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Objective: Assess whether propranolol modulates the trigeminovascular system in both men and women. Methods: We investigated the effect of propranolol (80 mg, 90 min after oral administration, corresponding to Tmax) on the increase in dermal blood flow of the forehead skin (innervated by the trigeminal nerve) by capsaicin application (0.6 mg/mL) and electrical stimulation (0.2–1.0 mA) before and after placebo (grapefruit juice) or propranolol (oral solution diluted in grapefruit juice) in a randomized, double-blind, placebo-controlled cross-over study, including healthy males (n = 10) and females on contraceptives (n = 11). Additionally, we compared our results with data from the Dutch IADB.nl prescription database by analyzing the change in triptan use after propranolol prescription in a population similar to our dermal blood flow study subjects (males and females, 20–39 years old). Results: Dermal blood flow responses to capsaicin were significantly attenuated after propranolol, but not after placebo. When stratifying by sex, no significant changes in the capsaicin-induced dermal blood flow were observed in females after propranolol, whereas they remained significant in males. Dermal blood flow responses to electrical stimulation were not modified in any case. In our prescription database study, after propranolol, a more pronounced decrease in triptan use was observed in male patients than in female patients. Interpretation: Propranolol (80 mg) inhibits capsaicin-induced increases in dermal blood flow in a sex-dependent manner. In patients, a more pronounced decrease in triptan use is observed in males when compared with females, suggesting an interaction between propranolol and sex steroids in the modulation of the trigeminovascular system.

Background: Low sFlt-1 (soluble Fms-like tyrosine kinase-1) and ET-1 (endothelin-1) levels have been reported in preeclamptic women using proton pump inhibitors. Methods: Here, we examined whether the proton pump inhibitor omeprazole could acutely reduce sFlt-1 and ET-1 (measured as CT-proET-1 [C-terminal pro-endothelin-1]), or increase free PlGF (placental growth factor) in 20 women with confirmed preeclampsia. Primary outcome was specified as the difference in sFlt-1, PlGF, or CT-proET-1 after 4 days of omeprazole versus 20 preeclamptic women not receiving omeprazole. Results: Mean maternal age was 30 years, and median gestational age was 30 +3 weeks. Baseline sFlt-1 levels were identical in both groups, and the same was true for PlGF or CT-proET-1. After 4 days, sFlt-1 levels remained similar in women not receiving omeprazole compared with women receiving omeprazole, while the levels of PlGF and CT-proET-1 also did not differ between groups. Women receiving omeprazole had a similar prolongation of pregnancy after inclusion compared with those in the nonomeprazole group (median 15 versus 14 days). Except for a higher neonatal intubation rate in the nonomeprazole group (31% versus 4%, P =0.02), there were no differences in maternal/perinatal complications. Finally, making use of the placenta perfusion model, we established that both omeprazole and its S-isomer, esomeprazole, when maternally applied, reached the fetal compartment (fetal-to-maternal ratio’s 0.43–0.59), while only esomeprazole inhibited placental sFlt-1 release. Conclusions: Administration of omeprazole to women with confirmed preeclampsia does not alter their circulating levels of sFlt-1, PlGF, or ET-1, arguing against a role of this drug as a treatment for this syndrome.

Vascular endothelial growth factor antagonism with angiogenesis inhibitors in cancer patients induces a ‘preeclampsia-like’ syndrome including hypertension, proteinuria and elevated endothelin (ET)-1. Cyclo-oxygenase (COX) inhibition with aspirin is known to prevent the onset of preeclampsia in high-risk patients. In the present study, we hypothesised that treatment with aspirin would prevent the development of angiogenesis inhibitor-induced hypertension and kidney damage. Our aims were to compare the effects of low-dose (COX-1 inhibition) and high-dose (dual COX-1 and COX-2 inhibition) aspirin on blood pressure, vascular function, oxidative stress, ET-1 and prostanoid levels and kidney damage during angiogenesis-inhibitor therapy in rodents. To this end, Wistar Kyoto rats were treated with vehicle, angiogenesis inhibitor (sunitinib) alone or in combination with low- or high-dose aspirin for 8 days (n=5–7/group). Our results demonstrated that prostacyclin (PGI2) and ET-1 were increased during angiogenesis-inhibitor therapy, while thromboxane (TXA2) was unchanged. Both low- and high-dose aspirin blunted angiogenesis inhibitor-induced hypertension and vascular superoxide production to a similar extent, whereas only high-dose aspirin prevented albuminuria. While circulating TXA2 and prostaglandin F2α levels were reduced by both low- and high-dose aspirin, circulating and urinary levels PGI2 were only reduced by high-dose aspirin. Lastly, treatment with aspirin did not significantly affect ET-1 or vascular function. Collectively our findings suggest that prostanoids contribute to the development of angiogenesis inhibitor-induced hypertension and renal damage and that targeting the prostanoid pathway could be an effective strategy to mitigate the unwanted cardiovascular and renal toxicities associated with angiogenesis inhibitors.

Objectives Preeclampsia is associated with hypertension in later life, but the underlying pathophysiological mechanisms remain uncertain. We aimed to explore whether the angiogenic markers soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) measured in women with preeclampsia could be associated with hypertension 1 year after delivery. Methods This is a secondary analysis of a prospective cohort study, originally aimed to evaluate the use of sFlt-1/PlGF ratio to predict adverse outcome in women with (suspected) preeclampsia. Office blood pressure (BP) was evaluated at 1 year postpartum in women who had a confirmed diagnosis of preeclampsia within one week of biomarker measurement. Results Eighty women were included with a median (interquartile range) gestational age (GA) at biomarker measurement of 30 (27–33) weeks. Twenty-three (29%) women had hypertension 1 year postpartum. These women showed higher median SBP during their pregnancy and lower GA at PE diagnosis compared to women without hypertension. Median PlGF levels were lower in women with hypertension 1 year postpartum compared to women without hypertension (23 vs. 48 pg/mL, p = 0.017), while no differences in sFlt-1 or sFlt-1/PlGF ratio were observed. Multivariable analysis adjusted for GA did not show significant association between PlGF (nor sFlt-1, sFlt-1/PlGF ratio) and hypertension 1 year postpartum (OR [95% CI] 0.9 [0.2–4.4], p = 0.97). Conclusion Our data indicate that sFlt-1, PlGF or their ratio measured during pregnancy are not suitable for the prediction of hypertension 1 year postpartum and hence guiding follow-up of women with previous preeclampsia.

AimsAlthough effective in preventing tumour growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin (ET)-1 up-regulation. ET-1 via stimulation of the ETA receptor has pro-hypertensive actions whereas stimulation of the ETB receptor can elicit both pro- or anti-hypertensive effects. In this study, our aim was to determine the efficacy of selective ETA vs. dual ETA/B receptor blockade for the prevention of angiogenesis inhibitor-induced hypertension and albuminuria.Methods and resultsMale Wistar Kyoto (WKY) rats were treated with vehicle, sunitinib (angiogenesis inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ETA/B receptor antagonist; 30 mg/kg/day) or sitaxentan (selective ETA receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Compared with vehicle, sunitinib treatment caused a rapid and sustained increase in mean arterial pressure of ∼25 mmHg. Co-treatment with macitentan or sitaxentan abolished the pressor response to sunitinib. Sunitinib did not induce endothelial dysfunction. However, it was associated with increased aortic, mesenteric, and renal oxidative stress, an effect that was absent in mesenteric arteries of the macitentan and sitaxentan co-treated groups. Albuminuria was greater in the sunitinib- than vehicle-treated group. Co-treatment with sitaxentan, but not macitentan, prevented this increase in albuminuria. Sunitinib treatment increased circulating and urinary prostacyclin levels and had no effect on thromboxane levels. These increases in prostacyclin were blunted by co-treatment with sitaxentan.ConclusionsOur results demonstrate that both selective ETA and dual ETA/B receptor antagonism prevents sunitinib-induced hypertension, whereas sunitinib-induced albuminuria was only prevented by selective ETA receptor antagonism. In addition, our results uncover a role for prostacyclin in the development of these effects. In conclusion, selective ETA receptor antagonism is sufficient for the prevention of sunitinib-induced hypertension and renal injury.

