Vasoactive Hormones Research Articles

Serum uromodulin is inversely associated with arterial hypertension and the vasoconstrictive prohormone CT-proET-1 in the population-based KORA F4 study.

ObjectivesUromodulin has been associated with arterial hypertension in genome-wide association studies, but data from clinical and preclinical studies are inconsistent. We here analyzed the association of serum uromodulin (sUmod) with arterial hypertension and vasoactive hormones in a population-based study.MethodsIn 1108 participants of the KORA F4 study aged 62–81 years, sUmod was measured and the association of sUmod with arterial hypertension was assessed using logistic regression models. The associations of sUmod with renin and aldosterone and with the vasoconstrictive prohormone C-terminal pro-endothelin-1 (CT-proET-1) were analyzed in 1079 participants and in 618 participants, respectively, using linear regression models.ResultsAfter multivariable adjustment including sex, age, eGFR, BMI, fasting glucose, current smoking, previous stroke and myocardial infarction, sUmod was inversely associated with arterial hypertension (OR 0.78; 95% CI 0.68–0.91; p = 0.001). SUmod was not significantly associated with renin and aldosterone after adjustment for sex, age and eGFR. However, sUmod was inversely associated with CT-proET-1 (β -0.19 ± 0.04; p < 0.001) after adjustment for sex, age, eGFR, BMI, arterial hypertension, fasting glucose, current smoking, previous stroke and myocardial infarction. The association with CT-proET-1 was stronger in participants with hypertension (β -0.22 ± 0.04) than in normotensive participants (β -0.13 ± 0.06; p for interaction hypertension = 0.003 in the model adjusted for hypertension).ConclusionsSUmod was inversely associated with arterial hypertension and the vasoconstrictive prohormone CT-proET-1, suggesting direct or indirect effects of sUmod on blood pressure regulation.

203-OR: ADA Presidents’ Select Abstract: Landscape of Liver Cell Heterogeneity and Reprogramming during NASH Pathogenesis Revealed by Single Cell RNA Sequencing

Nonalcoholic steatohepatitis (NASH) is rapidly emerging as a prevalent liver disease that is associated with metabolic syndrome. NASH increases the risk for end-stage liver diseases such as cirrhosis and liver cancer and currently has no effective treatments. Despite this, the pathophysiological mechanisms underlying NASH initiation and progression remain poorly understood. We and others have previously established a diet-induced NASH model in mice that recapitulates key aspects of human NASH pathologies, including hepatic steatosis, liver injury, inflammation, and liver fibrosis in the context of obesity and insulin resistance. Here we performed single-cell RNA sequencing (sc-RNAseq) analysis on liver cells isolated from healthy and diet-induced NASH mice to map the landscape of liver cell heterogeneity and reprogramming during NASH pathogenesis. Our analysis revealed a highly interconnected ligand-receptor signaling network among different liver cell types that is disrupted during NASH progression. Hepatic stellate cells are emerging as a hub of signaling in the liver by secreting “stellakines” and respond to vasoactive hormones. Finally, we identified TREM2-expressing macrophages as a unique disease-associated macrophage population that is linked to NASH severity in humans. This work reveals the transcriptomic landscape of liver cells at single-cell resolution and uncovers key aspects of NASH-associated reprogramming of liver non-parenchymal cells. Disclosure X. Xiong: None.

Angiotensin II Represses Guanylyl Cyclase/Natriuretic Peptide Receptor‐A Gene Expression and Receptor Signaling and Function

Atrial and brain natriuretic peptides (ANP and BNP) bind to guanylyl‐cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA) and regulate sodium excretion, water balance, vasorelaxation, and steroidogenesis; all directed to combat hypertension. ANP acting through NPRA lowers blood pressure and blood volume and protects the heart and vascular disorders and end‐organ damage. The two vasoactive hormones, angiotensin II (ANG II; vasoconstrictive) and atrial natriuretic peptide (ANP; vasodilatory) antagonize the biological actions of each other. The objective of the present study was to examine whether ANG II plays critical roles in the transcriptional repression of Npr1 (encoding for NPRA) and receptor function. To delineate the mechanisms of ANG II‐mediated repression of Npr1 transcription and function, we performed the promoter deletional analyses, which showed that region −1182/−914 base pairs upstream from the transcription start site of the Npr1 promoter contains cis‐acting elements for ANG II‐regulated repression of Npr1. ANG II significantly decreased the levels of NPRA mRNA (60%), NPRA protein (52%), and intracellular accumulation cGMP (65%) in cultured mesangial cells and attenuated ANP‐mediated relaxation of aortic rings ex vivo. The results showed that transcription factors, CREB and HSF‐4a facilitated the ANG II‐mediated repressive effects on Npr1 transcription and receptor function. The current findings suggest that ANG II‐mediated repressive mechanisms of Npr1 transcription and receptor function may provide new molecular targets for the treatment and prevention of hypertension and renal and vascular disorders.Support or Funding InformationThis work was supported by NIH grant HL062147

