C-natriuretic Peptide Research Articles

"Meiosis arrester" C-natriuretic peptide directly stimulates oocyte mtDNA accumulation and is implicated in aging-associated oocyte mtDNA loss.

C-natriuretic peptide (CNP) is the central regulator of oocyte meiosis progression, thus coordinating synchronization of oocyte nuclear-cytoplasmic maturation. However, whether CNP can independently regulate cytoplasmic maturation has been long overlooked. Mitochondrial DNA (mtDNA) accumulation is the hallmark event of cytoplasmic maturation, but the mechanism underlying oocyte mtDNA replication remains largely elusive. Herein, we report that CNP can directly stimulate oocyte mtDNA replication at GV stage, and deficiency of follicular CNP may contribute largely to lower mtDNA copy number in invitro matured oocytes. The mechanistic study showed that cAMP-PKA-CREB1 signaling cascade underlies the regulatory role of CNP in stimulating mtDNA replication and upregulating related genes. Of interest, we also report that CNP-NPR2 signaling is inhibited in aging follicles, and this inhibition is implicated in lower mtDNA copy number in oocytes from aging females. Together, our study provides the first direct functional link between follicular CNP and oocyte mtDNA replication, and identifies its involvement in aging-associated mtDNA loss in oocytes. These findings, not only update the current knowledge of the functions of CNP in coordinating oocyte maturation but also present a promising strategy for improving invitro fertilization outcomes of aging females.

A long-acting C-natriuretic peptide for achondroplasia

The C-natriuretic peptide (CNP) analog vosoritide has recently been approved for treatment of achondroplasia in children. However, the regimen requires daily subcutaneous injections in pediatric patients over multiple years. The present work sought to develop a long-acting CNP that would provide efficacy equal to or greater than that of vosoritide but require less frequent injections. We used a technology for half-life extension, whereby a drug is attached to tetra-polyethylene glycol hydrogels (tetra-PEG) by β-eliminative linkers that cleave at predetermined rates. These hydrogels-fabricated as uniform ∼60-μm microspheres-are injected subcutaneously, where they serve as a stationary depot to slowly release the drug into the systemic circulation. We prepared a highly active, stable CNP analog-[Gln6,14]CNP-38-composed of the 38 C-terminal amino acids of human CNP-53 containing Asn to Gln substitutions to preclude degradative deamidation. Two microsphere [Gln6,14]CNP-38 conjugates were prepared, with release rates designed to allow once-weekly and once-monthly administration. After subcutaneous injection of the conjugates in mice, [Gln6,14]CNP-38 was slowly released into the systemic circulation and showed biphasic elimination pharmacokinetics with terminal half-lives of ∼200 and ∼600 h. Both preparations increased growth of mice comparable to or exceeding that produced by daily vosoritide. Simulations of the pharmacokinetics in humans indicated that plasma [Gln6,14]CNP-38 levels should be maintained within a therapeutic window over weekly, biweekly, and likely, monthly dosing intervals. Compared with vosoritide, which requires ∼30 injections per month, microsphere [Gln6,14]CNP-38 conjugates-especially the biweekly and monthly dosing-could provide an alternative that would be well accepted by physicians, patients, and patient caregivers.

C-natriuretic peptide – as an indicator of persistent increase in blood pressure in men with hypertension

