Leucocyte telomere length (LTL) chronicles the cumulative burden of oxidative stress and inflammation over a life course. Activation of the renin-angiotensin-aldosterone system (RAAS) is associated with increased oxidative stress and inflammation. Therefore, LTL may be related to circulating biomarkers of the RAAS.
We evaluated the cross-sectional relations of LTL (dependent variable) to circulating renin and aldosterone concentrations and the renin-aldosterone ratio (all logarithmically-transformed; independent variables) in 1203 Framingham Study participants (mean age 59 years, 51% women). We used multivariable linear regression and adjusted for age, blood pressure, hypertension treatment, smoking, diabetes, body mass index, hormone replacement therapy, serum creatinine and the urine sodium-creatinine ratio.
Overall, multivariable-adjusted LTL was inversely related to renin (beta coefficient per unit increase [β]=-0.038; p= 0.036), directly related to aldosterone (β=0.099; p= 0.002), and inversely related to the renin-aldosterone ratio (β=-0.049; p= 0.003). Relations of LTL to biomarkers were stronger in those with hypertension, although a formal test of interaction was not statistically significant (p=0.20). Individuals with hypertension displayed significant associations of LTL with renin (β=-0.060; p= 0.005), aldosterone (β=0.134; p= 0.002) and renin-aldosterone ratio (β=-0.072; p<0.001). Participants with hypertension who were in the top tertile of the renin-aldosterone ratio had LTL that was 182 base pairs shorter relative to those in the lowest tertile.
In our community-based sample, LTL was shorter in individuals with a higher renin-aldosterone ratio, especially so in participants with hypertension. Additional investigations are warranted to confirm our observations.
Telomere; Renin; Aldosterone; Hypertension; Epidemiology; Association; Salt; Oxidative stress
Several biological pathways are activated concomitantly during left ventricular (LV) remodeling. However, the relative contribution of circulating biomarkers representing these distinct pathways to LV geometry is unclear.
Methods and Results
We evaluated 2119 Framingham Offspring Study participants (mean age 57 years; 57% women) who underwent measurements of biomarkers of inflammation (C-reactive protein, CRP), hemostasis (fibrinogen; plasminogen activator inhibitor 1, PAI-1), neurohormonal activation (B-type natriuretic peptide, BNP); renin-angiotensin-aldosterone system ([RAAS], aldosterone and renin modeled as a ratio, ARR), and echocardiography at a routine examination. LV geometry was defined based on sex-specific distributions of LV mass (LVM) and relative wall thickness (RWT): normal (LVM and RWT<80th percentile), concentric remodeling (LVM
Modeled individually, CRP, fibrinogen, PAI-1 and ARR were related to LV geometry (p<0.01). In multivariable analyses, the biomarker panel was significantly related to altered LV geometry (p<0.0001). Upon backwards elimination, logARR alone was significantly and positively associated with eccentric (odds ratio [OR] per standard deviation (SD) increment 1.20; 95% CI 1.05-1.37) and concentric LV hypertrophy (OR per SD increment 1.29; 95% CI 1.06-1.58).
Our cross-sectional observations on a large community-based sample identified ARR as a key correlate of concentric and eccentric LV hypertrophy, consistent with a major role for RAAS in LV remodeling.
epidemiology; ventricular hypertrophy; biomarkers; ventricular remodeling; renin angiotensin system; aldosterone; c-reactive protein; PAI-1; fibrinogen
BACKGROUND—It remains uncertain whether angiotensin converting enzyme (ACE) inhibitors benefit all heart failure patients or just those with renin-angiotensin-aldosterone system (RAAS) activation.
OBJECTIVE—To determine whether the response to an ACE inhibitor, assessed by urine sodium excretion, was different in patients with low renin versus those with high renin.
DESIGN—Plasma renin activity (PRA) was measured in 38 patients with stable chronic heart failure (21 male, 17 female; mean (SD) age 71 (6) years, range 59-82 years) on chronic diuretic treatment alone. They were divided into three groups: low (PRA ⩽ 1.5 ng/ml/h, n = 11); normal (1.5 < PRA < 5, n = 14); and high (PRA > 5, n = 13). The effect of ACE inhibition was then assessed on diuretic induced natriuresis with respect to renin status.
