[Natriuretic peptides as markers of development and prognosis of pulmonary hypertension severity in patients with chronic obstructive disease.]

Studied the diagnostic and prognostic significance of N-terminal precursor of natriuretic peptide С-type (NT-proCNP) and brain natriuretic peptide (NT-proBNP) in patients with COPD with pulmonary hypertension (PH). The study included 47 patients with COPD (II - IV degrees of severity, 2016 GOLD, men - 44, women -3, mean age 59,3±9.12 years, disease duration of 13.7±5.93 years, the index of Smoking at 23.1±10,93 pack-years, BMI of 27.2±12,06 m/kg2.). Criteria of pulmonary hypertension on the basis of the doppler-echocardiography was an increase of pulmonary artery systolic pressure (PASP) > 40 mmHg alone. Depending on the presence and degree of enhancement PASP patients were divided into three groups: 1 - without pulmonary hypertension (PASP < 40 mmHg, n=168), 2 - moderate pulmonary hypertension (PASP 40 - 55 mmHg, n=101), 3-group with severe pulmonary hypertension (PASP > 55 mmHg, n=19). There was a statistically significant intergroup differences (p1-2 0,001, p 2-3 0,001, p1-3 < 0,001) values of NT-proCNP and NT-proBNP. There was a significant correlation relationship SDLA with the concentration of NT-proCNP (r=0,53, p<0,05) and NT-proBNP (r=0,67; p=0,05). A high diagnostic value of determination of NT-proCNP and NT-proBNP to predict the development and severity of PH in patients with COPD. Cox regression analysis showed that elevated levels of NT-proCNP and NT-proBNP in COPD patients of PH c are the predictors of hospital mortality.

Serial Evaluation of Abdominal Fluid and Serum Amino-terminal pro-C-type Natriuretic Peptide in Dogs with Septic Peritonitis.

BACKGROUND: Serum N-terminal pro-C-natriuretic peptide (NT-proCNP) has shown promise as a diagnostic biomarker for sepsis. Its sensitivity to detect dogs with septic peritonitis (SP) is reportedly low, perhaps attributable to the compartmentalization of NT-proCNP in the abdominal cavity. OBJECTIVES: To evaluate the use of an ELISA for the measurement of NT-proCNP in canine abdominal fluid and to describe the peri-operative pattern of abdominal fluid and serum NT-proCNP concentrations in dogs with SP. ANIMALS: Five client-owned dogs with nonseptic abdominal effusion of varying etiologies and 12 client-owned dogs with SP undergoing abdominal surgery and placement of a closed-suction abdominal drain (CSAD). Six dogs were included upon hospital admission; 6 were included the day after surgery. METHODS: Prospective pilot study. A commercially available ELISA kit was analytically validated for use on canine abdominal fluid. The NT-proCNP concentrations were measured in the abdominal fluid of control dogs, and in serum and abdominal fluid of dogs with SP from admission for CSAD removal. RESULTS: In dogs with SP, admission abdominal fluid NT-proCNP concentrations were lower than the concurrent serum concentrations (P = 0.031), and lower than control canine abdominal fluid concentrations (P = 0.015). Postoperatively, abdominal fluid NT-proCNP concentrations remained lower than serum concentrations (P < 0.050), except on day 4. CONCLUSIONS AND CLINICAL IMPORTANCE: The ELISA kit was able to measure NT-proCNP in canine abdominal fluid. In dogs with SP, low serum NT-proCNP concentrations cannot be explained by abdominal compartmentalization.

C-type natriuretic peptide and its receptors in atherosclerotic plaques of the carotid artery of clinically asymptomatic patients.

OBJECTIVES: C-type natriuretic peptide (CNP) has anti-inflammatory, anti-proliferative and anti-migratory properties. No data exist on the presence of CNP in human atherosclerotic plaques of the carotid artery. Therefore, this study aimed to analyse qualitatively the distribution pattern and characteristics of CNP and its receptors in both, early and advanced human carotid plaques, as well as in stable and unstable lesions. In addition, the aim of this study was to evaluate CNP and its receptors as possible biomarkers to predict plaque stability in advanced lesions. METHODS: Advanced carotid artery plaques of 40 asymptomatic patients (20 histologically stable and 20 histologically unstable) and early arteriosclerotic lesions of three patients were analysed. RESULTS: Serum level of CNP was similar in patients with stable and unstable plaques (196 ± 19 pg ml(-1) vs. 198 ± 25 pg ml(-1), p = 0.948). Expression level of natriuretic peptide receptor 3 (NPR3) was significantly higher in unstable plaques compared to stable plaques (5.6 ± 1.8% vs. 1.7 ± 0.5%, p = 0.045). Expression levels of CNP and NPR2 were higher in unstable plaques but the differences were not statistically significant. The distribution pattern of CNP, NPR2 and NPR3 varied qualitatively between early and advanced carotid plaques. No relevant histological differences were observed with respect to plaque stability. CONCLUSIONS: This study shows the presence of CNP and its receptors in atherosclerotic plaques of human carotid artery, with increased expression of NPR3 in histologically unstable plaques. In this study, serum CNP was not associated with histological plaque stability. In future, larger studies are required to further evaluate whether proteins of the CNP axis would be useful as biomarkers.