Annotation. According to multiple studies hypertension (AH) is a multifactorial disease. It is recognized that one of the key mechanisms of persistent increase in blood pressure (BP) is the imbalance between vasoconstriction and vasodilation and endothelial dysfunction (ED) is one of the leading links in the pathogenesis of AH. The consequence of ED is a persistent vasoconstrictor reaction which results in myocardial remodeling in the form of left ventricular hypertrophy (LVH) and the subsequent development of congestive heart failure (CHF). One of the most important representatives of the group of vasoconstrictor peptides is endothelin-1 (ET-1). It has been previously shown that the polymorphism of the gene encoding it (Lys198Asn) is associated with fluctuations in ET-1 plasma concentration. In this regard, the corresponding changes in plasma levels of one of the most powerful vasodilators – C-natriuretic peptide (CNP) – remain poorly understood. CNP is a direct antagonist of ET-1 which increases in the blood in AH and can be used as a screening method to identify patients with high BP. The aim of the study – improving the detection of men with AH who has persistent long-term elevations in BP by using the plasma level of CNP and taking into account the carrier of polymorphic variants of the ET-1 gene. The study involved 191 men aged 40-60 years: 79 men were from control group, 62 patients with AH and LVH and 50 patients with AH complicated by CHF II-III classes for NYHA. Enzyme-linked immunosorbent assay was used to determine the plasma concentration of CNP. Genotyping of the ET-1 gene was performed using the polymerase chain reaction. Mathematical processing was performed on a personal computer using the standard statistical package STATISTICA 6.0. It is established that plasma CNP levels in men with AH and LVH (5.21±0.11) pmol/ml and in patients with AH and CHF (5.22±0.13) pmol/ml are significantly higher than in control patients (2.35±0.06) pmol/ml (p<0.0001) however did not differ in patients with AH from different groups. The obtained results allowed to calculate the limit level of CNP which is ≥3.37 pmol/ml and can be used for screening detection of males with persistently elevated BP in the survey of large populations. It was found that in patients with AH as in the control group the Lys/Lys genotype and the Lys allele of the ET-1 gene predominate. There was no significant difference in the frequency of ET-1 gene between groups (p>0.05). It should be noted that in patients with AH carrying all polymorphic variants of the ET-1 gene the level of CNP in blood was also significantly higher than in the control group, however in carriers of the Asn allele plasma level of CNP is higher than in individuals with the Lys/Lys genotype in all study groups. So it was investigated that the average plasma concentration of CNP in patients with AH is higher than in the control group which made it possible to establish a limit level of peptide for screening of individuals with persistent long-term elevation of BP. In men of the control group and in patients with AH the carrier of the Asn allele of the ET-1 gene is associated with a higher level of CNP but in all study groups the Lys/Lys genotype and the Lys allele of the ET-1 gene were dominant.

Role of PDE10A in vascular smooth muscle cell hyperplasia and pathological vascular remodelling.

Intimal hyperplasia is a common feature of vascular remodelling disorders. Accumulation of synthetic smooth muscle cell (SMC)-like cells is the main underlying cause. Current therapeutic approaches including drug-eluting stents are not perfect due to the toxicity on endothelial cells and novel therapeutic strategies are needed. Our preliminary screening for dysregulated cyclic nucleotide phosphodiesterases (PDEs) in growing SMCs revealed the alteration of PDE10A expression. Herein, we investigated the function of PDE10A in SMC proliferation and intimal hyperplasia both in vitro and in vivo. RT-qPCR, immunoblot, and in situ proximity ligation assay were performed to determine PDE10A expression in synthetic SMCs and injured vessels. We found that PDE10A mRNA and/or protein levels are up-regulated in cultured SMCs upon growth stimulation, as well as in intimal cells in injured mouse femoral arteries. To determine the cellular functions of PDE10A, we focused on its role in SMC proliferation. The anti-mitogenic effects of PDE10A on SMCs were evaluated via cell counting, BrdU incorporation, and flow cytometry. We found that PDE10A deficiency or inhibition arrested the SMC cell cycle at G1-phase with a reduction of cyclin D1. The anti-mitotic effect of PDE10A inhibition was dependent on cGMP-dependent protein kinase Iα (PKGIα), involving C-natriuretic peptide (CNP) and particulate guanylate cyclase natriuretic peptide receptor 2 (NPR2). In addition, the effects of genetic depletion and pharmacological inhibition of PDE10A on neointimal formation were examined in a mouse model of femoral artery wire injury. Both PDE10A knockout and inhibition decreased injury-induced intimal thickening in femoral arteries by at least 50%. Moreover, PDE10A inhibition decreased ex vivo remodelling of cultured human saphenous vein segments. Our findings indicate that PDE10A contributes to SMC proliferation and intimal hyperplasia at least partially via antagonizing CNP/NPR2/cGMP/PKG1α signalling and suggest that PDE10A may be a novel drug target for treating vascular occlusive disease.