Glucose and Blood Pressure-Dependent Pathways–The Progression of Diabetic Kidney Disease

The major clinical associations with the progression of diabetic kidney disease (DKD) are glycemic control and systemic hypertension. Recent studies have continued to emphasize vasoactive hormone pathways including aldosterone and endothelin which suggest a key role for vasoconstrictor pathways in promoting renal damage in diabetes. The role of glucose per se remains difficult to define in DKD but appears to involve key intermediates including reactive oxygen species (ROS) and dicarbonyls such as methylglyoxal which activate intracellular pathways to promote fibrosis and inflammation in the kidney. Recent studies have identified a novel molecular interaction between hemodynamic and metabolic pathways which could lead to new treatments for DKD. This should lead to a further improvement in the outlook of DKD building on positive results from RAAS blockade and more recently newer classes of glucose-lowering agents such as SGLT2 inhibitors and GLP1 receptor agonists.

Angiotensin II represses Npr1 expression and receptor function by recruitment of transcription factors CREB and HSF-4a and activation of HDACs

The two vasoactive hormones, angiotensin II (ANG II; vasoconstrictive) and atrial natriuretic peptide (ANP; vasodilatory) antagonize the biological actions of each other. ANP acting through natriuretic peptide receptor-A (NPRA) lowers blood pressure and blood volume. We tested hypothesis that ANG II plays critical roles in the transcriptional repression of Npr1 (encoding NPRA) and receptor function. ANG II significantly decreased NPRA mRNA and protein levels and cGMP accumulation in cultured mesangial cells and attenuated ANP-mediated relaxation of aortic rings ex vivo. The transcription factors, cAMP-response element-binding protein (CREB) and heat-shock factor-4a (HSF-4a) facilitated the ANG II-mediated repressive effects on Npr1 transcription. Tyrosine kinase (TK) inhibitor, genistein and phosphatidylinositol 3-kinase (PI-3K) inhibitor, wortmannin reversed the ANG II-dependent repression of Npr1 transcription and receptor function. ANG II enhanced the activities of Class I histone deacetylases (HDACs 1/2), thereby decreased histone acetylation of H3K9/14ac and H4K8ac. The repressive effect of ANG II on Npr1 transcription and receptor signaling seems to be transduced by TK and PI-3K pathways and modulated by CREB, HSF-4a, HDACs, and modified histones. The current findings suggest that ANG II-mediated repressive mechanisms of Npr1 transcription and receptor function may provide new molecular targets for treatment and prevention of hypertension and cardiovascular diseases.

The different hormonal system during exercise stress coping in horses.

