natriuretic-peptide--c-type and Hypertension--Pulmonary

Pulmonary hypertension (PH) due to left ventricular heart failure (LV-HF) is a disabling and life-threatening disease for which there is currently no single marketed pharmacological agent approved. Despite recent advances in the pathophysiological understanding, there is as yet no prospect of cure, and the majority of patients continue to progress to right ventricular failure and die. There is, therefore an urgent unmet need to identify novel pharmacological agents that will prevent or reverse the increase in pulmonary artery pressures while enhancing cardiac performance in PH due to LV-HF. In the present article, we first focused on the Natriuretic Peptide Receptor type C (NPR-C) based therapeutic strategies aimed at lowering pulmonary artery pressure. Second, we reviewed potential NPR-C therapeutic strategies to reverse or least halt the detrimental effects of diastolic dysfunction and impaired nitic oxide signalling pathways, as well as possibilities for neurohumoral modulation.

Topics: Animals; Cardiovascular Agents; Heart Failure; Humans; Hypertension, Pulmonary; Natriuretic Peptide, C-Type; Treatment Outcome; Ventricular Dysfunction, Left

Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and premature death. While recent data supports the initial combination of ambrisentan (a selective ERA) and tadalafil (a PDE5i) in functional class II or III patients, there is no published data describing the safety and efficacy of ambrisentan when added to patients currently receiving a PDE5i and exhibiting a suboptimal response. The ATHENA-1 study describes the safety and efficacy of the addition of ambrisentan in this patient population.. PAH patients with a suboptimal response to current PDE5i monotherapy were assigned ambrisentan in an open-label fashion and evaluated for up to 48 weeks. Cardiopulmonary hemodynamics (change in PVR as primary endpoint) were evaluated at week 24 and functional parameters and biomarkers were measured through week 48. Time to clinical worsening (TTCW) and survival are also described.. Thirty-three subjects were included in the analysis. At week 24, statistically significant improvements in PVR (-32%), mPAP (-11%), and CI (+25%) were observed. Hemodynamic improvements at week 24 were further supported by improvements in the secondary endpoints: 6-min walk distance (+18 m), NT-proBNP (-31%), and maintenance or improvement in WHO FC in 97% of patients. Adverse events were consistent with known effects of ambrisentan.. The hemodynamic, functional, and biomarker improvements observed in the ATHENA-1 study suggests that the sequential addition of ambrisentan to patients not having a satisfactory response to established PDE5i monotherapy is a reasonable option.

Topics: Adult; Antihypertensive Agents; Biomarkers; Dose-Response Relationship, Drug; Drug Therapy, Combination; Elapid Venoms; Endothelin A Receptor Antagonists; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, C-Type; Outcome Assessment, Health Care; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pyridazines; Survival; Tadalafil; Treatment Outcome

Lipopolysaccharide induces rapid deterioration of cardiac function in rats with pulmonary arterial hypertension. It was desired to investigate if this cardiac dysfunction could be treated by C-type natriuretic peptide. Rat pulmonary arterial hypertension was induced by intraperitoneal injection of monocrotaline. Hemodynamics and cardiac function were measured by pressure-volume (P-V) catheter before and after the rats were treated with lipopolysaccharide and C-type natriuretic peptide. Cyclic guanosine 3',5'-monophosphate (cGMP) level was determined by enzyme-linked immunosorbent assay analysis. After the rats were injected with low-dose lipopolysaccharide, they experienced left ventricle systolic function deterioration. Administration of C-type natriuretic peptide improved hemodynamics and left ventricle systolic function. cGMP level was elevated after C-type natriuretic peptide treatment. C-type natriuretic peptide could ameliorate lipopolysaccharide-induced cardiac dysfunction and restore hemodynamic deterioration in rats with pulmonary arterial hypertension.