The mRNA-destabilizing protein Tristetraprolin targets “meiosis arrester” Nppc mRNA in mammalian preovulatory follicles

C-natriuretic peptide (CNP) and its receptor guanylyl cyclase, natriuretic peptide receptor 2 (NPR2), are key regulators of cyclic guanosine monophosphate (cGMP) homeostasis. The CNP-NPR2-cGMP signaling cascade plays an important role in the progression of oocyte meiosis, which is essential for fertility in female mammals. In preovulatory ovarian follicles, the luteinizing hormone (LH)-induced decrease in CNP and its encoding messenger RNA (mRNA) natriuretic peptide precursor C (Nppc) are a prerequisite for oocyte meiotic resumption. However, it has never been determined how LH decreases CNP/Nppc In the present study, we identified that tristetraprolin (TTP), also known as zinc finger protein 36 (ZFP36), a ubiquitously expressed mRNA-destabilizing protein, is the critical mechanism that underlies the LH-induced decrease in Nppc mRNA. Zfp36 mRNA was transiently up-regulated in mural granulosa cells (MGCs) in response to the LH surge. Loss- and gain-of-function analyses indicated that TTP is required for Nppc mRNA degradation in preovulatory MGCs by targeting the rare noncanonical AU-rich element harbored in the Nppc 3' UTR. Moreover, MGC-specific knockout of Zfp36, as well as lentivirus-mediated knockdown in vivo, impaired the LH/hCG-induced Nppc mRNA decline and oocyte meiotic resumption. Furthermore, we found that LH/hCG activates Zfp36/TTP expression through the EGFR-ERK1/2-dependent pathway. Our findings reveal a functional role of TTP-induced mRNA degradation, a global posttranscriptional regulation mechanism, in orchestrating the progression of oocyte meiosis. We also provided a mechanism for understanding CNP-dependent cGMP homeostasis in diverse cellular processes.

Rationale, design, and methods of a randomized, controlled, open-label clinical trial with open-label extension to investigate the safety of vosoritide in infants, and young children with achondroplasia at risk of requiring cervicomedullary decompression surgery.

Achondroplasia causes narrowing of the foramen magnum and the spinal canal leading to increased mortality due to cervicomedullary compression in infants and significant morbidity due to spinal stenosis later in adulthood. Vosoritide is a C-natriuretic peptide analogue that has been shown to improve endochondral ossification in children with achondroplasia. The objective of this trial is to evaluate the safety of vosoritide and whether vosoritide can improve the growth of the foramen magnum and spinal canal in children that may require decompression surgery. An Achondroplasia Foramen Magnum Score will be used to identify infants at risk of requiring decompression surgery. This is a 2-year open label randomized controlled trial of vosoritide in infants with achondroplasia ages 0 to ≤12 months. Approximately 20 infants will be randomized 1:1 to either open label once daily subcutaneous vosoritide combined with standard of care or standard of care alone. The primary and secondary aims of the study are to evaluate the safety and efficacy of vosoritide in children with cervicomedullary compression at risk of requiring decompression surgery. The trial will be carried out in specialized skeletal dysplasia treatment centers with well established multidisciplinary care pathways and standardized approaches to the neurosurgical management of cervicomedually compression. After 2 years, infants randomized to standard of care alone will be eligible to switch to vosoritide plus standard of care for an additional 3 years. This pioneering trial hopes to address the important question as to whether treatment with vosoritide at an early age in infants at risk of requiring cervicomedullary decompression surgery is safe, and can improve growth at the foramen magnum and spinal canal alleviating stenosis. This in turn may reduce compression of surrounding structures including the neuraxis and spinal cord, which could alleviate future morbidity and mortality.Trial registrations: ClinicalTrials.gov, NCT04554940; EudraCT number, 2020-001055-40.

Actions of putative embryokines on development of the preimplantation bovine embryo to the blastocyst stage

Once it enters the uterus at d 4 to 5 after ovulation, the preimplantation bovine embryo is controlled in its development by regulatory signaling molecules from the mother called embryokines. Here, several cell-signaling molecules whose genes are expressed in the endometrium during d 5 to 7 after estrus were tested for the ability to affect the competence of the embryo for further development and the characteristics of the resultant blastocysts. Molecules tested were C-natriuretic peptide (CNP), IL-8, bovine morphogenetic protein 4 (BMP-4), IL-6, and leukemia inhibitory factor (LIF). None of the cell-signaling molecules tested improved the competence of the embryo to become a blastocyst; in fact, BMP-4 decreased development. All molecules modified attributes of the blastocyst formed in culture. In particular, CNP increased the number of cells in the ICM, whereas IL-8 decreased inner cell mass cell numbers and tended to increase the proportion of blastocysts that were hatching or hatched. In addition, BMP-4 decreased the proportion of blastocysts that were hatching. Interleukin-6 and, to a lesser extent, LIF activated the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in the inner cell mass, and LIF increased the percent of cells in the blastocyst that were positive for both NANOG and phosphorylated (activated) STAT3. In conclusion, our results indicate that CNP, IL-8, IL-6, LIF, and BMP-4 can modify embryonic development of the cow in a manner that affects characteristics of the resultant blastocyst. Further research is required to understand how these changes in characteristics of the blastocyst would affect competence of the embryo to establish and maintain pregnancy.