The review discusses the hormonal changes during exercise stress. The exercise generally produces a rise of adrenaline (A), noradrenaline (NA), adrenocorticotropic hormone (ACTH), cortisol, glucagon, growth hormone, arginine vasopressine, etc., and a drop of insulin. The hormonal events during reestablishment of homeostasis due to exercise stress can be divided into a catabolic phase, with decreased tolerance of effort, and reversible biochemical, hormonal and immunological changes, and an anabolic phase, with a higher adaptive capacity, and enhanced performance. The two main hormonal axes activated in the catabolic phase are sympathetic–adrenal–medullary system and hypothalamic-pituitary-adrenal (HPA) axis, while in the anabolic phase, growth hormone-insulin-like factor I axis, and gonadal axes. The hormonal responses during exercise and recovery can be regarded as regulatory and integrated endocrine responses. The increase of catecholamines and ACTH is dependent on the intensity of exercise; a marked increase in plasma A occurs during exercises with high emotional content. The response of cortisol is correlated with the duration of exercise, while the effect of exercise duration on b-endorphin changes is highly dependent on the type of exercise performed. Cortisol and b-endorphin changes usually occur in phase, but not during exercises with high emotional content. Glucocorticoids and iodothyronines are involved in meeting immediate energy demands, and a model of functional interactions between HPA axis and hypothalamic-pituitary-thyroid axis during exercise stress is proposed. A modulation of coping responses to different energy demanding physical activities required for sport activities could be hypothesized. This review supports the proposed regulation of hypophysiotropic TRHergic neurons as metabolic integrators during exercise stress. Many hormonal systems (ghrelin, leptin, glucose, insulin, and cortisol) are activated to control substrate mobilizations and utilization. The cardiovascular homeostasis, the fluid and electrolyte balance during exercise are highly dependent on vasoactive hormones (antidiuretic hormone, atrial natriuretic peptide, renin–angiotensin–aldosterone, and prostaglandins) control.

Mechanisms of Cardiac Dysfunction in Heart Failure due to Myocardial Infarction

Acute myocardial infarction (MI) is associated with marked elevation of plasma vasoactive hormones, ventricular arrhythmias, scar formation in the ischemic portion of left ventricle (LV) and hypertrophy of the viable LV as well as the right ventricle (RV). Particularly, elevated levels of plasma catecholamines and angiotensin II activate their membrane receptors and stimulate different signal transduction systems for producing cardiac hypertrophy, augmenting the activities of subcellular organelles and increasing cardiac function. While marked arrhythmias due to acute MI produce 30 to 40% mortality, hypertrophic alterations in the viable LV as well as RV are compensatory for maintaining hemodynamic homeostasis due to loss of cardiomyocytes. On the other hand, prolonged elevation of plasma vasoactive hormones in chronic MI produce deleterious effects on the hypertrophied heart by promoting the formation of oxyradicals, inducing Ca2+ - handling abnormalities in subcellular organelles, depressing cardiac gene expression, activating different proteases and resulting in the development of cardiac dysfunction. Thus, in view of the complexities of mechanisms for both acute and chronic effects of MI, there is a real challenge of developing new interventions for preventing the transition of cardiac hypertrophy to heart failure as well as progression of the MI-induced cardiovascular abnormalities.

Dobutamine reverses the cardio-suppressive effects of terlipressin without improving renal function in cirrhosis and ascites: a randomized controlled trial.

Acute kidney injury and hepatorenal syndrome (HRS) are frequent complications in patients with cirrhosis and ascites. First-line treatment is terlipressin, which reverses HRS in ~40% of patients but also lowers cardiac output (CO). We aimed to investigate whether reversing the cardio-suppressive effect of terlipressin with the β-adrenoceptor agonist dobutamine would increase CO and thereby increase the glomerular filtration rate (GFR). We randomized 25 patients with cirrhosis, ascites, and impaired renal function (2:2:1): group A received terlipressin followed by the addition of dobutamine; group B received dobutamine and terlipressin as monotherapies; and group C received placebo. Renal and cardiac functions were assessed during 8 clearance periods of 30 min, and concentrations of vasoactive hormones were measured. Dobutamine as a monotherapy increased CO (1.03 L/min, P < 0.01) but had no significant effects on GFR. Renin (P < 0.05), angiotensin II (P < 0.005), and aldosterone (P < 0.05) increased after dobutamine infusion. Terlipressin as a monotherapy improved GFR (18.9 mL·min-1·m-2, P = 0.005) and mean arterial pressure (MAP) (14 mmHg, P = 0.001) but reduced CO (-0.92 L/min, P < 0.005) and renin (P < .005). A combined treatment of dobutamine and terlipressin had a positive effect on CO (1.19 L/min, P < 0.05) and increased renin (P < 0.005), angiotensin II (P < 0.005), and aldosterone (P < 0.05), but it had no significant effects on MAP or GFR. Dobutamine reversed the cardio-suppressive effect of terlipressin in cirrhosis, ascites, and impaired renal function. However, dobutamine reduced peripheral vascular resistance, activated renin-angiotensin-aldosterone system, and did not improve GFR compared with terlipressin as a monotherapy. Therefore, dobutamine cannot be recommended in cirrhosis and ascites.NEW & NOTEWORTHY This study shows that the cardio-suppressive effects of the vasopressin receptor agonist terlipressin can be reversed by dobutamine. This is a novel observation in patients with decompensated cirrhosis. Furthermore, we show that dobutamine reduced the peripheral vascular resistance and activated the renin-angiotensin system, whereas renal function was not further improved by terlipressin alone.

Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis.

Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease.

Hypertension Editors' Picks Preeclampsia.

Hypertension Editors' Picks Preeclampsia.

Effect of 3% saline and furosemide on biomarkers of kidney injury and renal tubular function and GFR in healthy subjects \u2013 a randomized controlled trial

BackgroundChloride is speculated to have nephrotoxic properties. In healthy subjects we tested the hypothesis that acute chloride loading with 3% saline would induce kidney injury, which could be prevented with the loop-diuretic furosemide.MethodsThe study was designed as a randomized, placebo-controlled, crossover study. Subjects were given 3% saline accompanied by either placebo or furosemide. Before, during and after infusion of 3% saline we measured glomerular filtration rate (GFR), fractional excretion of sodium (FENa), urinary chloride excretion (u-Cl), urinary excretions of aquaporin-2 (u-AQP2) and epithelial sodium channels (u-ENaCγ), neutrophil gelatinase-associated lipocalin (u-NGAL) and kidney injury molecule-1 (u-KIM-1) as marker of kidney injury and vasoactive hormones: renin (PRC), angiotensin II (p-AngII), aldosterone (p-Aldo) and arginine vasopressin (p-AVP). Four days prior to each of the two examinations subjects were given a standardized fluid and diet intake.ResultsAfter 3% saline infusion u-NGAL and KIM-1 excretion increased slightly (u-NGAL: 17 ± 24 during placebo vs. -7 ± 23 ng/min during furosemide, p = 0.039, u-KIM-1: 0.21 ± 0.23 vs − 0.06 ± 0.14 ng/ml, p < 0.001). The increase in u-NGAL was absent when furosemide was given simultaneously, and the responses in u-NGAL were not significantly different from placebo control. Furosemide changed responses in u-KIM-1 where a delayed increase was observed. GFR was increased by 3% saline but decreased when furosemide accompanied the infusion. U-Na, FENa, u-Cl, and u-osmolality increased in response to saline, and the increase was markedly pronounced when furosemide was added. FEK decreased slightly during 3% saline infusion, but simultaneously furosemide increased FEK. U-AQP2 increased after 3% saline and placebo, and the response was further increased by furosemide. U-ENaCγ decreased to the same extent after 3% saline infusion in the two groups. 3% saline significantly reduced PRC, p-AngII and p-Aldo, and responses were attenuated by furosemide. p-AVP was increased by 3% saline, with a larger increase during furosemide.ConclusionThis study shows minor increases in markers of kidney injury after 3% saline infusion Furosemide abolished the increase in NGAL and postponed the increase in u-KIM-1. The clinical importance of these findings needs further investigation.Trial registration(EU Clinical trials register number: 2015–002585-23, registered on 5th November 2015)

Determining Risk Factors for Triple Whammy AKI using Computational Models of Long‐ Term Blood Pressure Regulation

Concurrent use of diuretics, angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB), and nonsteroidal anti‐inflammatory drugs (NSAIDs) increases the risk of acute kidney injury (AKI). AKI resulting from use of all three drugs is referred to as “triple whammy”. Diuretics and ACEI/ARB are often prescribed in tandem for the treatment of hypertension while some NSAIDs, such as ibuprofen, are available over the counter. As such, concurrent treatment with all three drugs is common.To address the critical need to better understand the mechanisms behind the increased risk of AKI and to identify potential risk factors, we use computational models of long‐term blood pressure regulation we developed previously. We hypothesize that individual variations in tubuloglomerular feedback, renal sympathetic nervous activity, and vasoactive hormones such as angiotensin II will determine whether or not triple whammy patients develop AKI. Other circumstances that we hypothesize to influence AKI development include hypertension, salt ingestion and sensitivity, and genetic polymorphisms in enzymes (ACE) or receptors (angiotensin type 1).The computational models used include variables describing the heart and circulation, kidney function, sodium and water reabsorption in the nephron, and the renin angiotensin system (RAS) and is fit separately for male and female humans.Support or Funding InformationThis research was supported by the Canada 150 Research Chair program and by the National Institutes of Health: National Institute of Diabetes and Digestive and Kidney Diseases, grant R01DK106102.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of ethanol and ethanol metabolites on intrinsic function of mesenteric resistance arteries.