Presence of dendroaspis natriuretic peptide and its binding to NPR-A receptor in rabbit kidney.

Natriuretic peptides help to maintain sodium and fluid volume homeostasis in a healthy cardio-renal environment. Since the identification of Dendroaspis natriuretic peptide (DNP) as a new member of the natriuretic peptide family, DNP has been considered as an important regulator of natriuresis and dieresis. The present study was undertaken to investigate the presence of immunoreactive Dendroaspis natriuretic peptide (DNP) and its specific receptor in rabbit. DNP was detected in heart, kidney, liver, brain, and plasma by radioimmunoassay (RIA). DNP contents of cardiac atrium and ventricle, renal cortex and medulla, liver, and brain were 1.42 ± 0.15, 1.0 6 ± 0.08, 2.55 ± 0.21, 1.81 ± 0.16, 1.36 ± 0.22, and 0.69 ± 0.15 pg/mg of wet weight, respectively. The concentration of DNP in plasma was 235.44 ± 15.44 pg/ml. By quantitative in vitro receptor autoradiography, specific ¹²5I-DNP binding sites were revealed in glomeruli, interlobular artery, acuate artery, vasa recta bundle, and inner medulla of the kidney with an apparent dissociation constant (K(d)) of 0.29 ± 0.05, 0.36 ± 0.03, 0.84 ± 0.19, 1.18 ± 0.23, and 10.91 ± 1.59 nM, respectively. Basal rate of 3', 5'-cyclic guanosine monophosphate (cGMP) production by particulate guanylyl cyclase (GC) activation of glomerular membranes was basally 13.40 ± 1.70 pmol/mg protein/min. DNP caused an increment of cGMP production in similar magnitude to that caused by ANP, BNP, and urodilatin, while the production of cGMP by CNP was significantly lower than that by DNP. Our results show that plasma levels of DNP were higher when compared to other tissues. DNP produces cGMP via the NPR-A receptor subtype in the kidney, similarly to ANP and BNP, suggesting that plasma DNP could have similar functions as ANP and BNP.

Molecular characterisation and functional interrogation of a local natriuretic peptide system in rodent pituitaries, alphaT3-1 and LbetaT2 gonadotroph cells.

In the pituitary, C-type natriuretic peptide (CNP) has been implicated as a gonadotroph-specific factor, yet expression of the CNP gene (Nppc) and CNP activity in gonadotrophs is poorly defined. Here, we examine the molecular expression and putative function of a local gonadotroph natriuretic peptide system. Nppc, along with all three natriuretic peptide receptors (Npr1, Npr2 and Npr3), was expressed in both alphaT3-1 and LbetaT2 cells and primary mouse pituitary tissue, yet the genes for atrial-(ANP) and B-type natriuretic peptides (Nppa and Nppb) were much less abundant. Putative processing enzymes of CNP were also expressed in alphaT3-1 cells and primary mouse pituitaries. Transcriptional analyses revealed that the proximal 50 bp of the murine Nppc promoter were sufficient for GNRH responsiveness, in an apparent protein kinase C and calcium-dependent manner. Electrophoretic mobility shift assays showed Sp1/Sp3 proteins form major complexes within this region of the Nppc promoter. CNP protein was detectable in rat anterior pituitaries, and electron microscopy detected CNP immunoreactivity in secretory granules of gonadotroph cells. Pharmacological analyses of natriuretic peptide receptor activity clearly showed ANP and CNP are potent activators of cGMP production. However, functional studies failed to reveal a role for CNP in regulating cell proliferation or LH secretion. Surprisingly, CNP potently stimulated the human glycoprotein hormone alpha-subunit promoter in LbetaT2 cells but not in alphaT3-1 cells. Collectively, these findings support a role for CNP as the major natriuretic peptide of the anterior pituitary, and for gonadotroph cells as the major source of CNP expression and site of action.

Atrial natriuretic peptide and related peptides.

In recent years, biomarkers have been recognized as important tools for diagnosis, risk stratification, and therapeutic decision-making in cardiovascular diseases. Currently, the clinical potential of several natriuretic peptides is under scientific investigation. The well-known counter-regulatory hormones are atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide (DNP) and urodilatin, which play an important role in the homeostasis of body fluid volume. ANP and BNP have already been demonstrated to have diagnostic usefulness in a great number of studies, which have progressed from bench to bedside. This article summarizes existing data on ANP and related peptides in cardiovascular and other disorders, and outlines the potential clinical usefulness of these markers.

