Brain Natriuretic Peptide Production Research Articles

Age and sex variations in serum brain natriuretic peptide level following doxorubicin-induced myocardial injury in Wistar rats

ABSTRACT Background: Brain natriuretic peptide (BNP), a cardiac hormone produced by ventricular myocytes, plays an important role in the regulation of blood pressure and fluid volume. Although serum BNP level increases with age in normals, this response and possible sex variations in the presence of drug-induced myocardial injury need to be explored further. Methods: Twenty-four Wistar rats were separated into two groups, the controls and doxorubicin-myocardial injury (DOX-MI) model group. Each group was further subdivided into aged (100–104 weeks) and young (13–14 weeks), having an equal number of males and females (n = 3). The DOX-MI Model group was given 2.5 mg/kg DOX through intra-peritoneal injection on alternate days to a cumulative dose of 12.5 mg/kg. Blood samples were then collected and centrifuged at 3000 g for 15 min and serum BNP analysis was conducted using BNP ELISA Kit (BIOTUVA LIFE SCIENCES, UK). Results: BNP was significantly lower (P = 0.003) in the aged (100–104 weeks) DOX-MI-model group compared to aged controls. Similarly, it was lower in the young (13–14 weeks) DOX-MI-Model group than the young controls, but the difference was not statistically significant (P = 0.16). The analysis between aged and young rats within each group indicated significantly higher BNP levels in the aged rats compared to the young in both groups (P = 0.01 for aged vs. young DOX-MI-Model and P = 0.02 for aged vs. young controls). Conclusion: DOX-induced-MI has caused a significant reduction in BNP production in the aged rats (100–104 weeks) compared to the young (13–14 weeks).

B-Type Natriuretic Peptide (BNP) Revisited—Is BNP Still a Biomarker for Heart Failure in the Angiotensin Receptor/Neprilysin Inhibitor Era?

Simple SummaryActive BNP-32, less active proBNP-108, and inactive N-terminal proBNP-76 all circulate in the blood. The circulating protease neprilysin has lower substrate specificity for BNP than ANP, while proBNP and N-terminal proBNP are not degraded by neprilysin. Currently available BNP immunoassays react with both mature BNP and proBNP; therefore, measured plasma BNP is mature BNP + proBNP. Because ARNI administration increases mature BNP, measured plasma BNP initially increases with ARNI administration by the amount of the increase in mature BNP. Later, ARNI administration reduces myocardial wall stress, and the resultant reduction in BNP production more than offsets the increase of mature BNP due to inhibition of degradation by neprilysin, resulting in lower plasma BNP levels. In the ARNI era, BNP remains a useful biomarker for heart failure, though mild increases early during ARNI administration should be taken into consideration.Myocardial wall stress, cytokines, hormones, and ischemia all stimulate B-type (or brain) natriuretic peptide (BNP) gene expression. Within the myocardium, ProBNP-108, a BNP precursor, undergoes glycosylation, after which a portion is cleaved by furin into mature BNP-32 and N-terminal proBNP-76, depending on the glycosylation status. As a result, active BNP, less active proBNP, and inactive N-terminal proBNP all circulate in the blood. There are three major pathways for BNP clearance: (1) cellular internalization via natriuretic peptide receptor (NPR)-A and NPR-C; (2) degradation by proteases in the blood, including neprilysin, dipeptidyl-peptidase-IV, insulin degrading enzyme, etc.; and (3) excretion in the urine. Because neprilysin has lower substrate specificity for BNP than atrial natriuretic peptide (ANP), the increase in plasma BNP after angiotensin receptor neprilysin inhibitor (ARNI) administration is much smaller than the increase in plasma ANP. Currently available BNP immunoassays react with both mature BNP and proBNP. Therefore, BNP measured with an immunoassay is mature BNP + proBNP. ARNI administration increases mature BNP but not proBNP, as the latter is not degraded by neprilysin. Consequently, measured plasma BNP initially increases with ARNI administration by the amount of the increase in mature BNP. Later, ARNI reduces myocardial wall stress, and the resultant reduction in BNP production more than offsets the increase in mature BNP mediated by inhibiting degradation by neprilysin, which lowers plasma BNP levels. These results suggest that even in the ARNI era, BNP can be used for diagnosis and assessment of the pathophysiology and prognosis of heart failure, though the mild increases early during ARNI administration should be taken into consideration.