Evidence suggests that ethanol-induced hypertension is associated with increased cardiovascular responsiveness to vasopressors in vivo and enhanced reactivity of isolated arteries to vasopressors ex vivo. The underlying mechanisms are not well understood and the contribution of ethanol metabolites to vascular effects induced by ethanol consumption are unclear. Mesenteric resistance arteries were harvested from Sprague-Dawley rats. Pressure myography was utilized to test effects of ethanol, acetaldehyde and phosphatidylethanol on myogenic tone and on vasoconstriction induced by phenylephrine, arginine vasopressin (aVP), endothelin-1 and KCl. Ethanol, acetaldehyde and phosphatidylethanol concentrations were monitored during the experiments. Ethanol concentrations in the vessel bath decreased with a half-life of 25min; acetaldehyde and phosphatidylethanol concentrations remained constant. Pretreatment with ethanol dose-dependently increased the potency of phenylephrine to induce vasoconstriction 4-fold (p<0.01). These effects were comparable when arteries were pre-treated with a single dose of ethanol for 30min and when ethanol concentrations were kept constant during 30min and 60min of pretreatment. While ethanol also dose-dependently increased the potency of aVP to induce vasoconstriction 1.7-fold (p<0.05), it did not affect vasoconstriction induced by endothelin-1 or KCl. Acetaldehyde pre-treatment (30 min) dose-dependently increased the potency of phenylephrine to induce vasoconstriction 2.7-fold (p<0.01) but did not affect other vasoconstrictor responses. Phosphatidylethanol did not affect any vasoconstrictor responses. Ethanol and its metabolites did not affect myogenic tone. These data suggest that ethanol and acetaldehyde selectively sensitize intrinsic constrictor responses upon activation of vascular α1-adrenergic and/or vasopressin receptors at clinically relevant concentrations. Our findings support the concept that enhanced vasoreactivity to vasoactive hormones contributes to the development of hypertension induced by ethanol consumption. Ex vivo exposure of resistance arteries to ethanol and acetaldehyde resembles effects of chronic ethanol consumption on intrinsic vascular function, and thus could serve as test platform to evaluate interventions aimed to mitigate vascular effects associated with ethanol consumption.

Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the Absence of a Corpus Luteum.

In vitro fertilization involving frozen embryo transfer and donor oocytes increases preeclampsia risk. These in vitro fertilization protocols typically yield pregnancies without a corpus luteum (CL), which secretes vasoactive hormones. We investigated whether in vitro fertilization pregnancies without a CL disrupt maternal circulatory adaptations and increase preeclampsia risk. Women with 0 (n=26), 1 (n=23), or >1 (n=22) CL were serially evaluated before, during, and after pregnancy. Because increasing arterial compliance is a major physiological adaptation in pregnancy, we assessed carotid-femoral pulse wave velocity and transit time. In a parallel prospective cohort study, obstetric outcomes for singleton livebirths achieved with autologous oocytes were compared between groups by CL number (n=683). The expected decline in carotid-femoral pulse wave velocity and rise in carotid-femoral transit time during the first trimester were attenuated in the 0-CL compared with combined single/multiple-CL cohorts, which were similar (group-time interaction: P=0.06 and 0.03, respectively). The blunted changes of carotid-femoral pulse wave velocity and carotid-femoral transit time from prepregnancy in the 0-CL cohort were most striking at 10 to 12 weeks of gestation ( P=0.01 and 0.006, respectively, versus 1 and >1 CL). Zero CL was predictive of preeclampsia (adjusted odds ratio, 2.73; 95% CI, 1.14-6.49) and preeclampsia with severe features (6.45; 95% CI, 1.94-25.09) compared with 1 CL. Programmed frozen embryo transfer cycles (0 CL) were associated with higher rates of preeclampsia (12.8% versus 3.9%; P=0.02) and preeclampsia with severe features (9.6% versus 0.8%; P=0.002) compared with modified natural frozen embryo transfer cycles (1 CL). In common in vitro fertilization protocols, absence of the CL perturbed the maternal circulation in early pregnancy and increased the incidence of preeclampsia.