To determine the impact of implementing the new WHO-2013 criteria on prevalence of gestational diabetes mellitus (GDM) and pregnancy outcomes compared to the WHO-1999 criteria.A retrospective study conducted in pregnant women who were referred to the Erasmus MC for an oral glucose tolerance test (OGTT) between 2010 and 2015.Of 3089 women, 11.5 % (n = 354) were diagnosed with GDM based on the WHO-1999 criteria and 17.0 % (n = 524) based on the 2013-criteria, with 97 (3.1 %) reclassified as non-GDM and 267 (8.6 %) reclassified as GDM when shifting from the 1999 to 2013-criteria. In contrast to 60 % of patients in the WHO-2013 group, only 2 % of the WHO-1999 group was diagnosed with GDM because of an elevated fasting glucose only. Patients reclassified as GDM by WHO-2013 criteria had a higher body mass index (p 0.001) and delivered babies with a higher birth weight (p = 0.01). Maternal and neonatal adverse outcomes were comparable between patients with GDM based on WHO-1999 criteria and patients newly included by WHO-2013 criteria.Implementing the new diagnostic criteria leads to a considerable increase of prevalence of GDM. The newly included patients were more frequently overweighed and delivered babies with a higher birth weight. The added diagnostic value of the fasting glucose threshold of the WHO-1999 criteria is very low compared to the 2-h post-OGTT threshold, supporting the use of a lower fasting glucose threshold value as advocated by the WHO-2013 criteria.The new WHO-2013 criteria leads to a considerable increase of prevalence of GDM.

BACKGROUND Aortic stiffness as measured by carotid–femoral pulse wave velocity (cfPWV) is known to depend on blood pressure (BP), and this dependency may change with age. Therefore, the hydrostatic BP gradient resulting from a change in body posture may elicit a cfPWV change that is age-dependent. We aimed to analyze the relationship between BP gradient—induced by head-up body tilting—and related changes in cfPWV in individuals of varying age. METHODS cfPWV and other hemodynamic parameters were measured in 30 healthy individuals at a head-up tilt of 0° (supine), 30°, and 60°. At each angle, the PWV gradient and resulting cfPWV were also estimated (predicted) by assuming a global nonlinear, exponential, pressure–diameter relationship characterized by a constant β0, and taking into account that (diastolic) foot-to-foot cfPWV acutely depends on diastolic BP. RESULTS cfPWV significantly increased upon body tilting (8.0 ± 2.0 m/s supine, 9.1 ± 2.6 m/s at 30°, 9.5 ± 3.2 m/s at 60°, P for trend CONCLUSIONS Under a hydrostatic pressure gradient, the pulse wave traveling along the aorta undergoes an age-related, nonlinear PWV increase exceeding the increase predicted from BP dependency.

Acute fatty liver of pregnancy (AFLP) is characterized by elevated circulating sFlt-1 (soluble Fms-like tyrosine kinase-1), although the free circulating levels of its ligand, PlGF (placental growth factor) are not decreased. Here, we hypothesized that women with AFLP exhibit elevated PlGF production in comparison to women with preeclampsia or hemolysis elevated liver enzymes and low platelet count syndrome. Making use of the well-known mathematical formulas describing drug-receptor interactions, we established that serum total PlGF could be accurately predicted from sFlt-1 and free PlGF levels (n=42; mean calculated K D of 50 pmol/L), yielding similar values as the previously published method of thermal dissociation of the sFlt-1-PlGF complexes ( r =0.94, P P P P

Preeclampsia (PE) is a pregnancy complication, featuring elevated blood pressure and proteinuria, with no appropriate treatment. Activation of the endothelin system has emerged as an important pathway in PE pathophysiology based on experimental PE models where endothelin receptor antagonists (ERAs) prevented or attenuated hypertension and proteinuria. Hence, ERAs have been suggested as potential therapy for PE. However, developmental toxicity studies in animals have shown severe teratogenic effects of ERAs, particularly craniofacial malformations. Nonetheless, sporadic cases of pregnancy in women using ERAs to treat pulmonary hypertension have been described. In this review we give an overview of cases describing ERA use in pregnancy and critically address their possible teratogenic effects. A systematic search in literature yielded 18 articles describing 39 cases with ERA exposure during human pregnancy. In most cases there was only exposure in the first trimester, but exposure later or throughout pregnancy was reported in five cases. Elective termination of pregnancy was performed in 12 pregnancies (31%), two ended in a spontaneous miscarriage (5%) and no fetal congenital abnormalities have been described in the remaining cases. These preliminary findings support the idea that ERA treatment for severe, early onset PE might be an option if applied later in pregnancy, when organogenesis is completed to avoid teratogenic risks. However, third trimester toxicology studies are warranted to evaluate drug safety. Subsequently, it remains to be established whether ERA treatment is effective for alleviating maternal symptoms, as demonstrated in preclinical PE models, allowing pregnancy prolongation without leading to adverse neonatal outcomes.

The endothelial glycoprotein thrombomodulin regulates coagulation, vascular inflammation and apoptosis. In the kidney, thrombomodulin protects the glomerular filtration barrier by eliciting crosstalk between the glomerular endothelium and podocytes. Several glomerular pathologies are characterized by a loss of glomerular thrombomodulin. In women with pre-eclampsia, serum levels of soluble thrombomodulin are increased, possibly reflecting a loss from the glomerular endothelium. We set out to investigate whether thrombomodulin expression is decreased in the kidneys of women with pre-eclampsia and rats exposed to an angiogenesis inhibitor. Thrombomodulin expression was examined using immunohistochemistry and qPCR in renal autopsy tissues collected from 11 pre-eclamptic women, 22 pregnant controls and 11 hypertensive non-pregnant women. Further, kidneys from rats treated with increasing doses of sunitinib or sunitinib in combination with endothelin receptor antagonists were studied. Glomerular thrombomodulin protein levels were increased in the kidneys of women with pre-eclampsia. In parallel, in rats exposed to sunitinib, glomerular thrombomodulin was upregulated in a dose-dependent manner, and the upregulation of glomerular thrombomodulin preceded the onset of histopathological changes. Selective ETAR blockade, but not dual ETA/BR blockade, normalised the sunitinib-induced increase in thrombomodulin expression and albuminuria. We propose that glomerular thrombomodulin expression increases at an early stage of renal damage induced by antiangiogenic conditions. The upregulation of this nephroprotective protein in glomerular endothelial cells might serve as a mechanism to protect the glomerular filtration barrier in pre-eclampsia.