Influence of thyroid dysfunction on brain natriuretic peptide level in health examination participants.

The tissue-specific circulating markers of thyroid hormone action on cardiac function have not been established. Although the relationship between thyroid function and plasma brain natriuretic peptide (BNP) levels has been evaluated in patients with thyroid disorders, the relationship between these parameters in the general population has not been yet studied. We conducted retrospective cohort study by health examination with concurrent measurements of TSH, free T4, body mass index, systolic blood pressure, hemoglobin, and estimated glomerular filtration rate from participants who visited the Department of Health Checkup, Enshu Hospital between July 2008 and March 2017. After participants with abnormal electrocardiogram and/or any history of cardiac disease were excluded, 2,807 individuals were subjected. Multivariate analyses demonstrated that, when compared to euthyroidism (n = 2,629), the increase in BNP levels was significant in overt thyrotoxicosis (n = 21) but not in subclinical thyrotoxicosis (n = 53) or subclinical hypothyroidism (n = 97). Interestingly, the standardized partial regression coefficient was the smallest for thyroid function category (overt thyrotoxicosis compared to euthyroidisim; β = 0.048, p = 0.006) among the independent variables including age, body mass index, systolic blood pressure, and hemoglobin. In longitudinal comparison, we identified 986 participants who had sequential data on the measurements and were stable as euthyroidism and subclinical hypothyroidism. Their annual percent change in BNP demonstrated no significant differences. In conclusion, a direct stimulatory effect of thyroid hormone on the secretion (or production) of BNP was confirmed even in a large number of health examination participants.

Renal papillary tip extract stimulates BNP production and excretion from cardiomyocytes.

BackgroundBrain natriuretic peptide (BNP) is an important biomarker for patients with cardiovascular diseases, including heart failure, hypertension and cardiac hypertrophy. It is also known that BNP levels are relatively higher in patients with chronic kidney disease and no heart disease; however, the mechanism remains unclear.Methods and resultsWe developed a BNP reporter mouse and occasionally found that this promoter was activated specifically in the papillary tip of the kidneys, and its activation was not accompanied by BNP mRNA expression. No evidence was found to support the existence of BNP isoforms or other nucleotide expression apart from BNP and tdTomato. The pBNP-tdTomato-positive cells were interstitial cells and were not proliferative. Unexpectedly, both the expression and secretion of BNP increased in primary cultured neonatal cardiomyocytes after their treatment with an extract of the renal papillary tip. Intraperitoneal injection of the extract of the papillary tips reduced blood pressure from 210 mmHg to 165 mmHg, the decrease being accompanied by an increase in serum BNP and urinary cGMP production in stroke-prone spontaneously hypertensive (SHR-SP) rats. Furthermore the induction of BNP by the papillary extract from rats with heart failure due to myocardial infarction was increased in cardiomyocytes.ConclusionsThese results suggested that the papillary tip express a substance that can stimulate BNP production and secretion from cardiomyocytes.

Inverse Correlation of Venous Brain Natriuretic Peptide Levels with Body Mass Index Is due to Decreased Production

