natriuretic-peptide--brain and Hyperaldosteronism

Adaptive immunity is crucial in cardiovascular and renal inflammation/fibrosis upon hyperactivation of mineralocorticoid receptor. We have previously demonstrated that dendritic cells can respond to mineralocorticoid receptor activation, and the neutrophil gelatinase-associated lipocalin (NGAL) in dendritic cells is highly increased during aldosterone (Aldo)/mineralocorticoid receptor-dependent cardiovascular damage. However, the interrelationship among dendritic cells, target organs inflammation/fibrosis induced by mineralocorticoid receptor, and NGAL-dependence remains unknown.. We studied the role of dendritic cells in mineralocorticoid receptor-dependent tissue remodeling and whether NGAL can modulate the inflammatory response of dendritic cells after mineralocorticoid receptor activation.. Cardiovascular and renal remodeling induced by Aldo and high-salt diet [nephrectomy-Aldo-salt (NAS) model] were analyzed in CD11c.DOG mice, a model which allows dendritic cells ablation by using diphtheria toxin. In addition, in-vitro studies in NGAL-knock out dendritic cells were performed to determine the immunomodulatory role of NGAL upon Aldo treatment.. The ablation of dendritic cells prevented the development of cardiac hypertrophy, perivascular fibrosis, and the overexpression of NGAL, brain natriuretic peptide, and two profibrotic factors induced by NAS: collagen 1A1 and connective tissue growth factor. We determined that dendritic cells were not required to prevent renal hypertrophy/fibrosis induced by NAS. Between different immune cells analyzed, we observed that NGAL abundance was higher in antigen-presenting cells, while in-vitro studies showed that mineralocorticoid receptor stimulation in dendritic cells favored NGAL and IL-23 expression (p19 and p40 subunits), which are involved in the development of fibrosis and the Th17-driven response, respectively.. NGAL produced by dendritic cells may play a pivotal role in the activation of adaptive immunity that leads to cardiovascular fibrosis during mineralocorticoids excess.

Topics: Aldosterone; Animals; Cardiomegaly; Cardiovascular System; CD11 Antigens; Coculture Techniques; Dendritic Cells; Female; Fibrosis; Hyperaldosteronism; Inflammation; Interleukin-23 Subunit p19; Kidney; Lipocalin-2; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Natriuretic Peptide, Brain; Receptors, Mineralocorticoid; Sodium Chloride, Dietary; T-Lymphocytes

To measure the plasma concentrations of adrenomedullin (ADM),atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP), and investigate their pathophysiological functions in patients with primary aldosteronism (PA). Between June 2006 and December 2012, we recruited 25 patients with untreated PA, 30 patients with untreated low-renin essential hypertension (EH), and 35 healthy control subjects. The plasma concentrations of ADM, ANP, and BNP were measured in all the subjects. After 4 weeks of effective antihypertensive therapy with slow-release nifedipine, the three peptides were measured again in the PA and low-renin EH subjects. Unilateral laparoscopic adrenalectomy was performed in all the PA patients; 2 weeks after surgery, the three peptides were measured again. The PA patients had significantly higher plasma concentrations of ADM, ANP, and BNP than the low-renin EH and control subjects. The low-renin EH and control subjects significantly differed in the concentrations of the three peptides between low-renin EH and control subjects. ADM was the most important peptide associated with aldosterone or blood pressure in the PA patients. Plasma ADM concentration was not only correlated with plasma aldosterone concentrations, but also with systolic and diastolic blood pressures, and plasma ANP and BNP concentrations in the PA patients. By contrast, ADM concentration was not related to blood urea nitrogen levels, serum creatinine levels, and glomerular filtration rates. After antihypertensive treatment, the concentrations of the three peptides significantly decreased in the low-renin EH patients, but remained unchanged in the PA subjects. However, these concentrations significantly decreased 2 weeks after laparoscopic adrenalectomy in the PA subjects. ADM, ANP, and BNP possibly participate in the mechanisms counteracting further elevation of blood pressure or plasma volume expansion resulting from aldosterone hypersecretion in PA patients. An ADM/aldosterone local regulatory mechanism may be involved in regulating adrenal adenoma functions.

Topics: Adrenalectomy; Adrenomedullin; Adult; Atrial Natriuretic Factor; Essential Hypertension; Female; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Nifedipine; Vasodilator Agents

Primary aldosteronism (PA) is the most frequent form of secondary hypertension, but diagnostic tools for this disease still lack optimal accuracy. The heart is one important target tissue for damage due to excess aldosterone, and the role of natriuretic peptides is well recognized in diagnosing heart failure. We hypothesized that measuring the NT-proBNP could improve the diagnostic evaluation of PA. We enrolled 132 hypertensive patients, who underwent aldosterone to renin ratio (ARR) screening, and 81 underwent an intravenous saline loading test (ivSLT) because of a high ARR. The NT-proBNP level positively correlated with the ARR and inversely correlated with the renin level. The NT-proBNP level was higher in patients with a high ARR than in those with a low ARR and higher in patients with a positive ivSLT than in those with a negative ivSLT. After logistic regression analysis, an NT-proBNP value above the median and male gender were predictors of a positive ivSLT. The proportion of patients with a positive ivSLT ranged from only 23 % in females with a low NT-proBNP to 93 % in males with a high NT-proBNP. NT-proBNP and gender are predictors of a positive PA confirmatory test. These findings highlight the possibility of using NT-proBNP to identify which patients with a high ARR should receive a complete PA diagnostic evaluation.