SAT-LB18 A Randomized Controlled Trial of Vosoritide in Children With Achondroplasia

Background: Achondroplasia is a disorder caused by specific mutations in the gene encoding the fibroblast growth factor receptor 3 (FGFR3) protein. Open-label, phase 2 trials in children with achondroplasia showed that administration of vosoritide, an analogue of C-natriuretic peptide, resulted in sustained increases in annualized growth velocity. Methods: This international, randomized, double-blind, phase 3 trial compared once-daily subcutaneous administration of vosoritide, at a dose of 15 μg per kg of body weight, with placebo in children with achondroplasia aged 5 to <18 years. Eligible patients had participated, for at least 6 months, in an observational growth study in order to calculate their baseline annualized growth velocity. The primary efficacy endpoint was the change from baseline in annualized growth velocity at week 52 of treatment. The primary analysis of the change from baseline in annualized growth velocity was performed using an ANCOVA model. Results: A total of 121 patients were randomized, with 60 assigned to receive vosoritide and 61 to receive placebo. A total of 119 patients completed the 52-week trial. The adjusted mean difference in annualized growth velocity between patients administered vosoritide and those administered placebo was 1.57 cm per year in favor of vosoritide (95% CI: [1.22, 1.93], two-sided p-value <0.001). A total of 119 patients experienced at least one adverse event (vosoritide group, 59 [98.3%], placebo group, 60 [98.4%]). Conclusions: Daily, subcutaneous administration of vosoritide to children with achondroplasia resulted in a significant increase in mean annualized growth velocity and similar incidence of adverse events compared to placebo.

INFLUENCE OF PULMONARY HYPERTENSION ON CLINICAL COURSE AND PROGNOSIS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Aim. Evaluation of clinical specifics, predictors of repeat hospitalizations and mortality in chronic obstructive pulmonary disease (COPD) patients according to pulmonary hypertension (PH) severity grade.Material and methods. To the study, 288 COPD patients included (II-IV severity grade, GOLD 2016; males 276, females 12; mean age 59,5±9,27 y. o., smoking 23,1±11,42 pack/years; 2,4±0,89 exacerbations annually, body mass index (BMI) 27,2±12,06 kg/m2). According to the presence and grade of systolic pressure increase in pulmonary artery (SPPA) the patients were selected to three groups: 1st — with no PH (SPPA &lt;40 mmHg, n=168), 2nd — with moderate PH (SPPA 40-55 mmHg, n=101), 3rd — with severe PH (SPPA &gt;55 mmHg, n=19).Results. Increase of SPPA was found in 120 (41,7%) patients: moderate PA — in 101 (35,1%), severe PH — 19 (6,6%). It was shown that the presence and severity of PH do increase the severity of clinical signs of COPD, hemodynamic disorders, increase the rate of repeat hospitalizations and mortality rate. The predictors of repeat hospitalizations in COPD patients are increased SPPA and C-reactive protein concentration (CRP); mortality predictors are severity of symptoms by CAT, Borg dyspnea, number of exacerbations during one year, size of the right atrium, grade of SPPA increase, CRP concentration, fibrinogen, N-terminal precursors of C-natriuretic peptide (NT-proCNP) and brain peptide (NT-proBNP) in the blood.Conclusion. PH in COPD patients in most cases is moderate, and it worsens the clinical picture, hemodynamic disorders, shows only moderate correlation with breathing disorders, increases the rate of rehospitalizations and mortality risk. The survival rate of COPD and PH patients depends on the severity.

Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature.