Objective: The aim of this paper was to study the association between body mass index (BMI) and coronary sinus (CS) brain natriuretic peptide (BNP) levels in patients with heart failure and reduced systolic function (HFrEF). Background: There is an inverse relationship between systemic venous BNP (V-BNP) levels and BMI in patients with HFrEF. It is unclear whether this finding is due to decreased production or due to an increased metabolism of BNP. Since CS-BNP levels reflect BNP production, we hypothesized that assessing the correlation of CS-BNP levels with BMI would provide insight into the mechanism of this inverse relationship of V-BNP and BMI. Methods: We prospectively enrolled 54 subjects with HFrEF who were to undergo cardiac resynchronization device implantation. CS-BNP, V-BNP, and arterial BNP (A-BNP) levels were measured during the implant procedure. Subjects were divided into 2 groups based on their BMI (group 1: BMI <30 and group 2: BMI ≥30). Results: The mean age of the overall study group was 64 ± 10 years. Average BMI for group 1 was 25.8 ± 2.8 and 36.8 ± 4.6 for group 2 (p < 0.03). A history of hypertension was present in 55% (n = 26) of the subjects, while diabetes was reported in 31% (n = 15). Serum creatinine was 1.0 ± 0.2 mg/dL and TSH 2.1 ± 1.4 mIU/L. 79% of the subjects were receiving β-blockers, while 94% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The mean CS-BNP, V-BNP, and A-BNP levels in group 2 were significantly lower than in group 1 (286.2 ± 170.5 vs. 417.5 ± 247.5 pg/mL, p = 0.04; 126.6 ± 32.5 vs. 228 ± 96.4 pg/mL, p = 0.01; and 151.9 ± 28.6 vs. 242 ± 88.8 pg/mL, p = 0.04, respectively). Univariate analysis and multivariate regression adjusted for age, diabetes mellitus, sex, glomerular filtration rate, and left atrial size confirmed BMI as an independent predictor of CS-BNP levels (β = -0.372, p = 0. 03) in our study. Conclusions: In this study, we demonstrate an inverse relationship between CS-BNP levels and BMI in patients with HFrEF. These findings suggest that the previously established inverse relationship between V-BNP and BMI is due to a decreased cardiac production of BNP in obese patients rather than from increased peripheral metabolism.

Levels of N-terminal pro-brain natriuretic peptide in brain injury patients

Currently, the most common way to predict the outcome of acute brain damage is to study the level of protein S-100 in the serum. This method lacks specificity as the concentration of protein S-100 significantly increases with age, more for men than women, and there are no data on prognostically significant changes in the level of S-100 after removal of the tumor and cerebral hemorrhages. Endothelins, vasopressin, some cytokines, excess sodium or calcium in serum, activation of the sympathoadrenal system, and tachycardia are the stimulants of brain natriuretic peptide production. The rise of the natriuretic peptide level in cases of acute brain damage has a functionally adaptive nature, based on vasodilation, diuretic action peptide and ability to reduce sympathoadrenal system activity. Thus, we can suppose that the more severe the damage, the higher the stimulation of natriuretic peptide. In this study we investigate the level of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with severe brain damage and find correlation between the level of peptide and outcome.

Epidermal growth factor-network signaling mediates luteinizing hormone regulation of BNP and CNP and their receptor NPR2 during porcine oocyte meiotic resumption.

The epidermal growth factor (EGF) network, induced by luteinizing hormone (LH), plays an essential role during the regulation of oocyte maturation, cumulus expansion, and ovulation. Binding of brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) to natriuretic receptor 2 (NPR2) generates cyclic guanosine monophosphate (cGMP), a key inhibitor that sustains porcine oocyte meiotic arrest. This correlation suggests that LH interacts with natriuretic-peptide signaling, possibly via the EGF network, to promote porcine meiotic resumption. In testing this hypothesis, we found that the majority of porcine oocytes remain arrested in the germinal-vesicle stage after 44 hr of co-culturing cumulus-oocyte complexes with 10(7) granulosa cells, which secreted active BNP and CNP; these natriuretic peptides associate with NPR2 on cumulus cells, thereby inhibiting porcine oocyte maturation. This inhibitory effect of BNP and CNP was relieved by EGF-like growth factors, whose expression naturally increases in granulosa cells 18 hr after human chorionic gonadotropin injection. LH and the EGF-like peptide amphiregulin (AREG) decreased BNP and CNP production in granulosa cells and down-regulated NPR2 expression in cumulus cells, which together decreased oocyte cGMP to levels that permit meiotic resumption. The effects of AREG on the gene expression of natriuretic-peptide signaling components and on oocyte maturation were completely blocked by the EGF receptor kinase inhibitor AG1478; the effect of LH, however, was only partially reversed by AG1478. Based on these results, LH regulates natriuretic-peptide signaling, although other pathways also cooperate with the EGF network to induce porcine oocyte maturation.