Topics: Adult; Aldosterone; Female; Humans; Hyperaldosteronism; Hypertension; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Renin; Sex Factors; Sodium Chloride

The renin-angiotensin-aldosterone system is involved in the arterial hypertension-associated cardiovascular remodeling. In this context, the development of cardiac fibrosis results from an imbalance between profibrotic and antifibrotic pathways, in which the role of aldosterone is yet not established. To determine the role of intracardiac aldosterone in the development of myocardial fibrosis during hypertension, we used a double transgenic model (AS-Ren) of cardiac hyperaldosteronism (AS) and systemic hypertension (Ren). The 9-month-old hypertensive mice had cardiac fibrosis, and hyperaldosteronism enhanced the fibrotic level. The mRNA levels of connective tissue growth factor and transforming growth factor-β1 were similarly increased in Ren and AS-Ren mice compared with wild-type and AS mice, respectively. Hyperaldosteronism combined with hypertension favored the macrophage infiltration (CD68(+) cells) in heart, and enhanced the mRNA level of monocyte chemoattractant protein 1, osteopontin, and galectin 3. Interestingly, in AS-Ren mice the hypertension-induced increase in bone morphogenetic protein 4 mRNA and protein levels was significantly inhibited, and B-type natriuretic peptide expression was blunted. The mineralocorticoid receptor antagonist eplerenone restored B-type natriuretic peptide and bone morphogenetic protein 4 levels and decreased CD68 and galectin 3 levels in AS-Ren mice. Finally, when hypertension was induced by angiotensin II infusion in wild-type and AS mice, the mRNA profiles did not differ from those observed in Ren and AS-Ren mice, respectively. The aldosterone-induced inhibition of B-type natriuretic peptide and bone morphogenetic protein 4 expression was confirmed in vitro in neonatal mouse cardiomyocytes. Altogether, we demonstrate that, at the cardiac level, hyperaldosteronism worsens hypertension-induced fibrosis through 2 mineralocorticoid receptor-dependent mechanisms, activation of inflammation/galectin 3-induced fibrosis and inhibition of antifibrotic factors (B-type natriuretic peptide and bone morphogenetic protein 4).

Topics: Aldosterone; Animals; Animals, Newborn; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Blood Pressure; Blotting, Western; Bone Morphogenetic Protein 4; Cells, Cultured; Cytochrome P-450 CYP11B2; Eplerenone; Female; Fibrosis; Galectin 3; Gene Expression; Hyperaldosteronism; Hypertension; Male; Mice; Mice, Transgenic; Mineralocorticoid Receptor Antagonists; Myocardium; Natriuretic Peptide, Brain; Organ Size; Renin; Reverse Transcriptase Polymerase Chain Reaction; Spironolactone

Brain natriuretic peptide (BNP) has important role in the diagnosis and management of heart failure. Data on the impact of blood pressure (BP) on BNP are controversial. In primary aldosteronism (PA), BNP production can be affected by both hypertension and specific endocrine mechanisms. This study was aimed at investigating the impact of hypertension and hyperaldosteronism on plasma BNP levels.. Plasma BNP concentration, casual and 24-h BP and echocardiographic indices were assessed in 40 patients with moderate to severe essential hypertension (EH), 40 BP-matched patients with PA, and 40 age- and sex-matched healthy controls.. BNP levels in PA and EH groups did not differ significantly and were higher compared with those in controls [median and interquartile range 26 (13-48) pg/ml, p = 0.01, and 23 (9-32) pg/ml, n.s., vs 14 (6-26) pg/ml in controls]. Remarkably elevated BNP was observed only in three PA and two EH patients, all having significant left ventricular (LV) hypertrophy. BNP levels in PA and EH groups correlated weakly with casual and 24-h BP, interventricular septal thickness and LV mass index (LVMI). Diastolic BP and LVMI were identified as the strongest independent determinants of BNP (p = 0.002 and p = 0.01, respectively).. Both PA and EH patients had modest and mutually comparable elevation of BNP, which was independently determined by diastolic BP and LVMI. Both subtypes of PA (aldosterone-producing adenoma and bilateral adrenal hyperplasia) had similar effect on BNP production. Specific impact of hyperaldosteronism on BNP was not confirmed.