Topics: Animals; Cyclic GMP; Heart Diseases; Heart Ventricles; Hemodynamics; Hypertension, Pulmonary; Lipopolysaccharides; Male; Monocrotaline; Natriuretic Peptide, C-Type; Pulmonary Artery; Rats; Rats, Sprague-Dawley

While N-terminal B-type natriuretic peptide (NT-proBNP) has been examined extensively in pulmonary hypertension (PH), limited data exists on the subtype A, C and D. The aim of this prospective pilot study was a head-to-head comparison of NPs in respect to haemodynamic parameters and the influence of renal function.. Plasma samples were drawn during routine right heart catheterization in 62 patients with precapillary PH and 20 control patients. MR-proANP measurements were performed on the automated Kryptor platform, NT-proBNP by CLIA, NT-proCNP and DNP levels by ELISA. Results are expressed as median [range] and tested non-parametrically. Non-parametric locally linear multiple regression was performed to determine the influence of renal function on NP levels. P-values <0.05 were considered significant.. Patients with PH had significantly higher MR-proANP and NT-proBNP levels. NT-proCNP showed a trend to higher levels, while DNP did not differ from control subjects. Both MR-proANP and NT-proBNP were associated with cardiac index (CI), right atrial pressure (RAP), mean pulmonary artery pressure (PAPm) and pulmonary vascular resistance index (PVRI). NT-proCNP was associated with RAP, while DNP showed no associations with haemodynamic variables. Associations of haemodynamic parameters with NPs were weakened in patients with in elevated serum creatinine and showed increased regression slopes.. MR-proANP demonstrated equivalent associations with haemodynamics compared to NT-proBNP, but both markers depend on intact renal function. NT-proCNP was correlated with RAP and renal function, while DNP showed no associations. Larger studies should evaluate MR-proANP as candidate prognostic biomarker in PH.

Topics: Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Case-Control Studies; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Kidney; Male; Middle Aged; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Peptide Fragments; Predictive Value of Tests; Prospective Studies

Idiopathic pulmonary fibrosis (IPF) is a progressive fibro-proliferative disorder refractory to current therapy commonly complicated by the development of pulmonary hypertension (PH); the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated PH, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder.. Pulmonary haemodynamics, right ventricular function and markers of lung fibrosis were determined in wild-type (WT) and natriuretic peptide receptor (NPR)-A knockout (KO) mice exposed to bleomycin (1 mg·kg(-1) ). Human myofibroblast differentiation was studied in vitro.. Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels (ecadotril) and potentiated natriuretic peptide-dependent signalling (sildenafil) reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFβ-induced human myofibroblast differentiation, a key driver of remodelling in IPF patients.. These data highlight an endogenous host-defence capacity of natriuretic peptides in lung fibrosis and PH. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with IPF.

Topics: Animals; Atrial Natriuretic Factor; Bleomycin; Cell Differentiation; Dose-Response Relationship, Drug; Humans; Hypertension, Pulmonary; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myofibroblasts; Natriuretic Peptide, C-Type; Natriuretic Peptides; Protein Precursors; Pulmonary Fibrosis; Structure-Activity Relationship; Transforming Growth Factor beta

C-type natriuretic peptide (CNP) is a local regulator of vascular tone and remodeling in many vascular beds. However, the role of CNP in modulating pulmonary arterial hypertensive and vascular remodeling responses is unclear. The purpose of this study was to determine if CNP is capable of preventing the development of pulmonary hypertension (PH).. We used animal models of PH caused by chronic hypoxia alone or in combination with the vascular endothelial growth factor (VEGF) receptor blocker SU5416. We measured pulmonary hemodynamics, right ventricular hypertrophy and vascular remodeling effects in response to a continuous infusion of low dose or high dose CNP or vehicle placebo.. Right ventricular hypertrophy and a marked elevation in right ventricular systolic pressure (RVSP) were seen in both models of PH. Rats treated with the combination of SU5416 and chronic hypoxia also developed pulmonary endothelial hyperproliferative lesions. Continuous intravenous infusion of CNP at either dose did not attenuate the development of PH, right ventricular hypertrophy or vascular remodeling in either of the models of PH despite a three-fold increase in serum CNP levels.. CNP does not prevent the development of PH in the chronic hypoxia or SU5416 plus hypoxia models of pulmonary hypertension suggesting that CNP may not play an important modulatory role in human PH.