RESULTS—There were no significant differences in age and sex distribution between the groups. Plasma angiotensin II and aldosterone increased serially from low to high renin groups, while 24 h urinary sodium concentrations fell from low to high renin groups (low PRA, 96.7 (39.5); normal PRA, 90.4 (26.7); high PRA, 66.3 (18.9) mmol/l; p = 0.033), despite a higher diuretic dose in the high renin group. This blunted natriuretic effect of loop diuretics was caused by RAAS activation, which could partly be reversed by ACE inhibition. ACE inhibitors increased natriuresis by 22% in the high renin group (p = 0.029), but had no effect in the normal and low renin groups. Within the low renin group, five of the 11 patients had persistently low renin levels despite ACE inhibition. There was a non-significant reduction in natriuresis (−9.6%, p = 0.335) following ACE inhibition in this subgroup of patients.
CONCLUSIONS—About one third of heart failure patients in our study had low renin status and a non-activated RAAS, despite diuretic treatment. ACE inhibitors did not alter natriuresis significantly in this subgroup of patients, and enhanced natriuresis only in patients with high renin. There is thus tentative support for renin profiling in targeting ACE inhibitors to the most deserving, by showing that short term sodium retention does not occur in low renin patients if ACE inhibitors are withdrawn.
Keywords: chronic heart failure; renin profiling; ACE inhibition; urinary sodium excretion
It is well established that in normal man the renin-angiotensin-aldosterone system is responsive to changes in volume. The present study was performed to determine whether sodium has an action apart from volume in the regulation of the secretion of renin and aldosterone. Acute volume expansion was induced either by saline, dextran, or glucose infusion in supine, normal subjects in balance on a 10 meq sodium/100 meq potassium diet. Plasma renin activity (PRA), angiotensin II (A II), aldosterone (PA), cortisol, serum sodium, and potassium were measured every 10 min for the first 30 min and then at 1, 2, 4, 6, and 8 h.
During saline infusion (500 cm3/h for 6 h) mean PRA and A II levels declined very rapidly, falling significantly below control at 10 min (P < 0.01) and by 50% at 60 min. Thereafter, the rate of fall was more gradual, reaching a nadir at 360 min (70-80% below control). PA declined in a parallel pattern except that a significant fall did not occur until 30 min.
In contrast to saline, dextran infusion (250 cm3/h for 4 h) did not produce a significant fall in PRA, A II, or PA until 4 h after the start of the infusion despite equivalent volume expansion. On the other hand, the infusion of 5% glucose and water (500 cm3/h for 6 h) did not produce a significant decline in PRA, A II, or PA over the first 6 h of the study. Although the response rate of PRA, A II, and PA was different in each of the three infusion studies, these parameters were significantly correlated within each study. Serum sodium and potassium levels did not change during any study except dextran infusion, where a significant fall in both occurred at 120 min. In all the infusion studies, plasma cortisol levels gradually declined during the 8-h study period consistent with its expected rhythm of diurnal secretion.
These results demonstrate that rate of response of the renin-angiotensin-aldosterone system to acute volume expansion with saline differed from that with dextran and glucose infusion in sodium-depleted man. The data support a specific role for volume expansion with saline or the sodium ion per se in the regulation of renin and aldosterone.
The renin-angiotensin-aldosterone-system (RAAS) plays a central role in the pathophysiology of heart failure and cardiorenal interaction. Drugs interfering in the RAAS form the pillars in treatment of heart failure and cardiorenal syndrome. Although RAAS inhibitors improve prognosis, heart failure–associated morbidity and mortality remain high, especially in the presence of kidney disease. The effect of RAAS blockade may be limited due to the loss of an inhibitory feedback of angiotensin II on renin production. The subsequent increase in prorenin and renin may activate several alternative pathways. These include the recently discovered (pro-) renin receptor, angiotensin II escape via chymase and cathepsin, and the formation of various angiotensin subforms upstream from the blockade, including angiotensin 1–7, angiotensin III, and angiotensin IV. Recently, the direct renin inhibitor aliskiren has been proven effective in reducing plasma renin activity (PRA) and appears to provide additional (tissue) RAAS blockade on top of angiotensin-converting enzyme and angiotensin receptor blockers, underscoring the important role of renin, even (or more so) under adequate RAAS blockade. Reducing PRA however occurs at the expense of an increase plasma renin concentration (PRC). PRC may exert direct effects independent of PRA through the recently discovered (pro-) renin receptor. Additional novel possibilities to interfere in the RAAS, for instance using vitamin D receptor activation, as well as the increased knowledge on alternative pathways, have revived the question on how ideal RAAS-guided therapy should be implemented. Renin and prorenin are pivotal since these are at the base of all of these pathways.