Angiogenesis is required for invasive tumor growth and metastasis which is controlled mainly by vascular endothelial growth factors (VEGF). Novel strategies for cancer treatment target VEGF signaling. These agents are featured by adverse events including hypertension. New concepts suggest that besides the kidneys, the skin also plays a role in body sodium homeostasis and blood pressure regulation by a VEGF-C–dependent buffering mechanism. Here, we tested the hypothesis that changes in blood pressure correspond to tissue sodium accumulation during sunitinib treatment of metastatic renal cell carcinoma patients (https://clinicaltrials.gov/identifier: NCT04368546; Charité ethical approval EA1/044/15).Male patients (n=4) took sunitinib according to the standard treatment protocol, 50 mg once daily, taken for 4 weeks followed by a 2-weeks off treatment period. Measurements were performed at baseline (before sunitinib treatment), and over a complete on-off-on period. Tissue sodium content was measured using non-invasive 23Na-MRI; skin sodium was measured in a group (n=5) of age-matched healthy subjects, as well. Blood pressure was measured according to AHA guidelines. Blood withdrawal followed after ca. 45 minutes of sitting to measure VEGF-A, VEGF-C, endothelin-1, renin and aldosterone levels.Elevated systolic blood pressure under sunitinib treatment decreased to the baseline level in the off-treatment phase (130.5 mmHg vs 117.5 mmHg, respectively, p

Increasing evidence suggests a role for the ET (endothelin) system in preeclampsia. Hence, blocking this system with endothelin receptor antagonists (ERAs) could be a therapeutic strategy. Yet, clinical studies are lacking due to possible teratogenic effects of ERAs. In this study, we investigated the placental transfer of ERAs and their effect on ET-1-mediated vasoconstriction. Term placentas were dually perfused with the selective ET A R (ET type A receptor) antagonists sitaxentan and ambrisentan or the nonselective ET A R/ET B R antagonist macitentan and subsequently exposed to ET-1 in the fetal circulation. ET-1 concentration-response curves after incubation with sitaxentan, ambrisentan, macitentan, or the selective ET B R antagonist BQ-788 were also constructed in isolated chorionic plate arteries using wire-myography, and gene expression of the ET-system was quantified in healthy and early onset preeclamptic placentas. At steady state, the mean fetal-to-maternal transfer ratios were 0.32±0.05 for sitaxentan, 0.21±0.02 for ambrisentan, and 0.05±0.01 for macitentan. Except for BQ-788, all ERAs lowered the response to ET-1, both in the perfused cotyledon and isolated chorionic plate arteries. Placental gene expression of ECE-1, ET A R, and ET B R were comparable in healthy and preeclamptic placentas, while ET-1 expression was higher in preeclampsia. Our study is the first to show direct transfer of ERAs across the term human placenta. Furthermore, ET A R exclusively mediates ET-1-induced constriction in the fetoplacental vasculature. Given its limited transfer, macitentan could be considered as potential preeclampsia therapy. Extending knowledge on placental transfer to placentas of preeclamptic pregnancies is required to determine whether ERAs might be applied safely in preeclampsia.

Background We aimed to evaluate the value of inhibin A and PAPP‐A2 (pregnancy‐associated plasma protein‐A2) as novel biomarkers in the prediction of preeclampsia‐related complications and how they compare with angiogenic biomarkers. Methods and Results Making use of a secondary analysis of a prospective, multicenter, observational study, intended to evaluate the usefulness of sFlt‐1 (soluble Fms‐like tyrosine kinase‐1)/PlGF (placental growth factor) ratio, we measured inhibin A and PAPP‐A2 levels in 524 women with suspected/confirmed preeclampsia. Women had a median gestational age of 35 weeks (range, 20–41 weeks) while preeclampsia occurred in 170 (32%) women. Levels of inhibin A and PAPP‐A2 were significantly increased in women with preeclampsia and in maternal perfusate of preeclamptic placentas. Inhibin A and PAPP‐A2 (C‐index = 0.73 and 0.75) significantly improved the prediction of maternal complications when added on top of the traditional criteria; gestational age, parity, proteinuria, and diastolic blood pressure (C‐index = 0.60). PAPP‐A2 was able to improve the C‐index from 0.75 to 0.77 when added on top of the sFlt‐1/PlGF ratio for the prediction of maternal complications. To discriminate fetal/neonatal complications on top of traditional criteria, inhibin A and PAPP‐A2 showed additive value (C‐index = 0.79 to 0.80 and 0.82, respectively) but their discriminative ability remained inferior to that of sFlt‐1/PlGF ratio or PlGF. Interestingly, the PAPP‐A2/PlGF ratio alone showed remarkable value to predict pregnancy complications, being superior to sFlt‐1/PlGF ratio in the case of maternal complications. Conclusions Inhibin A and PAPP‐A2 show significant potential to predict preeclampsia‐related pregnancy complications and might prove beneficial on top of the angiogenic markers.

Angiogenesis inhibition with bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGF-A), is an anticancer treatment associated with hypertension and renal glomerular toxicity referred to as a preeclampsia-like syndrome. In preeclampsia, podocyturia predates proteinuria and clinical features of preeclampsia, and is regarded as a biomarker of ongoing glomerular injury. Using a quantitative polymerase chain reaction of the podocyte-specific molecules nephrin, podocin, and VEGF-A in the urine, we examined whether podocyturia is present in bevacizumab-treated cancer patients, and whether it relates to proteinuria and the cumulative dose of bevacizumab. Urine samples were cross-sectionally collected from 43 bevacizumab-treated patients, 21 chemotherapy-treated patients, and 7 healthy controls. Urinary protein-to-creatinine ratio (mean and range) was 32.0 mg/mmol (5.2-284.4) in the bevacizumab group, compared with 11.4 mg/mmol (1.1-21.0) in the chemotherapy group and 7.4 mg/mmol (3.9-16.5) (P .05) in healthy controls, whereas urinary albumin-to-creatinine ratio values in the three groups were, respectively, 18.9 mg/mmol (0.1-227.7), 1.5 mg/mmol (0.2-3.5), and 0.2 mg/mmol (0.1-0.4) (P .05). The cumulative dose of bevacizumab ranged from 550 to 93,628 mg. Urinary podocin mRNA expression was undetectable in 59% of participants, urinary nephrin mRNA expression per mmol creatinine ranged from 0.0 to 5.3 and urinary VEGF-A mRNA expression from 0.0 to 2.7. Urinary nephrin mRNA expression did not correlate to the albumin-to-creatinine ratio or the cumulative dose of bevacizumab, whereas the latter correlated with the albumin-to-creatinine ratio (r = 0.77; P .001). Our results demonstrate that the cumulative dose of bevacizumab is closely correlated with albuminuria but not with podocyturia as measured with the quantitative polymerase chain reaction technique, challenging the feasibility of this measurement to monitor ongoing glomerular injury in patients chronically treated with bevacizumab.

Kidney damage is a common consequence of arterial hypertension, but is also a cause of atherogenesis. Dysfunction and/or harm of the endothelium in glomeruli and tubular interstitium damage the function of these structures and translates into dynamic changes of filtration fraction, with progressive reduction in glomerular filtration rate, expansion of extracellular fluid volume, abnormal ion balance, and hypoxia, ultimately leading to chronic kidney disease. Considering the key role played by endothelial dysfunction in chronic kidney disease, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension have critically reviewed available knowledge on the mechanisms underlying endothelial cell injury. This resulted into two articles: in the first, we herein examine the mechanisms by which endothelial factors induce vascular remodeling and the role of different players, including endothelin-1, the renin-angiotensin-aldosterone system and their interactions, and of oxidative stress; in the second, we discuss the role of endothelial dysfunction in the major disease conditions that affect the kidney.

Resistant hypertension is a common health problem leading to suboptimal cardiovascular prevention. A large number of patients with resistant hypertension have poor medication adherence explaining their assumed resistance to therapy. We combined directly observed therapy (DOT) with therapeutic drug monitoring (TDM) in 3 patients at several time points to enable an extensive feedback on blood pressure (BP) and drug levels. BP was measured with an automatic oscillatory device at regular intervals of 5 minutes (directly before and after drug intake) and at 30-minute intervals (at night) during admission. Blood samples were obtained at different time points (t = in hours; t = 0, 2, 4, 6, 12, and 24 hours after drug intake). DOT was performed under supervision of the physician. In 2 of the 3 patients, automated BP decreased directly after DOT, -10/0 and -5/-5 mm Hg, respectively. Plasma drug levels for several drugs or active metabolites were 0 at t = 0, whereas plasma levels were positive at t = 24 hours after observed intake. We recommend a more frequent use of TDM combined with repeated BP measurements in clinical practice because this is a convenient, objective method of measurement and to ensure that actual drug levels reflect the BP at the time of measurement.