Adrenomedullin disulfide bond mimetics uncover structural requirements for AM1 receptor activation.

Adrenomedullin (ADM) is a vasoactive peptide hormone of 52 amino acids and belongs to the calcitonin peptide superfamily. Its vasodilative effects are mediated by the interaction with the calcitonin receptor-like receptor (CLR), a class B G protein-coupled receptor (GPCR), associated with the receptor activity modifying protein 2 (RAMP2) and functionally described as AM-1 receptor (AM1 R). A disulfide-bonded ring structure consisting of six amino acids between Cys16 and Cys21 has been shown to be a key motif for receptor activation. However, the specific structural requirements remain to be elucidated. To investigate the influence of ring size and position of additional functional groups that replace the native disulfide bond, we generated ADM analogs containing thioether, thioacetal, alkane, and lactam bonds between amino acids 16 and 21 by Fmoc/t-Bu solid phase peptide synthesis. Activity studies of the ADM disulfide bond mimetics (DSBM) revealed a strong impact of structural parameters. Interestingly, an increased ring size was tolerated but the activity of lactam-based mimetics depended on its position within the bridging structure. Furthermore, we found the thioacetal as well as the thioether-based mimetics to be well accepted with full AM1 R activity. While a reduced selectivity over the calcitonin gene-related peptide receptor (CGRPR) was observed for the thioethers, the thioacetal was able to retain a wild-type-like selectivity profile. The carbon analog in contrast displayed weak antagonistic properties. These results provide insight into the structural requirements for AM1 R activation as well as new possibilities for the development of metabolically stabilized analogs for therapeutic applications of ADM.

Changes in Brachial and Central Blood Pressure after Short Term Continuous Positive Airway Pressure Treatment of Patients with Moderate-to-Severe Obstructive Sleep Apnoea and Impaired Renal Function

Background: Previous studies of continuous positive airway pressure (CPAP) treatment for obstructive sleep apnoea (OSA) have shown conflicting results on the effect on blood pressure (BP), and patients with chronic kidney disease (CKD) have not been included in these studies. As OSA is a frequent comorbidity in patients with CKD, it is of relevance to evaluate the effect of CPAP treatment on BP in this population. Aim: In this prospective follow-up study, we measured the effect of short term CPAP treatment of moderate-to-severe OSA on brachial and central BP, plasma level of syndecan-1 and vasoactive hormones, renal handling of sodium, subjective sleepiness, and quality of life in patients with impaired renal function. Methods: From December 2015 until March 2017, 25 patients were invited to participate in the study at the University Clinic in Nephrology and Hypertension, Aarhus University and Holstebro Hospital. At baseline and at follow-up after three to four months of CPAP treatment, we performed 24 h brachial and central ambulatory BP measurement, blood sampling measurements of plasma concentrations of syndecan-1, renin, angiotensin II, aldosterone, vasopressin, creatinine, haemoglobin A1c, and cholesterol, cardio respiratory monitoring, 24 h urine collection for measurement of urinary excretion of albumin, aquaporin-2, and epithelial sodium channel, Epworth Sleepiness Scale (ESS), and SF-36 (quality of life). Results: At follow-up, the 17 included patients with mean baseline estimated glomerular filtration rate 66 mL/min/1.73 m2 had a significant decrease in systolic office-, 24 h- and daytime-BP (13, 7, and 8 mmHg, respectively, p Conclusion: Short-term CPAP treatment of patients with moderate-to-severe OSA and reduced renal function decreased 24 h- and daytime-BP significantly and reduced urinary albumin excretion. Our results underline the importance of treatment of OSA in hypertensive patients with impaired renal function.

The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention.

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin-angiotensin system (RAS) is a major physiological regulatory pathway controlling salt-water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma.

Nocturnal blood pressure decrease in patients with chronic kidney disease and in healthy controls - significance of obstructive sleep apnea and renal function.