Heart failure; Renin; Prorenin; Cardiorenal
Combination therapy is necessary for most patients with hypertension, and agents that inhibit the renin-angiotensin-aldosterone system (RAAS) are mainstays in hypertension management, especially for patients at high cardiovascular and renal risk. Single blockade of the RAAS with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) confers some cardiorenal protection; however, these agents do not extinguish the RAAS as evidenced by a reactive increase in plasma renin activity (PRA), a cardiovascular risk marker, and incomplete cardiorenal protection. Dual blockade with an ACE inhibitor and an ARB offers no additional benefit in patients with hypertension and normal renal and left ventricular function. Indeed, PRA increases synergistically with dual blockade. Aliskiren, the first direct renin inhibitor (DRI) to become available has provided an opportunity to study the merit of DRI/ARB combination treatment. By blocking the first and rate-limiting step in the RAAS, aliskiren reduces PRA by at least 70% and buffers the compensatory increase in PRA observed with ACE inhibitors and ARBs. The combination of a DRI and an ARB or an ACE inhibitor is an effective approach for lowering blood pressure; available data indicate that such combinations favorably affect proteinuria, left ventricular mass index, and brain natriuretic peptide in patients with albuminuria, left ventricular hypertrophy, and heart failure, respectively. Ongoing outcome studies will clarify the role of aliskiren and aliskiren-based combination RAAS blockade in patients with hypertension and those at high cardiorenal risk.
aliskiren; valsartan; single-pill combination; hypertension; renin-angiotensin-aldosterone system; plasma renin activity
Objective. To observe the relationship between changes in renin-angiotensin-aldosterone system (RAAS) activity and blood plasma glucose after administration of hydrochlorothiazide (HCTZ) for one year in patients with hypertension. Methods. 108 hypertensive patients were given 12.5 mg HCTZ per day for one year. RAAS activity, plasma glucose levels, and other biochemical parameters, as well as plasma oxidized low density lipoprotein (oxLDL) levels, were measured and analyzed at baseline, six weeks, and one year after treatment. Results. After one year of treatment, the reduction in plasma glucose observed between the elevated plasma renin activity (PRA) group (−0.26 ± 0.26 mmol/L) and the nonelevated PRA group (−1.36 ± 0.23 mmol/L) was statistically significant (P < 0.05). The decrease of plasma glucose in the elevated Ang II group (−0.17 ± 0.18 mmol/L) compared to the nonelevated Ang II group (−1.07 ± 0.21 mmol/L) was statistically significant (P < 0.05). The proportion of patients with elevated plasma glucose in the elevated Ang II group (40.5%) was significantly higher than those in the nonelevated Ang II group (16.3%) (P < 0.05). The relative oxLDL level was not affected by the treatment. Conclusions. Changes in RAAS activity were correlated with changes in plasma glucose levels after one year of HCTZ therapy.
Obesity is a risk factor for type 2 diabetes mellitus (DM) and is associated with chronic kidney disease. Activation of the renin-angiotensin-aldosterone system (RAAS) is common in obesity. The RAAS is an important mediator of hypertension. Mechanisms involved in activation of the RAAS in obesity include sympathetic stimulation, synthesis of adipokines in the RAAS by visceral fat, and hemodynamic alterations. The RAAS is known for its role in regulating blood pressure and fluid and electrolyte homeostasis. The role of local/tissue RAAS in specific tissues has been a focus of research. Urinary angiotensinogen (UAGT) provides a specific index of the intrarenal RAAS. Investigators have demonstrated that sex steroids can modulate the expression and activity of the different components of the intrarenal RAAS and other tissues. Our data suggest that obese women without DM and hypertension have significantly higher levels of UAGT than their male counterparts. These differences existed without any background difference in the ratio of microalbumin to creatinine in the urine or the estimated glomerular filtration rate, raising a question about the importance of baseline gender differences in the endogenous RAAS in the clinical spectrum of cardiovascular diseases and the potential utility of UAGT as a marker of the intrarenal RAAS. Animal studies have demonstrated that modifying the amount of angiotensin, the biologically active component of the RAAS, directly influences body weight and adiposity. This article reviews the role of the RAAS in renal injury seen in obesity and the metabolic syndrome.