After examining in Part I the general mechanisms of endothelial cell injury in the kidney, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension will herein review current knowledge on the role of endothelial dysfunction in multiple disease conditions that affect the kidney, including diabetes mellitus, preeclampsia, solid organ transplantation, hyperhomocysteinemia and antiangiogenic therapy in cancer. The few available randomized controlled clinical trials specifically designed to evaluate strategies for correcting endothelial dysfunction in patients with hypertension and/or chronic kidney disease are also discussed alongside their cardiovascular and renal outcomes.

Physiologically, vascular endothelial growth factors (VEGF) and their receptors (VEGFR) play a critical role in vascular development, neogenesis, angiogenesis, endothelial function and vascular tone. Pathologically, VEGF-VEGFR signaling induces dysregulated angiogenesis, which contributes to the growth and spread of tumors. The development of VEGF-VEGFR inhibitors (VEGFIs) has thus proven to be a valuable strategy in the management of a number of malignancies, yielding improved survival outcomes. Not surprisingly, VEGFIs are now standard of care as first-line monotherapy for some cancers and the scope of this class of drugs is growing. However with the promise of improved outcomes, VEGFIs also led to clinically relevant toxicities, especially hypertension and cardiovascular disease (CVD). As such, cancer patients treated with VEGFIs may have improved cancer outcomes, but at the cost of an increased risk of CVD. Indeed, dose intensity and protracted use of these drugs can be limited by cardiovascular side effects and patients may require dose reduction or drug withdrawal, thus compromising anti-cancer efficacy and survival. Here we summarize the vascular biology of VEGF-VEGFR signaling and discuss the cardiovascular consequences and clinical impact of VEGFIs. New insights into molecular mechanisms whereby VEGFIs cause hypertension and heart disease are highlighted.

Objectives: Over 70% of patients who visit the emergency department with a hypertensive emergency or a hypertensive urgency have previously been diagnosed with hypertension. Drug nonadherence is assumed to play an important role in development of hypertensive urgency and hypertensive emergency, but exact numbers are lacking. We aimed to retrospectively compare characteristics of patients with hypertensive urgency and hypertensive emergency and to prospectively quantify the attribution of drug nonadherence. Methods: We retrospectively analysed clinical data including information on nonadherence obtained by treating physicians of patients with SBP at least 180 mmHg and DBP at least 110 mmHg visiting the emergency department between 2012 and 2015. We prospectively studied drug adherence among patients admitted to the emergency department with severely elevated BP by measuring plasma drug levels using liquid chromatography tandem mass spectrometry from September 2016 to March 2017. Results: Of the 1163 patients retrospectively analysed, 257 (22.0%) met the criteria for hypertensive urgency and 356 (30.6%) for hypertensive emergency. Mean SBP (SD) was 203 (19) mmHg and mean DBP 121 (12) mmHg. Mean age was 60.1 (14.6) years; 55.1% were men. In 6.3% of patients with hypertensive urgency or hypertensive emergency, nonadherence was recorded as an attributing factor. Of the 59 patients prospectively analysed, 18 (30.5%) were nonadherent for at least one of the prescribed antihypertensive drugs. Conclusion: Hypertensive urgency and hypertensive emergency are common health problems resulting in frequent emergency department admissions. Workup of patients with a hypertensive urgency or hypertensive emergency should include an assessment of drug adherence to optimize treatment strategy.

The recognition that angiogenesis is critical for tumor growth has stimulated the development of several agents that interfere with the process of angiogenesis. Of these agents, vascular endothelial growth factor (VEGF) signaling pathway (VSP) inhibitors have gained a prominent role in the treatment of a large variety of cancers. Along with their clinical introduction, treatment with VSP inhibitors appeared to be associated with the development of cardiovascular side effects, particularly hypertension, renal injury, cardiac dysfunction, thrombosis, and hemorrhage. When severe, these side effects are reason to discontinue VSP inhibitor treatment, obviously with repercussions for survival. In this review, we focus on mechanisms underlying the rise in blood pressure (BP) and kidney injury induced by VSP inhibitor treatment. Insight into the mechanisms of these side effects is not only of scientific interest, but may also provide a basis for their prevention with rational treatment. Because for a proportion of clinicians interested in hypertension the VEGF system is not common knowledge, we will start with a short description of this system and ways of its inhibition by pharmacological agents. The mammalian VEGF family includes the glycoproteins VEGF-A,VEGF-B, VEGF-C, VEGF-D, VEGF-E, and the placental growth factor, with VEGF-A, commonly referred to as VEGF, as the most prominent factor. The VEGFs are mainly present as homodimeric polypeptides. Alternative splicing and proteolytic processing increase the complexity of the VEGF system. For instance, alternative splicing of the gene encoding for VEGF-A gives rise to VEGF isoforms exerting antiangiogenic activity.1 VEGF is produced by most parenchymal cells, acting in a paracrine fashion on adjacent endothelial cells (ECs). The induction of VEGF is crucial for the initiation of angiogenesis, with hypoxia-inducible factor 1α and 2α and platelet-derived growth factor B as important positive regulators of its production.2 Genetic deletion experiments in mice have shown that the …

Background The N-terminal pro B-type natriuretic peptide (NT-proBNP) has a well-documented prognostic value for cardiovascular disease (CVD) and higher levels are associated with cognitive-dysfunction in patients with CVD. However, how NT-proBNP relates to incident dementia and cognitive-decline in community-dwelling persons is unknown. Methods Between 1997 and 2001, serum NT-proBNP was measured in 6040 participants (mean age 69 years, 57% women) free of heart-failure and dementia from the Rotterdam Study. Participants were continuously followed-up for incident dementia until 2012, for 56 616 person-years. Cognition was assessed at baseline and reassessed between 2002 and 2006 by Letter-Digit-Substitution-task, Stroop test and Word-Fluency test. Associations of NT-proBNP with dementia (555 cases), Alzheimer9s disease (357 cases) and vascular dementia (32 cases) were assessed linearly, and in quartiles using Cox regression. Associations of NT-proBNP with cognitive-decline were assessed using multiple linear regression. All analyses were repeated after excluding patients with CVD. Results Higher NT-proBNP was associated with a higher risk of dementia, even after excluding patients with CVD and adjusting for cardiovascular risk factors, HR per SD 1.27 (95% CI 1.13 to 1.44). Associations were particularly strong for vascular dementia, HR per SD 2.04 (95% CI 1.18 to 3.55), but also for Alzheimer9s disease when comparing the second and third quartile with first. Higher NT-proBNP was cross-sectionally associated with poorer performance in multiple cognitive tests but longitudinally only in Letter-Digit-Substitution-task. Conclusions NT-proBNP reflecting subclinical CVD is associated with dementia, particularly vascular dementia. NT-proBNP can be a useful marker of imminent cognitive-decline and dementia in absence of clinical CVD.

Preeclampsia is a systemic, pregnancy-related disorder featuring hypertension and proteinuria arising from placental overproduction of soluble FMS-like tyrosine kinase-1, resulting in an antiangiogenic state because of the inhibition of the vascular endothelial growth factor (VEGF) family. Similarly, antiangiogenetic treatment aimed at targeting VEGF in patients with cancer is associated with a preeclampsia-like syndrome. In this study we discuss the pathophysiological role of an activated endothelin system in both conditions.In different experimental forms of preeclampsia, in clinical preeclampsia, and in cancer patients on antiangiogenic treatment, activation of the endothelin axis invariably occurs and this activation is directly related to the circulating level of sFlt-1 or the intensity of antiangiogenic treatment. Administration of endothelin receptor A-selective or dual endothelin receptor antagonists can prevent or largely attenuate the hypertension and proteinuria in experimental forms of preeclampsia, as well as in rats exposed to receptor tyrosine-kinase inhibitors targeting VEGF-signaling, supporting the concept that activation of the endothelin axis plays a key role in the manifestations of these disorders.Activation of the endothelin axis has now emerged as a crucial player in the manifestations of preeclampsia and following antiangiogenic treatment. As a consequence, blockade of the endothelin system may be considered as a treatment option both in preeclampsia and in antiangiogenesis-induced hypertension and renal toxicity in patients with cancer.