Topics: Animals; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Indoles; Lung; Male; Natriuretic Agents; Natriuretic Peptide, C-Type; Protein Kinase Inhibitors; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Vascular Endothelial Growth Factor

To investigate the alteration of plasma and lung tissue homogenate urotensin II (U-II), nitric oxide (NO) and C-type natriuretic peptide (CNP) levels in rats with hypoxia-induced pulmonary hypertension (HPH) and to study the role of these factors and oxygen treatment in the development of HPH.. Thirty male Wistar rats were randomly divided into three groups: a control group, a group with hypoxia for 14 days and a group with oxygen treatment after hypoxia for 14 days, 10 rats per group. Mean pulmonary arterial pressure (mPAP), mean systematic arterial pressure (mSAP) and right ventriculo hypertrophy index (RVHI) were measured. The plasma levels of U-II, NO, CNP, and the lung tissue homogenate levels of U-II and CNP were measured. The structure of the pulmonary arteries was examined using optical microscope. The microstructure and ultrastructure changes in pulmonary small arteries were examined using electron microscope.. The mPAP and RVHI in the hypoxia group [(34.1 +/- 2.8) mm Hg, 0.43 +/- 0.11] were higher than those in the control group [(18.9 +/- 2.0) mm Hg, 0.28 +/- 0.04, all P < 0.01]. The plasma levels of U-II, NO, and CNP [(4.4 +/- 0.9) pg/ml, (20.8 +/- 7.0) micromol/L, (6.6 +/- 1.2) pg/ml], and the lung tissue homogenate levels of U-II and CNP [(6.3 +/- 0.5), (1.89 +/- 0.43) pg/ml] in the hypoxia group were higher than those in the control group [(0.9 +/- 0.4) pg/ml, (13.2 +/- 2.0) micromol/L, (4.0 +/- 0.6) pg/ml, (2.6 +/- 0.5) pg/ml, (0.69 +/- 0.21) pg/ml, respectively, all P < 0.01]. Compared with the hypoxia group, the mPAP, the plasma levels of U-II, NO, and CNP, and the lung tissue homogenate levels of U-II and CNP in the oxygen treatment group [(31.4 +/- 2.0) mm Hg, (2.1 +/- 0.7) pg/ml, (14.8 +/- 1.7) micromol/L, (4.4 +/- 0.7) pg/ml; (3.5 +/- 0.8) pg/ml, (0.74 +/- 0.17) pg/ml, respectively] were significantly decreased (all P < 0.01). The pulmonary vessel morphology changes of the oxygen treatment group were ameliorated.. U-II, NO and CNP are involved in the pathophysiologic process of HPH. Imbalance of these factors may be partially responsible for the development of the disease.

Topics: Animals; Hypertension, Pulmonary; Hypoxia; Male; Natriuretic Peptide, C-Type; Nitric Oxide; Rats; Rats, Wistar; Urotensins

C-type natriuretic peptide (CNP) has been shown to act as a local regulator of vascular tone and remodeling. We investigated whether CNP ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Rats received a continuous infusion of CNP or placebo. Significant pulmonary hypertension developed 3 weeks after MCT. However, infusion of CNP significantly attenuated the development of pulmonary hypertension and vascular remodeling. Neither systemic arterial pressure nor heart rate was altered. Interestingly, CNP enhanced Ki-67 expression, a marker for cell proliferation, in pulmonary endothelial cells and augmented lung tissue content of endothelial nitric oxide synthase. CNP significantly suppressed apoptosis of pulmonary endothelial cells, decreased the number of monocytes/macrophages, and inhibited expression of plasminogen activator inhibitor type 1, a marker for fibrinolysis impairment, in the lung. In addition, CNP significantly increased the survival rate in MCT rats. Finally, infusion of CNP after the establishment of pulmonary hypertension also had beneficial effects on hemodynamics and survival. In conclusion, infusion of CNP ameliorated MCT-induced pulmonary hypertension and improved survival. These beneficial effects may be mediated by regeneration of pulmonary endothelium, inhibition of endothelial cell apoptosis, and prevention of monocyte/macrophage infiltration and fibrinolysis impairment.

