumin excretion rate (AER), before and after treatment with angiotensin type 1 receptor blocker.Methods:We recruited 166 type 2 diabetic patients at various stages of diabetic nephropathy (DN) and 46 healthy control subjects for a cross-sectional study. We recruited another 42 hypertensive type 2 diabetic patients with microalbuminuria for a longitudinal study involving a 6-month irbesartan treatment protocol. Urinary VEGF (uVEGF) levels were determined using ELISA.Results:In the cross-sectional study, hypertensive type 2 diabetic patients who received RAS inhibitor presented lower uVEGF levels than those who did not receive the RAS inhibitor. Statistical analysis indicated that uVEGF level was independently correlated with the AER. In the longitudinal study involving the 6-month irbesartan treatment, we demonstrated that uVEGF levels decreased significantly in patients who achieved a 50% AER reduction (remission group, n=32). In contrast, uVEGF levels remained unchanged in patients who did not exhibit a 50% AER reduction (nonremission group, n=10). Furthermore, the change in uVEGF was significantly correlated with the change in AER (r=0.65, P<0.01) before and after 6 months of irbesartan treatment. This result held true even after we had adjusted for the decrease in average blood pressure.Conclusion:The protective effect of the RAS inhibitor in DN patients is associated with the suppression of VEGF. Accordingly, it may be possible to use uVEGF as a marker of DN progression. We suggest that uVEGF may be an important target for therapeutic intervention in the context of DN.Acta Pharmacologica Sinica (2009) 30: 242–250; doi: 10.1038/aps.2008.28; published online 26th January 2009 [ABSTRACT FROM AUTHOR]

The brain renin–angiotensin system (RAS) participates importantly in the regulation of endocrine, autonomic, and behavioral response to stress. Recent data indicate that central action of AT1 receptor antagonists can reduce anxiety symptoms in experimental animals. Furthermore, central inhibition of RAS activity decreases ethanol intake in an animal model of alcoholism. Pathological anxiety responses and the development of substance dependence are both critically mediated through corticotrophin-releasing hormone (CRH) systems, and the RAS is positioned to interact both with hypothalamic as well as extrahypothalamic CRH systems. The thesis of this paper is that the RAS is part of the neurochemical dysregulation underlying negative affective states, anxiety disorders, and ethanol dependence and that medications targeting the RAS should be considered to augment the treatment of these disorders. [ABSTRACT FROM AUTHOR]

Antihypertensive drugs based on the blockade of the renin–angiotensin system (RAS) target classical components of this system, i.e., angiotensin-converting enzyme (ACE) and angiotensin (Ang) II type 1 receptor. These antihypertensives are well-recognized and successful, if prescribed properly, in reducing high blood pressure, but much less effective in preventing and reverting end-organ damage induced by cardiovascular disease (CVD) and hypertension. Thus, new strategies and new drug targets that are more effective must be discovered. Recent identification of a counterregulatory axis of the RAS [ACE2, Ang-(1–7), and Mas receptor] that is potentially important in promoting vasoprotective effects offers a novel target for CVD therapeutics. In this brief review, we will highlight the functional characteristics of this axis with special emphasis on ACE2 and its possible involvement in the pathophysiology of the CVD. In addition, we will present our views on the potential of ACE2 as a new target for the development of innovative antihypertensives by highlighting the development and functional findings obtained with small molecules ACE2 activators. [ABSTRACT FROM AUTHOR]