The role of brain natriuretic peptide in maintaining myometrial quiescence during pregnancy

Myometrial quiescence is a physiological stage of the myometrium during pregnancy. It is a period of active relaxation of the myometrial smooth muscle cells; myometrial quiescence is responsible for maintaining pregnancy. The precise mechanisms underlying myometrial quiescence have not been completely elucidated, although many mediators and cellular pathways have been described as playing a role. Fetal membranes (chorion and amnion) produce and release one or more substances that inhibit myometrial contractions, playing a central role in the maintenance of myometrial quiescence. Brain natriuretic peptide (BNP) is more potent than any other natriuretic peptide in inhibiting myometrial contractions in vitro. Brain natriuretic peptide is produced by the chorion and amnion, mainly during myometrial quiescence, and decreasing towards the end of pregnancy. Production of BNP is reduced in fetal membranes obtained from women in preterm labour. It is postulated that BNP, acting in a paracrine fashion, plays a key role in the maintaining myometrial quiescence and, therefore, controlling the duration of pregnancy. Furthermore, it is postulated that a premature decrease of BNP production by the fetal membranes may cause preterm labour and preterm birth.

Mechanical Stretch Increases Brain Natriuretic Peptide Production and Secretion in the Human Fetal Membranes

Brain natriuretic peptide (BNP) is synthesized by human fetal membranes, both the amnion and chorion. This locally produced BNP inhibits the contraction of the human myometrium, contributing to the maintenance of myometrial quiescence during pregnancy. We tested the hypothesis that BNP production is increased by fetal membrane stretching, which is predicted to occur in the expanding uterus, and inhibited by epidermal growth factor (EGF), whose production in the fetal membranes increases in late pregnancy. Term fetal membranes were obtained during elective cesarean delivery before labor. Sections of membranes were placed in an isolated chamber containing DMEM: F12 medium (37°C) and stretched with a 35 g weight. Medium and tissue samples were collected at 0, 3, 6, 18, and 24hours for measurement of messenger RNA (mRNA) and BNP levels in the presence/absence of EGF (2 × 10(-9)mol/L). Inducible nitric oxide synthase (iNOS) and β-actin were also evaluated to discard a nonspecific effect of mechanical stretch on protein expression. We found that amnion and chorion stretching increased the BNP mRNA (reverse transcription-polymerase chain reaction [RT-PCR]) and protein (radioimmunosorbent assay [RIA]) levels from 18 hours onward. The effect of stretching was inhibited by EGF (2 × 10(-9) mol/L). Stretch did not increase iNOS or β-actin protein levels. We concluded that chorion and amnion stretching may increase BNP expression in the fetal membranes during pregnancy, while increasing biological activity of EGF may decrease BNP production in the chorion and amnion late in pregnancy. We postulate BNP is an important regulator of myometrial contractility during pregnancy, and its production is modulated by both stretch and progressive increase in EGF levels during pregnancy.

Involvement of Protein Kinase C and RhoA in Protease-Activated Receptor 1–Mediated F-Actin Reorganization and Cell Growth in Rat Cardiomyocytes

Protease-activated receptor 1 (PAR1) that can be activated by serine proteinases such as thrombin has been demonstrated to contribute to the development of cardiac remodeling and hypertrophy after myocardial injury. Here, we investigated the mechanisms by which PAR1 leads to hypertrophic cardiomyocyte growth using cultured rat neonatal ventricular myocytes. PAR1 stimulation with thrombin (1 U/ml) or a synthetic agonist peptide (TFLLR-NH2, 50 μM) for 48 h induced an increase in cell size and myofibril formation associated with BNP (brain natriuretic peptide) production. This actin reorganization assessed by fluorescein isothiocyanate (FITC)-conjugated phalloidin staining appeared at 1 h after PAR1 stimulation, and this response was reduced by a protein kinase C (PKC) inhibitor, chelerythrine, inhibitors of Rho (simvastatin) and Rho-associated kinase (ROCK) (Y-27632), but not by pertussis toxin (PTX). By Western blot analysis, translocation of PKCα or PKCε from the cytosol to membrane fractions was observed in cells stimulated with thrombin or TFLLR-NH2 for 2 – 5 min. In addition, PAR1 stimulation for 3 – 5 min increased the level of active RhoA. Furthermore, inhibitors of PKC and ROCK and Rho abrogated PAR1-mediated increase in cell size. Depletion of PKCα or PKCε by specific small interfering RNA also suppressed both actin reorganization and cell growth. These results suggest that PAR1 stimulation of cardiomyocytes induces cell hypertrophy with actin cytoskeletal reorganization through activation of PKCα and PKCε isoforms and RhoA via PTX-insensitive G proteins.