Renin-angiotensin-aldosterone system; RAAS; Renin-angiotensin system; Renal injury; Angiotensinogen; UAGT; Obesity; Metabolic syndrome; Chronic kidney disease; Diabetes mellitus; Gender differences; Hypertension; Blood pressure; Urine; Clinical study
Oral contraceptive (OC) use is associated with increased intra-renal renin-angiotensin-aldosterone system (RAA System) activity and risk of nephropathy, though the contribution of progestins contained in the OC in the regulation of angiotensin-dependent control of the renal circulation has not been elucidated. Eighteen OC users (8 non-diabetic, 10 Type 1 diabetic) were studied in high salt balance, a state of maximal RAA System suppression. Progestational and androgenic activity of the progestin in each OC was standardized to that of the reference progestin norethindrone. Renal plasma flow (RPF) was measured by paraaminohippurate clearance at baseline and in response to angiotensin converting enzyme (ACE)-inhibition. There was a positive correlation between OC progestational activity and the RPF response to ACE-inhibition (r=0.52, p=0.03). Similar results were noted with OC androgenic activity (r=0.54, p=0.02). On subgroup analysis, only non-diabetic subjects showed an association between progestational activity and angiotensin-dependent control of the renal circulation (r=0.71, p=0.05 non-diabetic; r=0.14, p=0.7 diabetic; p=0.07 between groups). Similar results were noted with respect to androgenic activity (r=0.88, p=0.005 non-diabetic; r=−0.33, p=0.3 diabetic; p=0.002 between groups). Our results suggest that the OC progestin component is a significant influence on the degree of angiotensin-dependent control of the renal circulation, though these findings may not apply to women with diabetes.
Progestational activity; Androgenic activity; Renal plasma flow; Female Oral contraceptive
The importance of renin-angiotensin-aldosterone system (RAAS) in diseases such as hypertension, congestive heart failure and chronic renal failure has long ago been recognized. It has also been established that inhibition of RAAS, using inhibitors of the angiotensin-converting enzyme (ACE) or angiotensin II receptor blockers (ARB), is an effective way to intervene with the pathogenesis of these disorders. Renin inhibitors block the RAAS at the highest level, at its origin, and might thus offer a new exciting approach for pharmacotherapy of arterial hypertension. Aliskiren is the first in a new class of orally active, non-peptide, low molecular weight renin inhibitors, and so far the only renin inhibitor that has progressed to phase III clinical trials. This review summarizes the available data on the pharmacokinetic and pharmacodynamic properties of aliskiren and its clinical development for treatment of arterial hypertension.
aliskiren; hypertension; renin-angiotensin-aldosterone system; renin inhibition; essential hypertension
Prior studies have suggested that circulating adiponectin concentrations are associated positively with vitamin D and negatively with body-mass index (BMI), but have not accounted for the influence of the renin-angiotensin-aldosterone system (RAAS) in this relationship. This is particularly relevant because increased RAAS activity is associated with obesity and is known to lower adiponectin levels. We evaluated the association between adiponectin and 25-hydroxyvitamin D (25[OH]D) after controlling RAAS activity with dietary sodium equilibration, and also evaluated whether this relationship was influenced by BMI.
Cross-sectional study of 115 hypertensive Caucasian men from the HyperPATH Consortium.
To manipulate RAAS activity, all subjects underwent one week of high sodium (HS) diet to suppress RAAS, and one week of low sodium (LS) diet to stimulate RAAS. Linear regression was used to evaluate the association between adiponectin and 25(OH)D, and the effect of BMI on this relationship, in each dietary condition.
Adiponectin was higher on HS, where circulating RAAS activity was low, when compared to LS (HS=2.9 versus LS=2.4 µg/mL, p<0.0001). 25(OH)D levels were positively associated with adiponectin, and BMI was a statistically significant effect modifier of the relationship between 25(OH)D and adiponectin on both diets (p-interaction < 0.01 between BMI and 25[OH]D).
Higher 25(OH)D concentrations were independently associated with higher adiponectin levels, particularly when BMI was high. Dietary sodium balance and circulating RAAS activity did not appear to affect this relationship. Future studies should explore whether vitamin D supplementation increases adiponectin levels in obesity.
Patients with type 1 diabetes mellitus (DM) and renal hyperfiltration also exhibit systemic microvascular abnormalities, including endothelial dysfunction. The effect of renal hyperfiltration on systemic blood pressure (BP) is less clear. We therefore measured BP, renal hemodynamic function and circulating renin angiotensin aldosterone system (RAAS) mediators in type 1 DM patients with hyperfiltration (n = 36, DM-H, GFR≥135 ml/min/1.73 m2) or normofiltration (n = 40, DM-N), and 56 healthy controls (HC). Since renal hyperfiltration represents a state of intrarenal RAAS activation, we hypothesized that hyperfiltration would be associated with higher BP and elevated levels of circulating RAAS mediators.