Patients with severe hypertension (>180/110 mm Hg) require large blood pressure (BP) reductions to reach recommended treatment goals (<140/90 mm Hg) and usually require combination therapy to do so. This 8-week, multicenter, randomized, double-blind, parallel-group study compared the tolerability and antihypertensive efficacy of the novel direct renin inhibitor aliskiren with the angiotensin converting enzyme inhibitor lisinopril in patients with severe hypertension (mean sitting diastolic blood pressure (msDBP)105 mm Hg and <120 mm Hg). In all, 183 patients were randomized (2:1) to aliskiren 150 mg (n=125) or lisinopril 20 mg (n=58) with dose titration (to aliskiren 300 mg or lisinopril 40 mg) and subsequent addition of hydrochlorothiazide (HCTZ) if additional BP control was required. Aliskiren-based treatment (ALI) was similar to lisinopril-based treatment (LIS) with respect to the proportion of patients reporting an adverse event (AE; ALI 32.8%; LIS 29.3%) or discontinuing treatment due to AEs (ALI 3.2%; LIS 3.4%). The most frequently reported AEs in both groups were headache, nasopharyngitis and dizziness. At end point, ALI showed similar mean reductions from baseline to LIS in msDBP (ALI −18.5 mm Hg vs LIS −20.1 mm Hg; mean treatment difference 1.7 mm Hg (95% confidence interval (CI) −1.0, 4.4)) and mean sitting systolic blood pressure (ALI −20.0 mm Hg vs LIS −22.3 mm Hg; mean treatment difference 2.8 mm Hg (95% CI −1.7, 7.4)). Responder rates (msDBP<90 mm Hg and/or reduction from baseline10 mm Hg) were 81.5% with ALI and 87.9% with LIS. Approximately half of patients required the addition of HCTZ to achieve BP control (ALI 53.6%; LIS 44.8%). In conclusion, ALI alone, or in combination with HCTZ, exhibits similar tolerability and antihypertensive efficacy to LIS alone, or in combination with HCTZ, in patients with severe hypertension.Journal of Human Hypertension (2007) 21, 780–787; doi:10.1038/sj.jhh.1002220; published online 31 May 2007 [ABSTRACT FROM AUTHOR]

The article focuses on the inhibition of the renin angiotensin system (RAS) as a way to intervene in the progression of cardiovascular and renal disorders. The system can be initiated at various points with resulting reduction in blood pressure. Beta blockers, ACE inhibitors and angiotensin receptor blockers inhibit renin.

High rates of uncontrolled hypertensives have been reported in France as well as in other countries, partly owing to an inadequate management of hypertension by clinicians. The objectives of the study were (1) to describe the therapeutic decisions faced by general practitioners (GP) in hypertensives not controlled by fixed-dose combination antihypertensive therapy with a renin–angiotensin system (RAS) inhibitor and a diuretic (D) and (2) to evaluate the frequency with which ambulatory blood pressure monitoring (ABPM) is used in these patients. Each GP had to include five uncontrolled hypertensives on fixed-dose RAS inhibitor and D combination. A total of 2118 GPs included 9551 patients; 8643 patients were receiving at least one of the two drugs at a low dose (group 1) and the remaining 908 patients were receiving high doses of both drugs (group 2). The most common therapeutic choice was that of a new combination, either a fixed-dose in one pill or with separate preparations: 65% (n=5621) in group 1 and 56% (n=505) in group 2. An increase in dose was chosen in 28% of patients in group 1 (n=2467) and continuation of treatment without modification in 27% of patients in group 2 (n=242). A third active principle was only added in 2.5% of patients in group 1 (n=219) and 11% in group 2 (n=103). Ambulatory blood pressure monitoring was employed in 25% of patients (n=2413). An improvement in hypertension management should be expected from the implementation of the 2005 French guidelines.Journal of Human Hypertension (2006) 20, 407–418. doi:10.1038/sj.jhh.1002000; published online 30 March 2006 [ABSTRACT FROM AUTHOR]

Clinical evidence supports the concept that there are racial differences in response to antihypertensive drugs. The high frequency of dietary salt sensitivity and low plasma renin activity (PRA) in hypertensives of African-American descent has been suggested by some to be the critical factor which explains this difference. Evaluation of the antihypertensive response of African-Americans to diuretics and calcium channel blockers compared to other drugs suggest that they may have an advantage in controlling blood pressure (BP). However, these comparative clinical trials have not assessed dietary salt consumption, the salt sensitivity status of the participants, nor have they explored full titration dosages of the comparative drugs. For these reasons, there is insufficient information to state with certainty whether some drugs may be more effective than others as mono-therapy in controlling BP in hypertensives of African-American descent. [ABSTRACT FROM AUTHOR]