Brain Natriuretic Peptide (BNP) Produced by the Human Chorioamnion May Mediate Pregnancy Myometrial Quiescence

We aim to demonstrate that Brain Natriuretic Peptide (BNP) is synthesized and released from the fetal membranes and mediates pregnancy myometrial quiescence. Myometrium and fetal membranes (FM) were obtained from term and preterm pregnancies at the time of cesarean section, either in labor or not in labor. BNP was measured in term and preterm FM, in culture cells, and conditioned media. We found BNP (but not ANP or CNP) inhibited contractions of preterm, but not term, human myometrium. BNP (both protein and mRNA) was detected in all tissues, conditioned media and cultured cells. BNP was higher in samples from preterm women not in labor compared to those at term not in labor. BNP concentrations were significantly reduced in women in spontaneous preterm labor. We conclude that locally produced BNP may be involved in generating myometrial quiescence during pregnancy. Further, a premature decrease of BNP production may cause preterm labor.

Changes of BNP Level and Pulmonary Arterial Pressure during An Acute Sickle Cell Crisis, Comparison with Steady State

Background: The heart is frequently involved in Sickle Cell Anemia (SCA). Cardiomegaly is a usual finding, significant arrythmias and sudden death are common, and 30% of patients with both homozygous and heterozygous SCA develop Pulmonary Arterial Hypertension (PAH), a major risk factor for higher mortality in this population. Brain Natriuretic Peptide (BNP) and echocardiographic data could provide important prognostic and diagnostic information about PAH in SCD. High levels of BNP, which is released from ventricular cardiomyocytes in response to their stretch, reflect cardiac chamber volume and pressure overload in various conditions. In patients with PAH, BNP levels correlate with the severity of Pulmonary Artery Pressure (PAP) elevation and right ventricular dysfunction. In human, the half life of BNP is 20 minutes, reflecting the fluctuation of BNP levels during different stages of any acute cardiac pathology.Methodology: The hypothesis of this prospective IRB approved study was to investigate the BNP level and PAP elevation during an acute Sickle Cell Crisis (SCC), in particular in those with intrathoracic structures involvement. Between December 2006 and July 2008, 81 patients were registered after a written informed consent was obtained. We collected the BNP levels and echocardiographic data of patients with SCD and compared them in two group; those who were admitted with Sickle Cell Crisis (SCC) and those who returned to clinic in Steady State (SS) for follow up. The data were obtained on the first day of admission in SCC group. The primary endpoint was the elevation of the BNP level and the secondary endpoint was elevation of the PAP during a SCC, which were compared with SS patients. The inclusion criterion was age above 18 and having one of the sickle cell syndromes, requiring hospital admission.Results: Forty nine patients (59%) were female, and 34 (41%) patients were male. Their ages ranged from 19 to 65, mean (SD) 30.2 (9.7) years. The mean (SD) levels of BNP were significantly higher in patients who were admitted with one of the acute complications or vaso-occlusive crisis of sickle cell, [177.3 (23.4) pg/ml], when compared with its levels in SS, [34.17 (6.1) pg/ml], (95% CI 61.4 to 225.0, p<.001) (Figure 1). An elevated BNP level was defined as levels more than 100 pg/ml. A further subgroup analysis revealed that the BNP levels were even more significantly higher in patients with acute chest syndrome or other intrathoracic events [(n= 17, mean (SD) 363.6 (121.3) pg/ml], when compared with those of simple acute sickle cell crisis, [(n= 35, mean (SD) 167.7 (26.8) pg/ml] (p=.038) (Figure 1). Topographic data about heart chambers' sizes, volumes, and pressures were obtained by Echocardiography and compared in two groups. While only 23.1% of patients in SS group had elevated PAP with a mean (SD) of 43 (2.1) mmHg, 41.1% (n=21) of patients with SCC had elevated PAP with mean (SD) 45.9 (2.1) mmHg, with no significant difference between two groups with PAH (p=.608).Conclusion: Patients with either homozygous or heterozygous forms of SCA can have cardiac complications, such systolic and diastolic dysfunction. Hypoxemia leads to raised levels of BNP production. In patients with SCA, an elevated BNP level largely reflects the severity of right ventricular dysfunction associated with PAH. Our data revealed that BNP level and PAP are increased during vaso-occlusive crisis of SCA, in particular during those life-threatening complications, such acute chest syndrome. These changes seem to be temporary and with clinical improvement, the majority of patients' BNP levels and PAP return to the baseline, although some will never normalize. [Display omitted]