Objective Amlodipine, a long-acting dihydropyridine calcium channel blocker, is frequently prescribed to pediatric patients. To date, no suitable pediatric formulation has been available. In this study, an amlodipine oral solution was developed and tested for bioequivalence to tablets in healthy adult volunteers. Methods This study was designed as an open-label, single-dose, twosequence, two-period, crossover trial to assess the bioequivalence of a newly developed amlodipine besylate oral solution 0.5 mg/mL compared to Norvasc® 5 mg tablets. 13 adult subjects (mean [standard deviation] age of 23.2 [3.6] years, weight 71.5 [7.7] kg) were included and blood samples were collected for 72 hours. Amlodipine plasma levels were determined using a validated UPLC-MS/MS assay. Non-compartmental pharmacokinetic parameters were compared between the formulations according to European Medicines Agency (EMA) bioequivalence guidelines. Results The 90% confidence intervals of the test/reference ratios of the geometric means for the primary pharmacokinetic parameters AUC(0-72) (88.24 - 104.37%) and C(max) (99.00 - 121.40%) were within the acceptance range of 80.00 - 125.00% for bioequivalence. Mean (SD) AUC(0-72) was 102.7 (26.8) (26.8) μg × h/L for the solution and 108.2 (30.6) μg × h/L for the tablet. Mean (SD) Cmax of the solution was 3.11(1.06) μg/L with a median (IQR) t(max) of 4.0 (2.6 - 7.5) hours. Mean (SD) C(max) of the tablet was 2.91 (0.84) μg/L with a median (IQR) tmax of 6.0 (4.0 - 14.0) hours. Intrasubject coefficients of variation were 10.2% (AUC(0-72)) and 12.4% (C(max)). Conclusions The formulations are bioequivalent according to EMA guidelines. This warrants further study of our novel amlodipine oral solution in pediatric patients.

Introduction: Acute, gravity-induced blood pressure (BP) changes during head-up tilt may generate concomitant variations in carotid-femoral pulse wave velocity (cf-PWV). We aimed to separate the pressure-dependent and -independent components of cf-PWV changes observed during head-up tilt. Methods: 30 healthy individuals (age 48 ± 18 years (mean ± SD), 38% males, BP 130/74 ± 12/8 mmHg) underwent head-up passive tilting at a = 0°, 30°, and 60°. BP was taken at the upper arm, constantly kept at heart level. Aortic BP was reconstructed from radial tonometry (SphygmoCor). Stiffness index b0 was estimated at 0°. 1 Assumptions: [1] from MRI2, the effective cf-PWV travel distance (ETD, 80% of straight carotid-to-femoral distance) begins at heart level; [2] the change in DBP along the aorta is predictable from the hydrostatic pressure gradient (0.73 mmHg/cm) 3; [3] cf-PWV and hydrostatic pressure relate linearly, hence predicted cf-PWV can be calculated as the average of aortic (PWVaorta, using b0 and aortic DBP) and femoral (PWVfem, using b0 and femoral DBP, corresponding to aortic DBP + (ETD × sin(a)*0.73)) PWVs. Results: Both young (24–48 years) and old (48–82 years) individuals showed increasing trends for peripheral SBP, DBP, PP, and central DBP with tilting; central SBP remained unchanged. Heart rate (HR) and cf-PWV increased with body tilt in both groups (Figure, left). b0 linearly correlated with age (R = 0.70, p < 0.01). After adjustment for HR4, observed-vs-predicted cf-PWV exponentially increased as a function of age (R2 = 0.38, p < 0.01 for quadratic equation, p = 0.04, vs. linear; Figure, right). Conclusion: With aging, the acute relationship between BP and cf-PWV becomes progressively nonlinear.

Vascular endothelial growth factor inhibitor (VEGFi)-induced hypertension and renal injury in cancer patients mimic the clinical phenotype of preeclampsia. ET-1 has been implicated to be involved. Since aspirin can prevent the onset of preeclampsia, we hypothesized that co-treatment of the VEGFi sunitinib (SU) with aspirin might be beneficial and may improve ET-1 status. Male WKY rats were treated with vehicle, 14 mg/kg/day SU, or SU + low or high dose aspirin (5 or 100 mg/kg/day) for 8 days. Mean arterial pressure (MAP) was measured via radiotelemetry. On day 8, 24h urine was collected to determine albuminuria and prostanoid (PGF2α and TxB2) levels. Plasma endothelin-1 (ET-1) was measured via ELISA. Endothelial dysfunction was assessed in iliac vessels and reactive oxygen species (ROS) was measured via aortic superoxide anion production. Renal cyclooxygenase (COX)-1, COX-2 and ET-1 mRNA expression were determined via PCR. SU induced a rapid and sustained increase in MAP (24±2 versus 1±1 mmHg in vehicle on day 6; P

Flow-mediated dilatation (FMD) is an established, but investigator-demanding method, used to non-invasively determine nitric oxide (NO)-dependent endothelial function in humans. Local thermal hyperemia (LTH) or post-occlusive reactive hyperemia (PORH) of the skin measured with a laser Doppler flow imager may be a less demanding alternative of FMD. We investigated the reproducibility of the different measures of vascular function, their interrelationship and the NO-dependency of LTH. Measurements were performed twice in 27 healthy men (8 smokers), one week apart. Local application of NG-monomethyl-l-arginine (L-NMMA) by means of iontophoresis was used to determine the NO-dependency of LTH. Using L-NMMA, the peak and plateau responses of LTH were reduced by 31% (p .001) and 65% (0.001), respectively. For all measurements the coefficient of variation (CV) was higher in smokers than in non-smokers. For non-smokers the CV of FMD was 12%, of LTH peak response 17%, of LTH plateau response 12%, of PORH peak response 14% and of PORH area under the curve response 11%. FMD correlated weakly with the PORH peak and area under the curve response (r = 0.39 and 0.43, p .05), whereas the LTH-plateau response correlated with the PORH peak response (r = 0.68, p .01) in non-smokers, but FMD and LTH peak or plateau responses were unrelated. In conclusion, the LTH plateau response is for two-third NO-dependent, but unrelated to FMD. Furthermore, despite easy to perform the LTH responses are not more reproducible than FMD. Given the weak associations, the different methods of vascular function assessment are not interchangeable.

A sFlt-1/PlGF ratio of ≤38 has been reported to predict the absence of preeclampsia (PE) in singleton pregnancies. We evaluated whether a sFlt-1/PlGF ratio of ≤38 could be used to predict the absence of PE in twin pregnancies and maternal and fetal/neonatal complications.This is a secondary analysis of a prospective multicenter cohort study that enrolled women with suspected or confirmed PE with the aim of evaluating the use of the sFlt-1, PlGF and their ratio to predict maternal and fetal/neonatal complications. Twin and singleton pregnancies with clinically suspected or confirmed PE were matched for gestational age and parity. Blood samples were drawn at time of study entry, but serum values of sFlt-1 and PlGF and their ratio were determined postpartum.Twenty-one women with twin and 21 with singleton gestations were included at a median gestational age of 30 weeks. At inclusion PE was diagnosed in 13 twin and 15 singleton pregnancies. In comparison to singleton control pregnancies, twin controls had a significantly higher sFlt-1 (6377 vs. 1732 pg/ml, p = 0.008), a higher sFlt-1/PlGF ratio 26 vs. 3 p = 0.361) and a lower PlGF (228 vs. 440 pg/ml p = 0.479). Compared to singleton preeclamptic pregnancies values of sFlt-1 (9134 vs. 8625 pg/ml) did not differ, whereas values of PlGF (185 vs. 33 pg/ml, p 0.001) were higher and values of the ratio (49 vs. 158, p = 0.002) were lower in preeclamptic twin pregnancies. All preeclamptic patients with a singleton pregnancy had a ratio38, but only 5 of the 13 patients with a preeclamptic twin pregnancy. Conversely, the ratio was ≤38 in 5 of the 6 control singleton, but in only 4 of the 8 control twin pregnancies. When classified according to a ratio ≤38 or38 at inclusion, maternal complications occurred more frequently in patients with a ratio38 both in singleton and twin pregnancies. In singleton pregnancies fetal/neonatal complications, except one admission to NICU, only occurred in patients with a ratio38. In twin pregnancies fetal/neonatal complications occurred equally frequent in women with a ratio ≤38 or38.Serum sFlt-1 levels are considerably higher in twin than in singleton control gestations. A sFlt-1/PlGF ratio of ≤38 to predict short-term absence of PE is not applicable to twin pregnancies in predicting either the absence of PE or the absence of adverse pregnancy outcomes.