PurposeC-type natriuretic peptide (CNP) and its principal receptor, natriuretic peptide receptor B (NPR-B), have been shown to be important in skeletal development. CNP and NPR-B are encoded by natriuretic peptide precursor-C (NPPC) and natriuretic peptide receptor 2 (NPR2) genes, respectively. While NPR2 mutations have been described in patients with skeletal dysplasias and idiopathic short stature (ISS), and several Npr2 and Nppc skeletal dysplasia mouse models exist, no mutations in NPPC have been described in patients to date.MethodsNPPC was screened in 668 patients (357 with disproportionate short stature and 311 with autosomal dominant ISS) and 29 additional ISS families in an ongoing whole-exome sequencing study.ResultsTwo heterozygous NPPC mutations, located in the highly conserved CNP ring, were identified. Both showed significant reductions in cyclic guanosine monophosphate synthesis, confirming their pathogenicity. Interestingly, one has been previously linked to skeletal abnormalities in the spontaneous Nppc mouse long-bone abnormality (lbab) mutant.ConclusionsOur results demonstrate, for the first time, that NPPC mutations cause autosomal dominant short stature in humans. The NPPC mutations cosegregated with a short stature and small hands phenotype. A CNP analog, which is currently in clinical trials for the treatment of achondroplasia, seems a promising therapeutic approach, since it directly replaces the defective protein.

Плазмові концентрації ендотеліну-1 та С-натрійуретичного пептиду у вагітних із гестаційною гіпертензією

Плазмові концентрації ендотеліну-1 та С-натрійуретичного пептиду у вагітних із гестаційною гіпертензією

0006 : Proliferation of the cardiac precursor cells expressing the stem cell antigen-1 is controlled by activation of the natriuretic peptide receptors

A part of the cardioprotective role of the Brain Natriuretic Peptide (BNP) in mouse hearts is due to its effect on the cardiac precursor cell (CPC) proliferation and differentiation. Thus, in this study we identified the CPC subset able to respond to BNP as well as the signaling pathway involved. We demonstrated by immunohistochemistry and by flow cytometry analysis that the c-kit + and the Sca-1 + cell subsets in neonatal and adult murine hearts express the NPR-A and NPR-B receptors and are thus able to be stimulated by BNP. In vitro , BNP only stimulated the proliferation of the Sca-1 + cells and not of the c-kit + cells. Among Sca-1 + cells, BNP treatment led to increased number of Sca-1 + Nkx2.5 + cells, which were able to differentiate into cardiomyocytes. To determine by which receptor BNP acts on Sca-1 + cells to stimulate their proliferation, cells were isolated from neonatal hearts of mice deficient for the NPR-A (NPRA-KO) or NPR-B receptor. BNP stimulated the proliferation of the Sca-1 + NPR-A KO cells but not of the Sca-1 + cells lacking the NPR-B receptor, demonstrating that Sca-1 + cell proliferation is linked to NPR-B activation. This was confirmed by stimulating the Sca-1 + cells by the C-Natriuretic Peptide able also to activate the NPR-B receptor. BNP binding to NPR-B receptor led in Sca-1 + cells to Protein Kinase G activation and increased phosphorylation of phospholamban and p38. Reducing PKG activation inhibited BNP-induced-Sca-1 + cell proliferation, whereas reducing p38 phosphorylation increased Sca-1 + cell proliferation after BNP treatment. Phosphorylation of p38 was not mediated by BNP binding to NPR-B receptor but by its binding to NPR-A. In this work, we identified the Sca-1 + cells as being the targets of BNP in vitro and in vivo. BNP via NPR-B binding and PKG activation clearly stimulated the proliferation of the CPCs expressing Sca-1. Interestingly, is the dual role of the NPR-A and NPR-B receptors which control Sca-1 + cell proliferation. The author hereby declares no conflict of interest

Utility of point-of-care testing of natriuretic peptides (brain natriuretic peptide and n-terminal pro-brain natriuretic peptide) in the emergency department.