Plasma brain natriuretic peptide at rest and after adenosine-induced myocardial ischemia in normotensive and essential hypertensive patients with suspected coronary artery disease

This study investigated plasma brain natriuretic peptide (BNP) levels in normotensive and hypertensive patients with suspected coronary artery disease during radionuclide pharmacological stress testing. Twenty-seven normotensive patients (15 males, aged 63.0 ± 4.5 years and 12 females, aged 63.0 ± 4.1 years) and 38 essential hypertensive patients (25 males, aged 63.3 ± 3.3 years and 13 females, aged 64.6 ± 2.6 years) with chest pain and exercise stress testing inconclusive for coronary artery disease underwent myocardial perfusion single-photon emission computed tomography (SPECT) using adenosine infusion. SPECT identified patients without (16 normotensive and 22 hypertensive) and patients with (11 normotensive and 16 hypertensive) transient perfusion defects. Basal BNP levels in normotensive patients without transient myocardial ischemia (3.1 ± 1.2 fmol/ml) were significantly ( P < 0.01) lower than those observed in normotensive patients with transient ischemia (8.2 ± 1.2 fmol/ml), whereas BNP levels in hypertensive patients without transient ischemia (8.2 ± 1.0 fmol/ml) did not significantly differ from those in hypertensive patients with transient ischemia (8.1 ± 2.0 fmol/ml). No significant difference was found in BNP levels between males or females either in normotensive or hypertensive patients without or with ischemia. Adenosine infusion did not significantly change BNP levels in any subject group without or with myocardial perfusion defects. Our findings show that increases in BNP allow early detection of myocardial ischemia in normotensive patients, but not in hypertensive patients with suspected coronary artery disease. Adenosine-induced myocardial ischemia does not affect BNP production already activated by coronary artery disease in normotensive patients and by hemodynamic changes in hypertensive patients.

Chromogranin B Regulates Calcium Signaling, Nuclear Factor κB Activity, and Brain Natriuretic Peptide Production in Cardiomyocytes

Altered regulation of signaling pathways can lead to pathologies including cardiac hypertrophy and heart failure. We report that neonatal and adult cardiomyocytes express chromogranin B (CGB), a Ca(2+) binding protein that modulates Ca(2+) release by the inositol 1,4,5-trisphosphate receptor (InsP(3)R). Using fluorescent Ca(2+) indicator dyes, we found that CGB regulates InsP(3)-dependent Ca(2+) release in response to angiotensin II, an octapeptide hormone that promotes cardiac hypertrophy. ELISA experiments and luciferase reporter assays identified angiotensin II as a potent inducer of brain natriuretic peptide (BNP), a hormone that recently emerged as an important biomarker in cardiovascular disease. CGB was found to regulate angiotensin II-stimulated and basal secretion, expression and promoter activity of BNP that depend on the InsP(3)R. Moreover, we provide evidence that CGB acts via the transcription activity of nuclear factor kappaB in an InsP(3)/Ca(2+)-dependent manner but independent of nuclear factor of activated T cells. In vivo experiments further showed that cardiac hypertrophy induced by angiotensin II, a condition characterized by increased ventricular BNP production, is associated with upregulation of ventricular CGB expression. Overexpression of CGB in cardiomyocytes, in turn, induced the BNP promoter. The evidence presented in this study identifies CGB as a novel regulator of cardiomyocyte InsP(3)/Ca(2+)-dependent signaling, nuclear factor kappaB activity, and BNP production.