BP, glomerular filtration rate (GFR - inulin), effective renal plasma flow (paraaminohippurate) and circulating RAAS components were measured in DM-H, DM-N and HC during clamped euglycemia (4–6 mmol/L). Studies were repeated in DM-H and DM-N during clamped hyperglycemia (9–11 mmol/L).
Baseline GFR was elevated in DM-H vs. DM-N and HC (167±6 vs. 115±2 and 115±2 ml/min/1.73 m2, p<0.0001). Baseline systolic BP (SBP, 117±2 vs. 111±2 vs. 109±1, p = 0.004) and heart rate (76±1 vs. 67±1 vs. 61±1, p<0.0001) were higher in DM-H vs. DM-N and HC. Despite higher SBP in DM-H, plasma aldosterone was lower in DM-H vs. DM-N and HC (42±5 vs. 86±14 vs. 276±41 ng/dl, p = 0.01). GFR (p<0.0001) and SBP (p<0.0001) increased during hyperglycemia in DM-N but not in DM-H.
DM-H was associated with higher heart rate and SBP values and an exaggerated suppression of systemic aldosterone. Future work should focus on the mechanisms that explain this paradox in diabetes of renal hyperfiltration coupled with systemic RAAS suppression.
Several clinical and experimental lines of evidence have highlighted the detrimental effects of visceral adipose tissue excess on cardiometabolic parameters. Besides, recent findings have shown the effects of gluco-and mineralocorticoid hormones on adipose tissue and have also underscored the interplay existing between such adrenal steroids and their respective receptors in the modulation of adipose tissue biology. While the fundamental role played by glucocorticoids on adipocyte differentiation and storage was already well known, the relevance of the mineralocorticoids in the physiology of the adipose organ is of recent acquisition. The local and systemic renin–angiotensin–aldosterone system (RAAS) acting on adipose tissue seems to contribute to the development of the cardiometabolic phenotype so that its modulation can have deep impact on human health. A better understanding of the pathophysiology of the adipose organ is of crucial importance in order to identify possible therapeutic approaches that can avoid the development of such cardiovascular and metabolic sequelae.
adipose tissue; glucocorticoids; mineralocorticoids
Aldosterone, one of the main peptides in renin angiotensin aldosterone system (RAAS), has been suggested to mediate liver fibrosis and portal hypertension. Spironolactone, an aldosterone antagonist, has beneficial effect on hyperdynamic circulation in clinical practice. However, the mechanisms remain unclear. The present study aimed to investigate the role of spionolactone on liver cirrhosis and portal hypertension.
Liver cirrhosis was induced by bile duct ligation (BDL). Spironolactone was administered orally (20 mg/kg/d) after bile duct ligation was performed. Liver fibrosis was assessed by histology, Masson's trichrome staining, and the measurement of hydroxyproline and type I collagen content. The activation of HSC was determined by analysis of alpha smooth muscle actin (α-SMA) expression. Protein expressions and protein phosphorylation were determined by immunohistochemical staining and Western blot analysis, Messenger RNA levels by quantitative real time polymerase chain reaction (Q-PCR). Portal pressure and intrahepatic resistance were examined in vivo.
Treatment with spironolactone significantly lowered portal pressure. This was associated with attenuation of liver fibrosis, intrahepatic resistance and inhibition of HSC activation. In BDL rat liver, spironolactone suppressed up-regulation of proinflammatory cytokines (TNFα and IL-6). Additionally, spironolactone significantly decreased ROCK-2 activity without affecting expression of RhoA and Ras. Moreover, spironolactone markedly increased the levels of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS and the activity of NO effector- protein kinase G (PKG) in the liver.
Spironolactone lowers portal hypertension by improvement of liver fibrosis and inhibition of intrahepatic vasoconstriction via down-regulating ROCK-2 activity and activating NO/PKG pathway. Thus, early spironolactone therapy might be the optional therapy in cirrhosis and portal hypertension.
We investigated the effects of aliskiren in terms of its inhibition of the renin–angiotensin–aldosterone system (RAAS) as well as that on blood pressure (BP), and renal and cardiac protection in elderly chronic kidney disease (CKD) patients with hypertension.
Nineteen elderly CKD patients (nine males, ten females, aged 74.6 ± 5.8 years) were assigned to receive 150 mg/day of aliskiren added to existing antihypertensives for 6 months. Changes in plasma renin activity (PRA), angiotensin I (Ang I), angiotensin II (Ang II), aldosterone (Ald), BP, estimated glomerular filtration rate (eGFR), urine albumin/creatinine ratio (UACR), left ventricular ejection fraction (LVEF), interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), and plasma brain natriuretic peptide (BNP) levels were evaluated.