Aims More than 50% of patients with heart failure have preserved ejection fraction characterized by diastolic dysfunction. The prevalance of diastolic dysfunction is higher in females and associates with multiple comorbidities such as hypertension (HT), obesity, hypercholesterolemia (HC), and diabetes mellitus (DM). Although its pathophysiology remains incompletely understood, it has been proposed that these comorbidities induce systemic inflammation, coronary microvascular dysfunction, and oxidative stress, leading to myocardial fibrosis, myocyte stiffening and, ultimately, diastolic dysfunction. Here, we tested this hypothesis in a swine model chronically exposed to three common comorbidities. Methods and results DM (induced by streptozotocin), HC (produced by high fat diet), and HT (resulting from renal artery embolization), were produced in 10 female swine, which were followed for 6 months. Eight female healthy swine on normal pig-chow served as controls. The DM + HC + HT group showed hyperglycemia, HC, hypertriglyceridemia, renal dysfunction and HT, which were associated with systemic inflammation. Myocardial superoxide production was markedly increased, due to increased NOX activity and eNOS uncoupling, and associated with reduced NO production, and impaired coronary small artery endothelium-dependent vasodilation. These abnormalities were accompanied by increased myocardial collagen content, reduced capillary/fiber ratio, and elevated passive cardiomyocyte stiffness, resulting in an increased left ventricular end-diastolic stiffness (measured by pressure–volume catheter) and a trend towards a reduced E/A ratio (measured by cardiac MRI), while ejection fraction was maintained. Conclusions The combination of three common comorbidities leads to systemic inflammation, myocardial oxidative stress, and coronary microvascular dysfunction, which associate with myocardial stiffening and LV diastolic dysfunction with preserved ejection fraction.

Women with preeclampsia display low renin–angiotensin–aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin–angiotensin–aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and renin–angiotensin–aldosterone system components in pregnant women with a high (≥85; n=38) or low (2 receptor-mediated response to angiotensin II. In conclusion, a high antiangiogenic state associates with ET-1 activation, which together with the increased mean arterial pressure may underlie the parallel reductions in renin and aldosterone in preeclampsia. Because ET-1 also was a major determinant of urinary protein, our data reveal a key role for ET-1 in the pathogenesis of preeclampsia. Finally, the enhanced angiotensin responsiveness in preeclampsia involves constrictor AT 2 receptors.

Blockers of the renin–angiotensin–aldosterone system (RAAS), that is, renin inhibitors, angiotensin (Ang)-converting enzyme (ACE) inhibitors, Ang II type 1 receptor antagonists, and mineralocorticoid receptor antagonists, are a cornerstone in the treatment of hypertension. How exactly they exert their effect, in particular in patients with low circulating RAAS activity, also taking into consideration the so-called Ang II/aldosterone escape that often occurs after initial blockade, is still incompletely understood. Multiple studies have tried to find parameters that predict the response to RAAS blockade, allowing a personalized treatment approach. Consequently, the question should now be answered on what basis (eg, sex, ethnicity, age, salt intake, baseline renin, ACE or aldosterone, and genetic variance) a RAAS blocker can be chosen to treat an individual patient. Are all blockers equal? Does optimal blockade imply maximum RAAS blockade, for example, by combining ≥2 RAAS blockers or by simply increasing the dose of 1 blocker? Exciting recent investigations reveal a range of unanticipated extrarenal effects of aldosterone, as well as a detailed insight in the genetic causes of primary aldosteronism, and mineralocorticoid receptor blockers have now become an important treatment option for resistant hypertension. Finally, apart from the deleterious ACE-Ang II-Ang II type 1 receptor arm, animal studies support the existence of protective aminopeptidase A-Ang III-Ang II type 2 receptor and ACE2-Ang-(1 to 7)-Mas receptor arms, paving the way for multiple new treatment options. This review provides an update about all these aspects, critically discussing the many controversies and allowing the reader to obtain a full understanding of what we currently know about RAAS alterations in hypertension.

Angiogenesis inhibition, targeting vascular endothelial growth factor (VEGF) or its receptors, is an established treatment for solid tumors. A common side effect of this treatment is the development of sometimes severe hypertension. This hypertension is associated with a decrease in nitric oxide production, activation of the endothelin-signaling pathway and renin suppression. The mechanism underlying activation of the endothelin-signaling pathway is not fully understood. Both activation of endothelial cells and disinhibition of the VEGF-induced suppression of endothelin production by endothelial cells may be involved. The development of hypertension can be a reason to discontinue the angiogenesis inhibitor, thereby compromising anticancer treatment, but possibly is also a biomarker for a favorable antitumor response.

Angiogenesis inhibitors are a mainstay treatment for cancer. While effective in preventing tumor growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin-1 (ET-1) upregulation. ET-1 via stimulation of the ET A receptor causes pro-hypertensive effects whereas stimulation of the ET B receptor can elicit both pro- or anti-hypertensive effects. In the present study, we hypothesized that selective ET A receptor blockade versus dual ET A /ET B blockade provides better cardiovascular protection from angiogenesis inhibitor-induced hypertension. Male WKY rats were treated with vehicle, sunitinib (VEGF inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ET A/B receptor antagonist; 30 mg/kg/day) or sitaxentan (ET A receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Mean arterial pressure (MAP) was measured via radiotelemetry at baseline and days 1-6 of treatment. Vasoreactivity to acetylcholine (ACh) and ET-1 was assessed in iliac vessels. Compared to vehicle treatment, sunitinib treatment caused a rapid and sustained increase in MAP (1±1 versus 23±2 mmHg on day 6 of treatment, respectively, PB receptor stimulation yielded a constrictor response after 8 days of sunitinib treatment, while the response to ACh was unaltered. Both macitentan and sitaxentan reversed the constrictor ET B receptor response. Our results support a key role for the ET-1 system in the development of sunitinib-induced hypertension and suggest that selective ET A receptor blockade is sufficient to block this effect.

Preeclamptic patients display elevated placenta-derived soluble Fms-like tyrosine kinase-1 (sFlt-1) and endoglin levels, and decreased placental growth factor (PlGF) levels. Proton pump inhibitors (PPIs) decrease trophoblast sFlt-1 and endoglin secretion in vitro. PPIs are used during pregnancy, to combat reflux disease. Here we investigated whether PPIs affect sFlt-1 in women with confirmed/suspected preeclampsia, making use of a prospective cohort study involving 430 women. Of these women, 40 took PPIs (6 esomeprazole, 32 omeprazole and 2 pantoprazole) for 8-45 (median 29) days before sFlt-1 measurement. Measurements were only made once, at study entry between weeks 20-41 (median 33 weeks). PPI use associated with lower sFlt-1 levels, with no change in PlGF levels, both when compared to all non-PPI users, and to 80 gestational age-matched controls selected from the non-PPI users. No sFlt-1/PlGF alterations were observed in women using ferrous fumarate or macrogol, while, as expected, women using antihypertensive medication displayed higher sFlt-1 levels and/or lower PlGF levels. The PPI use-associated decrease in sFlt-1 was independent of the application of antihypertensive drugs and also occurred when restricting our analysis to patients with hypertensive disease of pregnancy at study entry. PPI users displayed more cases with preexisting proteinuria, less gestational hypertension, and a lower number of neonatal sepsis cases. Finally, their plasma endoglin and endothelin-1 levels were lower, while sFlt-1 levels correlated positively with both. In conclusion, PPI use associates with low sFlt-1, endoglin, and endothelin-1 levels, warranting prospective trials to investigate the therapeutic potential of PPIs in preeclampsia.