Rapid and accurate diagnosis of a patient with an acute disease is a challenge for emergency physicians. Natriuretic peptides have emerged as important tools for diagnosis, risk stratification and therapeutic decision making for some categories of emergency patients. Brain natriuretic peptide (BNP) is a member of a four natriuretic peptides family that shares a common 17-peptide ring structure. Atrial natriuretic peptide, C-natriuretic peptide (CNP), and D-type natriuretic peptide are the other natriuretic peptide, which share the same common 17-peptide ring structure. The N-terminal fragment of pro-BNP, N-terminal pro-brain natriuretic peptide (NT-proBNP) consists of 76 amino acids, which is biologically inert, while the active component BNP contains 32 amino acids. BNP and NT-proBNP are secreted in the plasma in equimolar quantities and are frequently used in the diagnosis of congestive heart failure, and distinguishing between patients with dyspnea of cardiac or pulmonary origin. Both natriuretic peptides have also been evaluated for use in the assessment and management of several other conditions including sepsis, cirrhosis of liver and renal failure. However, one should remember that the values of natriuretic peptides are affected by age and weight of the patients, and presence of several comorbidities such as chronic renal failure, type 2 diabetes mellitus, anemia, pulmonary embolism, and acute coronary syndrome. Values of these peptides also vary depending on the type of test used. The performance characteristics of these natriuretic peptides vary depending on the patients on whom they are used. Therefore determination of reference values for these peptides represents a challenge.

Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia

Achondroplasia (ACH) is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR3 encoding the fibroblast growth factor receptor 3. We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR3 signaling in ACH. We found that meclozine, an anti-histamine drug that has long been used for motion sickness, facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF2-treated rat chondrosarcoma (RCS) cells. Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS-2/8) cells that were infected with lentivirus expressing constitutively active mutants of FGFR3-K650E causing thanatophoric dysplasia, FGFR3-K650M causing SADDAN, and FGFR3-G380R causing ACH. Similarly, meclozine alleviated abnormally suppressed differentiation of ATDC5 chondrogenic cells expressing FGFR3-K650E and -G380R in micromass culture. We also confirmed that meclozine alleviates FGF2-mediated longitudinal growth inhibition of embryonic tibia in bone explant culture. Interestingly, meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF2 treatment. Analyses of intracellular FGFR3 signaling disclosed that meclozine downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells. Similarly, meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK, which suggests that meclozine downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation. We used the C-natriuretic peptide (CNP) as a potent inhibitor of the FGFR3 signaling throughout our experiments, and found that meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling. We propose that meclozine is a potential therapeutic agent for treating ACH and other FGFR3-related skeletal dysplasias.

Impaired Vasodilation in the Pathogenesis of Hypertension: Focus on Nitric Oxide, Endothelial‐Derived Hyperpolarizing Factors, and Prostaglandins

Under resting conditions the arterial vasculature exists in a vasoconstricted state referred to as vascular tone. Physiological dilatation in response to increased flow, a function of normal endothelium is necessary to maintain normal blood pressure. Endothelial dysfunction in vascular smooth muscle cells thus results in loss of normal vasorelaxant function and the inability of arteries to appropriately dilate in response to increased blood flow in either a systemic or regional vascular bed, resulting in increased blood pressure, a sequence that may represent a common pathway to hypertension. Normal vasorelaxation is mediated by a number of endothelial systems including nitric oxide (NO), prostaglandins (PGI2 and PGE2), and a family of endothelial-derived hyperpolarizing factors (EDHF). In response to hemodynamic shear stress, endothelium continuously releases NO, EDHF, and PGI2 to provide vasodilatation. EDHF, not a single molecule but rather a group of molecules that includes epoxyeicosatrienoic acids, hydrogen peroxide, carbon monoxide, hydrogen sulfide, C-natriuretic peptide, and K+ itself, causes vasodilatation by activation of vascular smooth muscle cell K+ channels, resulting in hyperpolarization and thus vasorelaxation. The understanding and effective management of blood pressure requires an understanding of both physiologic and pathophysiologic regulation of vascular tone. This review describes molecular mechanisms underlying normal endothelial regulation and pathological states, such as increased oxidative stress, which cause loss of vasorelaxation. Possible pharmacological interventions to restore normal function are suggested.