BackgroundChronic kidney disease (CKD) is often associated with a blunted nocturnal BP decrease and OSA. However, it is not fully clear whether a relationship exists between reduction in renal function and obstructive sleep apnea (OSA) on the one hand and relative nocturnal BP decrease in CKD patients on the other. The aim of this study was to investigate the association between nocturnal BP decrease and renal function, the degree of OSA, vasoactive hormones, and renal sodium handling in CKD3-4 patients and healthy age-matched controls.MethodsWe performed brachial and central 24-hour ambulatory BP measurement and CRM in 70 CKD3-4 patients and 56 controls. In plasma, we measured renin, AngII, aldosterone, and vasopressin. In urine, 24-hour excretion of sodium, protein fractions from the epithelial sodium channel (u-ENaCγ), and the AQP2 water channels (u-AQP2) were measured.ResultsCKD patients had lower relative nocturnal BP decrease than controls: brachial (10% vs 17%, P=0.001) and central (6% vs 10%, P=0.001). Moderate-to-severe OSA was more frequent in patients (15 vs 1%, P<0.0001). Neither the presence of OSA nor eGFR were predictors of either brachial or central nocturnal BP decrease. CKD3-4 nondippers were more obese, had higher HbA1c level, and more often a history of acute myocardial infarction than CKD3-4 dippers (P<0.05).ConclusionCKD3-4 patients had lower brachial and central nocturnal BP decrease than healthy controls. OSA and eGFR were not associated with nondipping in CKD patients or healthy controls. Nondipping in CKD3-4 was associated with obesity, diabetes, and cardiovascular disease.ClinicalTrials.gov IDNCT01951196.

Human Relaxin-2 Fusion for the Treatment of Heart Failure

Introduction: Human relaxin-2 (hRelaxin-2), a vasoactive hormone with hemodynamic, anti-fibrotic, and cardioprotective effects, has been pursued as a potential therapy for acute decompensated heart failure. It binds to RXFP1, its cognate receptor, and to a lesser extent to RXFP2. In clinical trials, intravenous (IV) administration of recombinant hRelaxin-2 (Serelaxin) improved markers of cardiac, renal, and hepatic damage and reduced congestion. However, these effects diminished rapidly upon treatment termination. We hypothesized that the transient treatment benefits could be due to the short half-life (T1/2=4.6 hours) of Serelaxin since continuous infusion of hRelaxin-2 using subcutaneous implanted minipump has resulted in long term benefits in animal studies (Hypertension. 2014;64:315-322). To test this hypothesis, we constructed a novel hRelaxin-2 fusion (hRLX2) and evaluated its activity in vitro and its pharmacokinetic (PK) profile in vivo.

Nocturnal Blood Pressure Decrease in Hypertensive Patients and Normotensives- Association with Obstructive Sleep Apnoea and Renal Function

Background:Blunted nocturnal Blood Pressure (BP) decrease is seen in patients with hypertension and obstructive sleep apnoea (OSA). The influence of OSA and renal function on nocturnal BP decrease is not fully clarified.Objective:In this case control study of hypertensive patients and healthy controls, we aimed to analyse the relationship between nocturnal BP decrease on one hand and presence of OSA, renal function, plasma levels of syndecan and vasoactive hormones, and urinary sodium excretion on the other.Methods:In 75 hypertensive patients and 56 controls, we performed brachial and central 24h ambulatory BP measurement and cardio respiratory monitoring. We measured syndecan, renin, angiotensinII, aldosterone, vasopressin, and brain natriuretic peptide in plasma and 24h urinary excretion of sodium, aquaporin2, and a component of the epithelial sodium channel (u-ENaCγ).Results:Nocturnal BP decrease was lower in patients than controls, brachial (13% versus 17%,p=0.001) and central (8% versus 10%,p=0.019). Moderate-to-severe OSA was present in 13% of patients, 2% of controls (p&lt;0.005). Neither brachial nor central nocturnal BP decrease was associated with OSA, renal function, plasma levels of vasoactive hormones, syndecan-1, or urinary sodium excretion. P-syndecan and u-ENaCɣ were higher in patients than controls.Conclusion:Both brachial and central nocturnal BP decrease was lower in patients than in controls. Neither brachial nor central nocturnal BP decrease was associated with the presence of OSA, renal function, or plasma levels of vasoactive hormones. Increased syndecan in plasma in hypertensive patients suggested damage to the endothelial glycocalyx.