Los péptidos natricuréticos en insuficiencia cardíaca (Revisión) / The natriuretics peptides in cardiac insuficiente (Review)

El enfoque clínico y fisiopatológico de la insuficiencia cardíaca va variando conforme se conocen nuevos detalles. A inicios del siglo XX su enfoque partía de un exceso de líquidos dentro del organismo que obligaba a los médicos en la eliminación de líquidos y cambios en su distribución a través de torniquetes o sangrías. Ya ha mediados del siglo pasado este sufre un cambio de perspectiva al verse al ICC como un fenómeno de falla de bomba; pero el mayor cambio es el que vivimos actualmente en el cual es vista la ICC como un fenómeno neurohormonal, con participación de hormonas y sus receptores en la génesis fisiopatología de la IC. Es menester de este artículo presentar a la familia de los péptidos natriuréticos atriales y su participación en los eventos fisiopatológicos de la ICC y su estado actual como marcador de severidad de la misma.

Identification of novel bradykinin-potentiating peptides and C-type natriuretic peptide from Lachesis muta venom.

The generation of expressed sequence tags (ESTs) from the pit-viper snake Lachesis muta venom glands allowed us to identify two cDNA isoforms which encode the precursors for bradykinin-potentiating peptides (BPPs) and a C-type natriuretic peptide (CNP). The sequence data derived from these cDNAs combined with the venom peptides identification using MALDI-TOF mass spectrometry analysis predicted that these molecules are the precursor protein isoforms that are further processed to produce five novel BPPs and a CNP. They were identified directly in crude venom using MALDI-TOF. The BPPs sequences were further confirmed by MALDI-TOF/TOF de novo sequencing, and an unusual BPP with a residue of tryptophan at the N-terminus (usually it is pyroglutamate) was identified. The putative processing steps required to form the mature BPPs and CNP seem to be similar to those proposed for the ones found in the venom of Bothrops jararaca and Glodyus blomhoffi.

Natriuretic peptides in relation to the cardiac innervation and conduction system.

During the past two decades, the heart has been known to undergo endocrine action, harbouring peptides with hormonal activities. These, termed "atrial natriuretic peptide (ANP)," "brain natriuretic peptide (BNP)," and "C-type natriuretic peptide (CNP)," are polypeptides mainly produced in the cardiac myocardium, where they are released into the circulation, producing profound hypotensive effects due to their diuretic, natriuretic, and vascular dilatory properties. It is, furthermore, well established that cardiac disorders such as congestive heart failure and different forms of cardiomyopathy are combined with increased expression of ANP and BNP, leading to elevated levels of these peptides in the plasma. Besides the occurrence of natriuretic peptides (NPs) in the ordinary myocardium, the presence of ANP in the cardiac conduction system has been described. There is also evidence of ANP gene expression in nervous tissue such as the nodose ganglion and the superior cervical ganglion of the rat, ganglia known to be involved in the neuronal regulation of the heart. Furthermore, in the mammalian heart, ANP appears to affect the cardiac autonomic nervous system by sympathoinhibitory and vagoexcitatory actions. This article provides an overview of the relationship between the cardiac conduction system, the cardiac innervation and NPs in the mammalian heart and provides data for the concept that ANP is also involved in neuronal cardiac regulation.

Expression of C-type natriuretic peptide during development of rat lung.

C-type natriuretic peptide (CNP), recently found to be secreted from vascular endothelial cells, is now viewed as a novel endothelium-derived relaxing peptide. However, the distribution and expression of CNP during cardiopulmonary development is unclear. To follow changes in the expression of CNP during lung development, we examined rat embryos and neonates using Northern blot analysis and in situ hybridization for CNP mRNA and radioimmunoassay and immunohistochemistry for CNP protein. A substantial expression of CNP mRNA was first detected on postnatal day 2, and it thereafter remained fairly steady. The level of CNP protein also increased rapidly after postnatal day 1, reaching a settled level on postnatal day 4. CNP protein and mRNA were detected in the endothelium and smooth muscle cells of blood vessels and in bronchial airway and alveolar epithelia. Immunoreactivity for CNP protein in the endothelium of blood vessels increased to an intense level after the saccular stage. These results suggest that the changes in CNP levels may be related to the occurrence of pulmonary vasodilation after birth.

Natriuretic peptides in the lung modulated by pneumonectomy.

BACKGROUND: Natriuretic peptides are vasodilator hormones involved in the regulation of blood pressure and volume homeostasis. However, the mechanism of these peptides after pneumonectomy remains obscure. METHODS: We investigated changes in the pulmonary arterial pressure and the localization and changes in the atrial (A-type) natriuretic peptide (ANP) and the C-type natriuretic peptide (CNP) in the lung, using immunohistochemistry and radioimmunoassay (RIA) in anesthetized dogs. Furthermore, we examined guanosine 3', 5'-monophosphate (cGMP) levels in plasma and in the contralateral lung. RESULTS: Pulmonary arterial pressure was significantly increased after pneumonectomy. The immunoreactivities of both ANP and CNP were detected in the endothelium of the pulmonary artery. In the contralateral lung, the concentrations of ANP and CNP were both significantly increased. In plasma, only ANP levels were significantly increased. In contrast, the plasma and lung cGMP levels were significantly reduced after pneumonectomy. CONCLUSIONS: We postulate that the processes from secretion in the vascular endothelial cells to the action via ANP and CNP receptors are effected in the contralateral lung tissue at the acute stage of pneumonectomy.