Topics: Adult; Aged; Blood Pressure; Case-Control Studies; Diastole; Electrocardiography; Female; Humans; Hyperaldosteronism; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Natriuretic Peptide, Brain

Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones with natriuretic and vasodilator actions. The present study was carried out to determine the natriuretic peptide that is closely related to cardiac load and volume retention in patients with primary aldosteronism (PA).. We examined 11 patients with PA due to aldosterone-producing adrenal adenoma before and after surgical resection. Plasma levels of ANP and BNP were measured by specific immunoradiometric assays, and total blood volume was determined by a plasma tracer method with (131)I-human albumin.. Plasma levels of ANP and BNP were elevated in the PA patients compared with normotensive control subjects (P < .01), and the elevated ANP and BNP levels were reduced (P < .01) after adenoma resection. When analyzed with the pre- and postoperative data, a significant relationship was observed between mean blood pressure and plasma levels of ANP (r = 0.64, P < .01) and BNP (r = 0.58, P < .01). The BNP was significantly correlated with the SV1 + RV5 voltage (r = 0.65, P < .01) and with total blood volume (r = 0.57, P < .01), but this was not the case for ANP.. The present results suggest that the plasma level of BNP is more closely related to cardiac load or volume status than ANP is, in patients with PA due to adrenal adenoma.

Topics: Adenoma; Adrenal Gland Neoplasms; Adult; Atrial Natriuretic Factor; Biomarkers; Blood Volume; Cardiac Volume; Female; Humans; Hyperaldosteronism; Male; Middle Aged; Natriuretic Peptide, Brain

The present study was designed to determine whether brain natriuretic peptide (BNP) is synthesized in the human adrenal gland and, if so, to investigate the BNP content of adrenal tissue and the changes in BNP messenger ribonucleic acid (mRNA) in patients with primary aldosteronism. A considerable amount of BNP-like immunoreactive substances was extracted from the adrenal glands of kidney donors for transplantation (0.21 +/- 0.02 pmol/g wet tissue; n = 3) and the remnant nontumorous adrenal glands of patients with primary aldosteronism (0.20 +/- 0.05 pmol/g wet tissue; n = 3; mean +/- SEM). Immunohistochemical study with a specific antihuman BNP antibody revealed that BNP-like immunoreactivity was localized in the adrenal medullary area, and an in situ hybridization study indicated that the BNP mRNA was mainly expressed in the cells of adrenal medulla. Using a reverse transcription and polymerase chain reaction technique, BNP complementary DNA was cloned from the human adrenal gland, and the sequence was identical to that of BNP identified in the atria. The level of BNP mRNA in the adrenal glands of patients with primary aldosteronism (n = 4) was obviously elevated compared to that in the kidney donors (n = 4), as determined by Northern blot analysis. Quantitative polymerase chain reaction measurements of BNP and atrial natriuretic peptide (ANP) mRNAs showed that both of the adrenomedullary natriuretic peptide gene transcriptions were enhanced in patients with primary aldosteronism, but the amount of ANP mRNA was far higher than that of BNP mRNA in the human adrenal gland. Our results are the first to indicate that BNP is synthesized in the human adrenal medulla, and that such medullary BNP synthesis increases in patients with primary aldosteronism. These facts support the proposal that adrenomedullary BNP along with ANP may play some role in water and electrolyte homeostasis or act in a paracrine manner to regulate adrenocortical functions.

Topics: Adrenal Medulla; Adult; Atrial Natriuretic Factor; Base Sequence; Blotting, Northern; DNA, Complementary; Humans; Hyperaldosteronism; Immunohistochemistry; In Situ Hybridization; Male; Molecular Sequence Data; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Polymerase Chain Reaction; Radioimmunoassay; RNA, Messenger

The human heart secretes both atrial natriuretic peptide and brain natriuretic peptide. This study attempts to clarify the pathophysiological significance of the peptides in cardiovascular diseases. Using immunoradiometric assay, plasma brain natriuretic peptide and atrial natriuretic peptide levels in essential hypertension, various secondary hypertension, chronic renal failure, chronic heart failure during cardiac pacing, and acute myocardial infarction were determined. Mean plasma brain natriuretic peptide and atrial natriuretic peptide levels in healthy subjects were 3.7 +/- 0.3 and 5.7 +/- 0.3 pmol/L, respectively, and increased as a function of age. Plasma brain natriuretic peptide levels showed a larger increase than atrial natriuretic peptide levels in various cardiovascular diseases. In chronic renal failure, whereas plasma atrial natriuretic peptide levels decreased significantly after hemodialysis and were correlated with the changes in body weight, changes in plasma brain natriuretic peptide levels were less prominent and did not show such a correlation. In chronic heart failure, both basal plasma brain natriuretic peptide and atrial natriuretic peptide levels were also significantly elevated. However, in response to acute ventricular or atrial pacing, brain natriuretic peptide levels did not show any increase in contrast to the marked increase of atrial natriuretic peptide levels. In acute myocardial infarction, brain natriuretic peptide levels showed more prominent changes than atrial natriuretic peptide levels and were correlated with serum levels of creatine kinase and cardiac myosin light chain I in most patients. These results suggest that both brain and atrial natriuretic peptides play an important role in the regulation of cardiovascular homeostasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenal Gland Neoplasms; Adult; Aged; Aging; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cardiovascular Diseases; Female; Heart Failure; Humans; Hyperaldosteronism; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Nerve Tissue Proteins; Pheochromocytoma; Reference Values; Regression Analysis; Renal Dialysis