Aliskiren suppressed the RAAS as follows: PRA 1.3 ± 1.0 to 0.3 ± 0.3 ng/mL/hour, P < 0.05; Ang I 59.5 ± 32.1 to 26.0 ± 17.3 pg/mL, P < 0.05; Ang II 58.4 ± 62.1 to 14.3 ± 9.0 pg/mL, P < 0.05; and Ald 86.1 ± 38.3 to 80.1 ± 52.6 pg/mL, not significant (NS). Aliskiren reduced BP (153.6/77.2 ± 14.9/10.4 to 130.9/72.2 ± 15.6/9.9 mmHg, P < 0.05). It also reduced UACR (747.1 ± 1121.4 to 409.6 ± 636.8 mg/g, P < 0.05), whereas it did not change eGFR (52.1 ± 29.2 to 51.2 ± 29.3 mL/min/1.73 m2, NS), LVEF (66.8 ± 7.9 to 66.5% ± 6.8%, NS), IVST (10.1 ± 1.8 to 9.9 ± 1.8 mm, NS), LVPWT (10.0 ± 1.6 mm to 10.0 ± 1.4 mm, NS), or BNP (48.2 ± 46.0 to 54.9 ± 41.1 pg/mL, NS).
Aliskiren was effective for BP control and reduced UACR while maintaining eGFR and heart function in elderly CKD patients with hypertension.
aliskiren; renin–angiotensin–aldosterone system; blood pressure; albuminuria; elderly chronic kidney disease
Nonenzymatic cardiac activities of renin are well described during the last years and contribute either to cardiac-specific effects of the renin-angiotensin-aldosterone-system (RAAS) or to the pharmacological effects of RAAS inhibition. The interaction of renin with insulin-like growth factor II/mannose-6-phosphate (IGFII/M6P) receptors participates in nonclassical renin effects and contributes to cardiac remodelling caused by RAAS activation. The current findings suggest an important role for renin IGFII/M6P receptor interaction in cardiac adaptation to stress and support the idea that excessive accumulation of renin during inhibition of RAAS directly contributes to blood pressure-independent effects of these pharmacological interventions. It becomes a challenge for future studies focussing on chronic hypertension or myocardial infarction to comprise regulatory adaptations of the kidney, the main source of plasma renin and prorenin, because they directly contribute to key steps in regulation of cardiac (mal)adaptation via IGFII/M6P receptors. This receptor system is part of peptide/receptor interactions that modifies and possibly limits adverse remodelling effects caused by angiotensin II. Evaluation of interactions of renin with other pro-hypertrophic agonists is required to decide whether this receptor may become a target of pharmacological intervention.
Obesity and hypertension, major risk factors for the metabolic syndrome, render individuals susceptible to an increased risk of cardiovascular complications, such as adverse cardiac remodeling and heart failure. There has been much investigation into the role that an increase in the renin-angiotensin-aldosterone system (RAAS) plays in the pathogenesis of metabolic syndrome and in particular, how aldosterone mediates left ventricular hypertrophy and increased cardiac fibrosis via its interaction with the mineralocorticoid receptor (MR). Here, we review the pertinent findings that link obesity with elevated aldosterone and the development of cardiac hypertrophy and fibrosis associated with the metabolic syndrome. These studies illustrate a complex cross-talk between adipose tissue, the heart, and the adrenal
cortex. Furthermore, we discuss findings from our laboratory that suggest that cardiac hypertrophy and fibrosis in the metabolic syndrome may involve cross-talk between aldosterone and adipokines (such as adiponectin).
Both resistin and vitamin D have been associated with the renin-angiotensin-aldosterone system (RAAS). We investigated the association between resistin and the RAAS, and resistin and vitamin D under controlled dietary sodium conditions.
Retrospective cross-sectional study of subjects from the HyperPATH Consortium, who were maintained in high dietary sodium (HS) and low dietary sodium (LS) balance for one week each.
Caucasian subjects with hypertension (n=177).
25-hydroxyvitamin D (25[OH]D) levels were used to assess vitamin D status. Plasma resistin and RAAS measures were evaluated on each dietary intervention.
Resistin levels were significantly higher in LS, where RAAS activity was high, when compared to HS balance, where RAAS activity was suppressed (6.36 vs. 5.86 µg/L, p<0.0001); however, resistin concentrations were not associated with plasma renin activity or serum aldosterone on either diet. 25(OH)D levels were positively and independently associated with resistin in both dietary conditions (HS: β=0.400, p-trend=0.027; LS: β=0.540, p-trend=0.014).