To assess the incremental value of a single determination of the serum levels of sFlt-1 (soluble Fms-like tyrosine kinase 1) and PlGF (placental growth factor) or their ratio, without using cutoff values, for the prediction of maternal and fetal/neonatal complications and pregnancy prolongation, 620 women with suspected/confirmed preeclampsia, aged 18 to 48 years, were included in a prospective, multicenter, observational cohort study. Women had singleton pregnancies and a median pregnancy duration of 34 (range, 20–41) weeks. Complications occurred in 118 women and 248 fetuses. The median duration between admission and delivery was 12 days. To predict prolongation, PlGF showed the highest incremental value ( R 2 =0.72) on top of traditional predictors (gestational age at inclusion, diastolic blood pressure, proteinuria, creatinine, uric acid, alanine transaminase, lactate dehydrogenase, and platelets) compared with R 2 =0.53 for the traditional predictors only. The sFlt-1/PlGF ratio showed the highest value to discriminate women with and without maternal complications (C-index=0.80 versus 0.63 for the traditional predictors only), and to discriminate fetal/neonatal complications (C-index=0.86 versus 0.78 for the traditional predictors only). Applying previously suggested cutoff values for the sFlt-1/PlGF ratio yielded lower incremental values than applying continuous values. In conclusion, sFlt-1 and PlGF are strong and independent predictors for days until delivery along with maternal and fetal/neonatal complications on top of the traditional criteria. Their use as continuous variables (instead of applying cutoff values for different gestational ages) should now be tested in a prospective manner, making use of an algorithm calculating the risk of an individual woman with suspected/confirmed preeclampsia to develop complications.

Background Chlorthalidone is a very effective antihypertensive drug, but it has not been studied prospectively in kidney transplant recipients with hypertension. Recent data indicate that calcineurin inhibitors activate the thiazide-sensitive sodium chloride cotransporter, providing further rationale to test thiazides in this population. Study Design Randomized noninferiority crossover trial (noninferiority margin, −2.8mmHg). Setting & Participants Hypertensive kidney transplant recipients using tacrolimus (median duration, 2.4 years after transplantation; mean estimated glomerular filtration rate, 63±27 [SD] mL/min/1.73m2; mean systolic blood pressure [SBP], 151±12mmHg). Intervention Amlodipine (5-10mg) and chlorthalidone (12.5-25mg) for 8 weeks (separated by 2-week washout). Outcomes Average daytime (9 am to 9 pm) ambulatory SBP. Measurements Blood pressure and laboratory parameters. Results 88 patients underwent ambulatory blood pressure monitoring, of whom 49 (56%) with average daytime SBP>140mmHg were enrolled. 41 patients completed the study. Amlodipine and chlorthalidone both reduced ambulatory SBP after 8 weeks (mean changes of 150±12 to 137±12 [SD] vs 151±12 to 141±13mmHg; effect size, −4.2 [95% CI, −7.3 to 1.1] mmHg). Despite these similar blood pressure responses, chlorthalidone reduced proteinuria by 30% (effect size, −65 [95% CI, −108 to −35] mg/g) and also reduced physician-assessed peripheral edema (22% to 10%; P Limitations Open-label design, short follow-up, per-protocol analysis. Conclusions Chlorthalidone is an antihypertensive drug equally effective as amlodipine after kidney transplantation.

In response to salt loading, Na + and Cl − accumulate in the skin in excess of water, stimulating skin lymphangiogenesis via activation of the mononuclear phagocyte system cell-derived vascular endothelial growth factor-C–vascular endothelial growth factor type 3 receptor signaling pathway. Inhibition of this pathway results in salt-sensitive hypertension. Sunitinib is an antiangiogenic, anticancer agent that blocks all 3 vascular endothelial growth factor receptors and increases blood pressure. We explored the salt dependency of sunitinib-induced hypertension and whether impairment of skin lymphangiogenesis is an underlying mechanism. Normotensive Wistar–Kyoto rats were exposed to a normal or high salt with or without sunitinib administration. Sunitinib induced a 15 mm Hg rise in telemetrically measured blood pressure, which was aggravated by a high-salt diet (HSD), resulting in a decline of the slope of the pressure–natriuresis curve. Without affecting body weight, plasma Na + concentration or renal function, Na + and Cl − skin content increased by 31% and 32% with the high salt and by 49% and 50% with the HSD plus sunitinib, whereas skin water increased by 17% and 24%, respectively. Skin mononuclear phagocyte system cell density increased both during sunitinib and a HSD, but no further increment was seen when HSD and sunitinib were combined. HSD increased skin lymphangiogenesis, while sunitinib tended to decrease lymphangiogenesis, both during a normal-salt diet and HSD. We conclude that sunitinib induces hypertension that is aggravated by high salt intake and not accompanied by impaired skin lymphangiogenesis.

Renin, a key component in the regulation of blood pressure in mammals, is produced by the rare and highly specialized juxtaglomerular cells of the kidney. Chronic stimulation of renin release results in a recruitment of new juxtaglomerular cells by the apparent conversion of adjacent smooth muscle cells along the afferent arterioles. Because juxtaglomerular cells rapidly dedifferentiate when removed from the kidney, their developmental origin and the mechanism that explains their phenotypic plasticity remain unclear. To overcome this limitation, we have performed RNA expression analysis on 4 human renin-producing tumors. The most highly expressed genes that were common between the reninomas were subsequently used for in situ hybridization in kidneys of 5-day-old mice, adult mice, and adult mice treated with captopril. From the top 100 genes, 10 encoding for ligands were selected for further analysis. Medium of human embryonic kidney 293 cells transfected with the mouse cDNA encoding these ligands was applied to (pro)renin-synthesizing As4.1 cells. Among the ligands, only platelet-derived growth factor B reduced the medium and cellular (pro)renin levels, as well as As4.1 renin gene expression. In addition, platelet-derived growth factor B–exposed As4.1 cells displayed a more elongated and aligned shape with no alteration in viability. This was accompanied by a downregulated expression of α-smooth muscle actin and an upregulated expression of interleukin-6, suggesting a phenotypic shift from myoendocrine to inflammatory. Our results add 36 new genes to the list that characterize renin-producing cells and reveal a novel role for platelet-derived growth factor B as a regulator of renin-synthesizing cells.

Patients with preeclampsia display elevated placenta-derived sFlt-1 (soluble Fms-like tyrosine kinase-1) and endoglin levels and decreased placental growth factor levels. Proton pump inhibitors (PPIs) decrease trophoblast sFlt-1 and endoglin secretion in vitro. PPIs are used during pregnancy to combat reflux disease. Here, we investigated whether PPIs affect sFlt-1 in women with confirmed/suspected preeclampsia, making use of a prospective cohort study involving 430 women. Of these women, 40 took PPIs (6 esomeprazole, 32 omeprazole, and 2 pantoprazole) for 8 to 45 (median 29) days before sFlt-1 measurement. Measurements were only made once, at study entry between weeks 20 and 41 (median 33 weeks). PPI use was associated with lower sFlt-1 levels, with no change in placental growth factor levels, both when compared with all non-PPI users and with 80 gestational age-matched controls selected from the non-PPI users. No sFlt-1/placental growth factor alterations were observed in women using ferrous fumarate or macrogol while, as expected, women using antihypertensive medication displayed higher sFlt-1 levels and lower placental growth factor levels. The PPI use-associated decrease in sFlt-1 was independent of the application of antihypertensive drugs and also occurred when restricting our analysis to patients with hypertensive disease of pregnancy at study entry. PPI users displayed more cases with preexisting proteinuria, less gestational hypertension, and a lower number of neonatal sepsis cases. Finally, their plasma endoglin and endothelin-1 levels were lower while sFlt-1 levels correlated positively with both. In conclusion, PPI use associates with low sFlt-1, endoglin, and endothelin-1 levels, warranting prospective trials to investigate the therapeutic potential of PPIs in preeclampsia.