Angiotensin II receptor antagonism reverts the selective cardiac BNP upregulation and secretion observed in myocarditis

The cardiac natriuretic peptides atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are discoordinately regulated in myocardial inflammation associated with acute allograft rejection in humans and during in vitro exposure of cardiocyte cultures to some proinflammatory cytokines. We used experimental autoimmune myocarditis (EAM) to determine whether the discoordinate regulation of ANF and BNP was specific to the situations above or was generally associated with other types of myocardial inflammation. The dependency of this process to angiotensin signaling was also determined, given that previous work demonstrated beneficial effects of the angiotensin receptor blocker olmesartan in myocarditis. Histopathological changes, plasma and cardiac ANF, BNP, and selected cytokines gene expression as well as plasma cytokine levels using a cytokine array were determined in EAM, angiotensin receptor blocker-treated, and control rats. It was found that EAM specifically increases BNP but not ANF circulating levels, thus mimicking the findings in acute cardiac allograft rejection and the effect of some proinflammatory cytokines on cardiocyte cultures in vitro. Plasma cytokine array and real-time PCR revealed that lipopolysaccharide-induced CXC chemokine, monocyte chemotactic protein-1, and tissue inhibitor of metalloproteinase-1 were increased in plasma and in the myocardium of EAM rats. Olmesartan treatment reversed virtually all neuroendocrine and histopathological cardiac changes induced by EAM, thus providing a mechanistic insight into this phenomenon. It is concluded that the inflammatory process contributes specific cytokines, leading to the disregulation of cardiac ANF and BNP production observed during myocardial inflammation, and that this process is angiotensin receptor 1 dependent.

Myocardial stiffness is an important determinant of the plasma brain natriuretic peptide concentration in patients with both diastolic and systolic heart failure

Plasma brain natriuretic peptide (BNP) concentration increases in proportion to heart failure (HF) severity. Although plasma BNP decreases to a certain level by optimal treatment, there is significant heterogeneity in the baseline value among individuals. The underlying mechanism of the steady-state plasma BNP levels remains still controversial. We investigated the hypothesis that myocardial stiffness (K(m)) is a major determinant of the plasma BNP level. In 19 patients with diastolic HF [DHF; left ventricular ejection fraction (LVEF) > or =4 5%], 18 with systolic HF (SHF; LVEF < 45%), and 12 controls, left ventricular (LV) performance variables and the results of the stress-strain analyses were obtained by the combined simultaneous measurement of echocardiographic and haemodynamic data, and compared with the plasma BNP level. In DHF, a significant correlation was observed between plasma BNP and fractional shortening (P = 0.010), pulmonary capillary wedge pressure (P = 0.030), end-diastolic pressure (P = 0.006), time constant of the LV isovolumic-pressure decline (P = 0.049), end-diastolic stress (P = 0.012), and K(m) (P = 0.004), respectively. In SHF, a significant correlation was observed between plasma BNP and end-diastolic stress (P = 0.036), chamber stiffness (P = 0.048), and K(m) (P = 0.003), respectively. In stable conditions, K(m) may be the most important determinant of the plasma BNP production in patients with both DHF and SHF.

Impact of essential hypertension and primary aldosteronism on plasma brain natriuretic peptide concentration

Introduction. 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. Methods. 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. Results. 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). Conclusions. 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.