Dietary sodium loading reduced resistin levels, possibly by suppressing the RAAS; however, circulating RAAS components were not related to resistin concentrations within each specific dietary sodium condition. 25(OH)D was positively associated with resistin and may be involved in resistin regulation through an unknown mechanism. Further studies to better understand resistin regulation in human hypertension are warranted.
resistin; renin; angiotensin; sodium; vitamin D
Eight infants had paired measurements of plasma aldosterone and plasma renin activity while being treated for congestive heart failure. There is parallelism with aldosterone and renin activity in the presence of a hyperactive renin-angiotensin-aldosterone system. Six patients had plasma renin activity and plasma aldosterone measured after commencing captopril and we have shown biochemical blockade of the renin-angiotensin-aldosterone system.
Hypercortisolism as a sign of hypothamamus-pituitary-adrenocortical (HPA) axis overactivity and sleep EEG changes are frequently observed in depression. Closely related to the HPA axis is the renin-angiotensin-aldosterone system (RAAS) as 1. adrenocorticotropic hormone (ACTH) is a common stimulus for cortisol and aldosterone, 2. cortisol release is suppressed by mineralocorticoid receptor (MR) agonists 3. angiotensin II (ATII) releases CRH and vasopressin from the hypothalamus. Furthermore renin and aldosterone secretion are synchronized to the rapid eyed movement (REM)-nonREM cycle.
Here we focus on the difference of sleep related activity of the RAAS between depressed patients and healthy controls. We studied the nocturnal plasma concentration of ACTH, cortisol, renin and aldosterone, and sleep EEG in 7 medication free patients with depression (1 male, 6 females, age: (mean +/-SD) 53.3 ± 14.4 yr.) and 7 age matched controls (2 males, 5 females, age: 54.7 ± 19.5 yr.). After one night of accommodation a polysomnography was performed between 23.00 h and 7.00 h. During examination nights blood samples were taken every 20 min between 23.00 h and 7.00 h. Area under the curve (AUC) for the hormones separated for the halves of the night (23.00 h to 3.00 h and 3.00 h to 7.00 h) were used for statistical analysis, with analysis of co variance being performed with age as a covariate.
No differences in ACTH and renin concentrations were found. For cortisol, a trend to an increase was found in the first half of the night in patients compared to controls (p < 0.06). Aldosterone was largely increased in the first (p < 0.05) and second (p < 0.01) half of the night. Cross correlations between hormone concentrations revealed that in contrast to earlier findings, which included only male subjects, in our primarily female sample, renin and aldosterone secretion were not coupled and no difference between patients and controls could be found, suggesting a gender difference in RAAS regulation. No difference in conventional sleep EEG parameters were found in our sample.
Hyperaldosteronism could be a sensitive marker for depression. Further our findings point to an altered renal mineralocorticoid sensitivity in patients with depression.
Inhibition of the renin-angiotensin-aldosterone system (RAAS) slows down the progression of chronic renal diseases (CKD) including IgA nephropathy (IgAN). Herein, we studied the pathogenetic roles of aldosterone (Aldo) in IgAN.
Human mesangial cells (HMC) was activated with polymeric IgA (pIgA) from IgAN patients and the effects on the expression of RAAS components and TGF-β synthesis examined. To study the roles of RAAS in the glomerulotubular communication, proximal tubular epithelial cells (PTEC) was cultured with conditioned medium from pIgA-activated HMC with eplerenone or PD123319, the associated apoptotic event was measured by the generation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS).
Polymeric IgA up-regulated the Aldo synthesis and aldosterone synthase expression by HMC. The release of TGF-β by HMC was up-regulated synergistically by AngII and Aldo and this was inhibited by incubation of HMC with losartan plus eplerenone. Cultured PTEC express the mineralocorticoid receptor, but not synthesizing aldosterone. Apoptosis, demonstrated by cleaved PARP expression and caspase 3 activity, was induced in PTEC activated by conditioned medium prepared from HMC cultured with pIgA from IgAN patients. This apoptotic event was associated with increased generation of NADPH oxidase and ROS. Pre-incubation of PTEC with PD123319 and eplerenone achieved complete inhibition of PTEC apoptosis.
Our data suggest that AngII and Aldo, released by pIgA activated HMC, served as mediators for inducing apoptosis of PTEC in glomerulo-tubular communications. Crosstalk between AngII and Aldo could participate in determining the tubular pathology of IgAN.