Topics: Animals; Antihypertensive Agents; Apoptosis; Cell Proliferation; Chemotaxis, Leukocyte; Fibrinolysis; Hemodynamics; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Models, Animal; Monocrotaline; Natriuretic Peptide, C-Type; Pulmonary Artery; Rats; Rats, Wistar; Respiratory Mucosa; Survival Analysis; Toxins, Biological; Treatment Outcome

Natriuretic peptides (NPs), such as atrial natriuretic peptide (ANP), C-type natriuretic peptide (CNP), and adrenomedullin (ADM), are endogenous vasodilators acting via specific receptors. This study addressed the question of how pulmonary artery (PA) responses to these peptides and the gene expression of their receptors are modulated in pulmonary hypertension rat models exposed to chronic hypoxia. In this study, isometric tension was measured in PA rings exposed to these NPs and 8-bromoguanosine 3', 5'-cyclic monophosphate (8-bromo-cGMP). It was compared with messenger ribonucleic acid (mRNA) levels of NP-A and -B receptors, which bind to ANP and CNP, respectively, as determined by ribonuclease (RNase) protection assay. Chronic hypoxia increased the maximal relaxation elicited by ANP, but the responses to CNP and 8-bromo-cGMP were unchanged. Chronic hypoxia did not change NP-A and -B receptor mRNA levels. The results showed that pulmonary artery response to atrial natriuretic peptide is selectively enhanced, possibly via a post-transcriptional modulation of its receptor in chronically hypoxia rats. These pharmacological characteristics of atrial natriuretic peptide are consistent with the hypothesis that the atrial natriuretic peptide system is protective against the progression of pulmonary hypertension.

Topics: Adrenomedullin; Animals; Atrial Natriuretic Factor; Calcitonin Gene-Related Peptide; Hypertension, Pulmonary; Hypoxia; Male; Natriuretic Peptide, C-Type; Peptides; Pulmonary Artery; Rats; Rats, Wistar; Up-Regulation; Vasodilation; Vasodilator Agents

Pulmonary vascular resistance falls rapidly after birth, but endothelium-dependent relaxation is relatively poor during the perinatal period. Atrial natriuretic peptide (ANP) is a potent vasodilator; however, its role in the process of perinatal adaptation is uncertain. Porcine intrapulmonary conduit arteries (IPA) from fetal, newborn (< 5 min), 3-, 6-, and 17-d-old, and adult pigs, and from piglets made hypoxic from 0 to 3, 3 to 6, or 14 to 17 d, were isolated and mounted for isometric force recording. Rings were precontracted with prostaglandin-F2 alpha (PGF2 alpha, 10 microM) or KCl (40 mM). ANP was added cumulatively (10 pM to 100 nM). C-type natriuretic peptide (CNP) was added as a single concentration of 100 nM. Accumulation of cGMP under basal conditions and stimulated by ANP or CNP was measured by radioimmunoassay system. Frozen sections of lung tissue were incubated with 125I-labeled alpha-ANP, and binding site density was assessed on IPA with an image analysis system. ANP relaxed IPA in pigs at all ages, but the effect was significantly greater at 6 and 17 d of age. Hypoxia in animals from 14 to 17 d old impaired ANP-induced relaxation. CNP relaxed IPA poorly: < 12% at all ages. ANP increased cGMP accumulation in both normal and hypoxic animals. CNP did not increase cGMP generation in IPA from normal animals but did so in IPA from 3-d-old hypoxic animals. ANP-specific binding sites were demonstrated on the pulmonary artery smooth muscle cells, with greater binding in the young animals. The increased relaxant responses to ANP during adaptation may be important in maintaining low pulmonary vascular resistance. In contrast, CNP was largely ineffective in relaxing pulmonary arteries.

Topics: Age Factors; Animals; Animals, Newborn; Atrial Natriuretic Factor; Binding Sites; Cyclic GMP; Fetus; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Natriuretic Peptide, C-Type; Pulmonary Artery; Sus scrofa; Vascular Resistance; Vasodilator Agents

Topics: Atrial Natriuretic Factor; Blood Pressure; Gene Expression Regulation; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Hypoxia; Lung Diseases, Obstructive; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Nerve Tissue Proteins; Proteins; Receptors, Atrial Natriuretic Factor; Up-Regulation; Vascular Resistance; Vasodilator Agents