OBJECTIVE Catheter-based renal nerve ablation is a novel therapy for treatment-resistant hypertension. Although the precise mechanism is unknown, a reduction in global sympathetic tone and renal sympathetic tone, potentially resulting in a decrease in renin, may account for the antihypertensive effect. DESIGN AND METHODS In 17 patients (mean age 51.2 ± 9.4 years) with treatment-resistant hypertension (antihypertensive drugs 4.7 ± 1.3), office and ambulatory blood pressure (BP) measurements and circulating concentrations of catecholamines, renin, aldosterone and endothelin-1 were measured at baseline and 6 and 12 months after ablation. Office BP was measured for 1 h at 5-min intervals using an automatic device. RESULTS Office BP (164.7 ± 27.7/102.3 ± 19.3 mmHg) decreased by 5.7 ± 18.8 mmHg (P = 0.11) systolic and by 2.6 ± 10.7 (P = 0.33) mmHg diastolic after 6 months, whereas after 12 months decreases were 12.7 ± 16.0 mmHg (P = 0.007) and 7.3 ± 11.9 mmHg (P = 0.02). Heart rate, 24-h (151.8 ± 12.6/94.2 ± 10.3 mmHg) and day and night ambulatory BP did not change, after either 6 or 12 months. Of the neurohormones, only plasma noradrenaline (397 pg/ml, interquartile range 268-461 pg/ml) decreased by 128 ± 167 pg/ml (P = 0.008) after 6 months, whereas other neurohormones remained unchanged. Forty-seven percent of patients had at least 10 mmHg decrease in 24-h ambulatory SBP. In these responders, office and ambulatory BP tended to be higher than in nonresponders, but neurohormones or changes after ablation between responders and nonresponders did not differ. CONCLUSION Renal nerve ablation in treatment-resistant hypertensive patients had a moderate effect on office BP and is associated with a decrease in plasma noradrenaline but not in renin. The absent decrease in renin may imply that the intensity of efferent renal denervation achieved with the number of ablations applied was insufficient.

Significance: Angiogenesis inhibition with humanized antibodies targeting vascular endothelial growth factor (VEGF) or orally active small tyrosine kinase inhibitors targeting VEGF receptors has become an established treatment modality for various forms of cancer. A common side effect of angiogenesis inhibition is the development of sometimes severe hypertension, which simultaneously appears to be predictive for a favorable antitumor response. Recent Advances: Since VEGF increases the expression and activity of endothelial nitric oxide synthase, it has been assumed that the mean blood pressure (MAP) rise during angiogenesis inhibition is caused by a decrease in nitric oxide bioavailability. Yet, the results from experimental and clinical studies exploring this possibility are conflicting. Recent studies provided evidence that the MAP rise during angiogenesis inhibition rather is mediated by activation of the endothelin-1 (ET-1) axis, which, among others, induces oxidative stress. Nevertheless, conclusive evidence for the involvement of reactive oxygen species in the MAP rise could not be obtained so far. Critical Issues: The mechanism underlying activation of the ET-1 axis during angiogenesis inhibition is unclear, and this activation was not anticipated in view of studies showing that VEGF stimulates both the expression and production of ET-1 by endothelial cells. Future Directions: In fact, this activation of the ET-1 axis may support the use of ET receptor antagonists for the treatment of angiogenesis inhibition-induced hypertension, especially because ET receptor stimulation in vascular smooth muscle cells results in VEGF production and mitogenesis in a mitogen-activated protein kinase pathway-dependent manner. Antioxid. Redox Signal. 20, 135-145.

Item does not contain fulltext BACKGROUND: The aldosterone-to-renin ratio (ARR) is a widely used screening test for primary aldosteronism. Current guidelines recommend a cut-off value of 91 pmol/mU. Studies on its sensitivity, specificity, reproducibility and the role of medication have been conflicting. We prospectively assessed the test characteristics of the ARR and the effect of combination antihypertensive treatment. METHODS: In 178 patients with persistent hypertension despite the use of at least two antihypertensives, plasma renin and aldosterone were assessed twice within an interval of 4 weeks. All patients underwent an intravenous salt loading test. A posttest plasma aldosterone exceeding 235 pmol/l was considered diagnostic for primary aldosteronism. ARR was repeated after 4 weeks of standardized treatment with a calcium channel blocker and/or alpha-adrenergic-receptor blocker. RESULTS: The prevalence of primary aldosteronism was 15.2%. The median ARR was 35.0 (interquartile range 16.2-82.0) in primary aldosteronism versus 7.1 (2.2-17.5) pmol/mU in essential hypertensive patients (P < 0.001). Under random medication, the ARR had 22.2% sensitivity and 98.7% specificity. On standardized treatment, the ARR rose from 9.6 (2.5-24.8) to 21.4 (10.8-52.1) (P < 0.001). Multivariate regression showed that angiotensin-converting enzyme (ACE)-inhibitors and angiotensin II-receptor blockers were responsible for the lower ARR during random treatment. The area under the receiver operating characteristic curve was, however, similar under random and standardized treatment (84 vs. 86%, respectively, P = 0.314). Bland-Altman plots showed an almost five-fold difference in ARR values taken under the same conditions. CONCLUSION: ARR sensitivity for primary aldosteronism is low when the recommended cut-off is used. Reproducibility is also poor, stressing the need for alternative screening tests.

Objectives: Renal neurogenic hypertension (RNH) contributes to cardiovascular morbidity. Renal hypoxia may cause RNH and vice versa, leading to a vicious circle. Hypoxia adaptation is conferred through hypoxia-inducible factors (HIFs). We hypothesized that acute RNH is accompanied by increased renal vascular resistance (RVR) and that hypertension and increased RVR are countered by increasing HIF-1 alpha by cobalt chloride (CoCl2) preconditioning. Methods: First, we studied mean arterial pressure (MAP) and RVR in innervated or denervated contralateral kidneys in anesthetized rats before and after unilateral intrarenal injection of phenol, a manoeuvre known to elicit acute RNH. Then HIF alpha was induced by CoCl2 in drinking water (2mM, 10 days) after which we compared intrarenal isotonic saline or phenol injection on MAP and RVR in CoCl2 preconditioned and control rats. HIF-1 alpha was determined by immunohistochemistry. Results: Unilateral intrarenal phenol induced immediate rise in MAP and contralateral RVR, and comparable HIF-1 alpha upregulation in both kidneys, consistent with bi-renal hypoxia. Removing the phenol-injected kidney immediately normalized MAP. Contralateral renal denervation had no effect on the rise in MAP, but abrogated the contralateral increase in RVR, suggesting mediation by increased efferent nerve activity. Strong renal staining for HIF-1a confirmed efficacy of CoCl2 preconditioning, and time-dependent increase in heme oxygenase-1 gene expression stabilization of HIFa. CoCl2 preconditioning prior to phenol reduced both delta MAP (+10 +/- 2 vs. +20 +/- 3%, P=0.015) and delta RVR (+21 +/- 11 vs. +90 +/- 26%, P=0.003). Conclusion: Acute RNH leads to renal vasoconstriction and increased renal HIF-1 alpha. Increasing HIF-1 alpha by CoCl2 preconditioning ameliorates intrarenal phenol-induced RNH and renal vasoconstriction.