Hypertension is the most prevalent cardiovascular disease of adults and is a major risk factor for cardiovascular (CV) and cerebrovascular morbidity and mortality worldwide. Treatment of hypertension leads to reduction of CV morbidity and mortality through blood pressure reduction. The role of renin–angiotensin–aldosterone system (RAAS) in the pathophysiology of hypertension is mainly through generation of potent vasoconstrictor angiotensin II, stimulation of aldosterone secretion, and increase in sympathetic activation. Angiotensin II receptor blockers such as candesartan, a long-acting agent, alter this system by blocking the activation of angiotensin I receptors. Several important clinical trials have tested the efficacy of candesartan with placebo, antihypertensive agents, or other agents that block the RAAS for the control of hypertension and reduction of key CV risk factors such as microalbuminuria, heart failure, retinopathy, and carotid intima medial thickness. Candesartan has been shown to be a well-tolerated and effective antihypertensive agent with positive metabolic characteristics and additional benefits on CV and cerebrovascular outcomes. The aim of this review is to discuss the pharmacology, efficacy, and safety of candesartan, with an overview of key hypertension and CV studies involving candesartan.
ACE inhibitor; ARB; blood pressure; treatment; heart
The renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathogenesis of cardiovascular disorders including hypertension and is one of the most important targets for drugs. A whole body physiologically based pharmacokinetic (wb PBPK) model integrating this hormone circulation system and its inhibition can be used to explore the influence of drugs that interfere with this system, and thus to improve the understanding of interactions between drugs and the target system. In this study, we describe the development of a mechanistic RAAS model and exemplify drug action by a simulation of enalapril administration. Enalapril and its metabolite enalaprilat are potent inhibitors of the angiotensin-converting-enzyme (ACE). To this end, a coupled dynamic parent-metabolite PBPK model was developed and linked with the RAAS model that consists of seven coupled PBPK models for aldosterone, ACE, angiotensin 1, angiotensin 2, angiotensin 2 receptor type 1, renin, and prorenin. The results indicate that the model represents the interactions in the RAAS in response to the pharmacokinetics (PK) and pharmacodynamics (PD) of enalapril and enalaprilat in an accurate manner. The full set of RAAS-hormone profiles and interactions are consistently described at pre- and post-administration steady state as well as during their dynamic transition and show a good agreement with literature data. The model allows a simultaneous representation of the parent-metabolite conversion to the active form as well as the effect of the drug on the hormone levels, offering a detailed mechanistic insight into the hormone cascade and its inhibition. This model constitutes a first major step to establish a PBPK-PD-model including the PK and the mode of action (MoA) of a drug acting on a dynamic RAAS that can be further used to link to clinical endpoints such as blood pressure.
physiologically based pharmacokinetic model; cardiovascular; renin-angiotensin-aldosterone system; enalapril; enalaprilat
Although the anorexic effects of leptin are lost in obesity, leptin-mediated sympatho-activation is preserved. The cardiovascular consequences of leptin-mediated sympatho-activation in obesity are poorly understood. We tested the hypothesis that 32 weeks of high fat diet (HFD) induces metabolic leptin resistance but preserves leptin-mediated sympatho-activation of the cardiovascular system. HFD in mice significantly increased body weight and plasma leptin concentrations but significantly reduced the anorexic effects of leptin. HFD increased heart rate (HR), stroke volume, cardiac output and plasma aldosterone levels but not blood pressure (BP). As reflected by the contractile response to phenylephrine measured both in vivo and ex vivo, vascular adrenergic reactivity was reduced by HFD suggesting that reductions in sympathetic tone to the periphery vasculature may mitigate sympatho-activation of the heart and the renin angiotensin aldosterone system (RAAS). Tachyphlyaxis was partially restored by symptho-inhibition and not present in ob/ob and db/db mice, despite obesity, arguing for a sympatho-mediated and leptin-specific mechanism. While infusion of leptin in HFD mice had no effect on HR or BP, it further increased aldosterone levels and further reduced vascular adrenergic tone in the absence of weight loss, indicating persistent leptin-mediated stimulation of the cardiovascular system in obesity. In conclusion, these data indicate that despite metabolic leptin resistance, leptin-mediated stimulation of the heart, the vasculature and aldosterone production persists in obesity. BP effects in response to leptin may be limited by a tachyphylactic response in the circulation suggesting that failure of adrenergic desensitization may be a requisite step for hypertension in the context of obesity.
blood pressure; adrenergic reactivity; cardiac output; aldosterone; high fat diet