Peroxisome Proliferator-Activated Receptor-γ Ligands Attenuate Brain Natriuretic Peptide Production and Affect Remodeling in Cardiac Fibroblasts in Reoxygenation After Hypoxia

Cardiac fibroblasts (CFs) participate in cardiac remodeling after hypoxic cardiac damage, and remodeling is thought to be mediated by CF synthesis of brain natriuretic peptide (BNP). It is unknown whether the peroxisome proliferator-activated receptors (PPARs), which mediate cellular signaling for growth and migration, affect BNP synthesis and whether PPARs participate in regulation of extracellular matrix protein (ECM) expression for remodeling. We examined the production of BNP in cultured neonatal ventricular CFs and its signaling system on collagen synthesis and on activation of matrix metalloproteinases (MMPs) in reoxygenation after hypoxia. BNP mRNA was detected in CFs, and a specific BNP protein, BNP1-32, was secreted into the media. Abundance of collagen I and III was increased in the media at reoxygenation. mRNA and protein levels for MMP-2 and the tissue inhibitor of metalloproteinase (TIMP)-1 were enhanced in CFs at reoxygenation. These observations also were noted in CFs after incubation with angiotensin II (10 microM) for 24 h. Pretreatment with pioglitaozone (0.1-10 microM) attenuated BNP mRNA and protein abundance of collagen III, MMP-2, and TIMP-1 in CFs at reoxygenation. The secreted BNP was also decreased by pioglitaozone in the media. Furthermore, PPAR activators inhibited reoxygenation-induced activation of nuclear factor (NF)-kappaB. These results demonstrate that PPAR activators inhibit BNP synthesis in CFs and imply that PPAR activators may regulate ECM remodeling partially through the NF-kappaB-mediated pathway.

NT-ProBNP: The Mechanism Behind the Marker

Brain natriuretic peptide (BNP) was isolated originally from porcine brain extracts but was soon defined as a cardiac natriuretic hormone. Together with the highly homologous atrial natriuretic peptide, it forms a dual natriuretic peptide system of the heart. The main stimulus for proBNP synthesis and secretion from cardiac myocytes is myocyte stretch. On secretion, the propeptide is split into the biologically active BNP and the remaining part of the prohormone N-terminal proBNP (NT-proBNP). In heart failure increased wall stretch, neurohormonal activation and hypoxia stimulate BNP secretion. The recently demonstrated production of BNP by stimulated cardiac fibroblasts is of uncertain pathophysiologic importance. In contrast to atrial natriuretic peptide, BNP is a constitutively secreted hormone with relatively little intracellular storage of mature peptide. In the normal state, the atrium is the main cardiac production site, but as heart failure develops, there is a profound activation of ventricular NT-proBNP synthesis. BNP acts on distant tissues and causes diuresis, vasodilatation, and decreased renin and aldosterone secretion. Known mechanisms of BNP clearance from plasma include binding to the natriuretic peptide clearance receptor type-C and proteolysis by peptidase NEP 24.11. NT-proBNP has a longer half-life and thus higher plasma concentration than BNP. It probably is cleared from plasma by renal excretion and possibly other unknown pathways.

Molecular regulation of the brain natriuretic peptide gene

After brain natriuretic peptide (BNP) was isolated in 1988, rapid progress was made in cloning its cDNA and gene, facilitating studies of tissue-specific expression and molecular regulation of gene expression. This review focuses on the molecular determinants of regulation of the rat and human BNP genes, including signaling pathways that impact on changes in gene expression and cis regulatory elements responsive to these signaling pathways. For both rat and human genes, elements in the proximal promoter (−124 to −80), including GATA, MCAT, and AP-1-like, have been shown to contribute to basal and inducible regulation. More distal elements in the human BNP gene respond to calcium signals (an NF-AT site at −927), thyroid hormone (a thyroid-responsive element at −1000), and mechanical stretch (shear stress-responsive elements at −652 and −162). Understanding how BNP is regulated by signaling molecules that are activated in the hypertrophied and ischemic heart should be useful in understanding the underlying pathology. This may lead to therapeutic strategies that prevent hypertrophy while allowing for the beneficial effects of BNP production.