Patent Highlights

Patent Highlights

From humans to giraffes: The evolution of hypertension and hormones

From humans to giraffes: The evolution of hypertension and hormones

Vessel dilator and C-type natriuretic peptide enhance the proliferation of human osteoblasts

C-natriuretic peptide (CNP) has been shown to regulate proliferation of mouse and rat osteoblasts. Genetic deletion of CNP results in dwarfism. Overexposure of CNP has been associated with arachnodactyly of hands and feet with a very long hallux bilaterally in a 14-y-old girl. CNP effects on bone growth involve inhibition of MEK 1 and ERK 1/2 kinases mediated via the intracellular messenger cGMP. Vessel dilator is another natriuretic peptide synthesized by the atrial natriuretic peptide gene whose biologic half-life is 12 times longer than CNP. Vessel dilator's biologic effects on proliferating cells are mediated via inhibiting MEK 1/2 and ERK 1/2 kinases via cGMP. Vessel dilator has never been studied on osteoblasts. CNP at 10 (nanomolar) nM (p = 0.02) and vessel dilator at 10 nM, 1 nM, 100 (picomolar) pM, and 10 pM (p ≤ 0.01) in dose-response studies enhanced human osteoblasts' proliferation. This first study of human osteoblasts would suggest that vessel dilator with a much longer biologic half-life and with osteoblast-stimulatory effects at lower concentrations than CNP may have therapeutic potential in human achondroplasia, short stature, and osteoporosis. Vessel dilator stimulates osteoblast proliferation whereas most current therapies of osteoporosis target osteoclasts.

Changes of coagulation parameters during high altitude expedition.

Data on changes of haemostatic parameters at altitudes above 5000 m are very limited. So far it is unknown, whether altered coagulation could contribute to the development of acute mountain sickness. Thirty four healthy mountaineers were randomised to two acclimatisation protocols and undertook an expedition on Muztagh Ata (7549 m) in China. Tests were performed at five altitudes up to 6865 m. Haemostatic parameters, such as PT, aPTT, D-Dimer, APC-Resistance (APCR), von Willebrand Factor activity (RCo), ADAMTS-13 & C-Natriuretic Peptide (CNP) were assessed together with Lake Louise AMS score. D-Dimer significantly increased with increasing altitude (median 0.62 to 0.81 mcg/L, p <0.0001). During ascent, PT increased (83% to >100%) and APCR decreased significantly from 0.95 to 0.8 (p <0.01). Furthermore, a significant increase of aPTT (38 to 43 sec) was paralleled by significant changes of RCo (102% to 62%) (both p <0.001). There were no significant changes in ADAMTS-13 and CNP. No significant relationship between investigated parameters and AMS scores could be detected. When comparing the participants of the two acclimatisation protocols, there was an overall higher RCo in patients with a faster ascent protocol (p = 0.04). This was accompanied by lower ADAMTS-13 of the coagulation system in these patients (p = 0.04). Coagulation parameters change significantly during hypobaric hypoxia. Whereas we could detect no association between AMS scores and coagulation parameters, our results do show some parameters to be associated with an acclimatisation protocol and a successful ascent to the summit.

Changes of coagulation parameters during high altitude expedition.

Data on changes of haemostatic parameters at altitudes above 5000 m are very limited. So far it is unknown, whether altered coagulation could contribute to the development of acute mountain sickness. Thirty four healthy mountaineers were randomised to two acclimatisation protocols and undertook an expedition on Muztagh Ata (7549 m) in China. Tests were performed at five altitudes up to 6865 m. Haemostatic parameters, such as PT, aPTT, D-Dimer, APC-Resistance (APCR), von Willebrand Factor activity (RCo), ADAMTS-13 & C-Natriuretic Peptide (CNP) were assessed together with Lake Louise AMS score. D-Dimer significantly increased with increasing altitude (median 0.62 to 0.81 mcg/L, p <0.0001). During ascent, PT increased (83% to >100%) and APCR decreased significantly from 0.95 to 0.8 (p <0.01). Furthermore, a significant increase of aPTT (38 to 43 sec) was paralleled by significant changes of RCo (102% to 62%) (both p <0.001). There were no significant changes in ADAMTS-13 and CNP. No significant relationship between investigated parameters and AMS scores could be detected. When comparing the participants of the two acclimatisation protocols, there was an overall higher RCo in patients with a faster ascent protocol (p = 0.04). This was accompanied by lower ADAMTS-13 of the coagulation system in these patients (p = 0.04). Coagulation parameters change significantly during hypobaric hypoxia. Whereas we could detect no association between AMS scores and coagulation parameters, our results do show some parameters to be associated with an acclimatisation protocol and a successful ascent to the summit.