bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 358: Excess Cardio-renal Damage in Aldosterone-producing Adenoma Patients With Somatic Mutations in the KCNJ5 Gene
Authors: Rossi Gian Paolo , Seccia Teresa M , Letizia Claudio , Cicala Maria Verena , Zinnamosca Laura , Kuppusamy Maniselvan , Cesari Maurizio , Sciomer Susanna , Mantero Franco , Pessina Achille C 
Published: July 2021

Aldosterone exerts detrimental cardiovascular (CV) effects, and aldosterone producing adenoma (APA) patients carrying somatic mutations in the KCNJ5 K+ channel (mutAPA) have higher plasma aldosterone concentration (PAC) than those wild-type (wtAPA).
We therefore investigated whether mutAPA patients develop a more prominent CV and renal damage than wtAPA patients.
From 250 consecutive PA patients, we identified 170 who had a diagnosis of APA by the 'four corners' criteria and high-quality echocardiographic data. Of them 106 with KCNJ5 sequencing information and long-term follow-up data could be compared for echocardiographic changes and eGFR (by CKD-EPI equation) according to presence (mutAPA, 18.8%) or absence (wtAPA, 81.2%) of the KCNJ5 mutations.
At baseline the mutAPA had lower eGFR (75±29 ml/min vs 84±20, p<0.05), and higher left ventricular mass index (LVMI, 61.9±21.4 mg/h2.7vs 49.5±11.3, p=0.001), PAC (48.9 [37.4-77.1] ng/dl vs 37.0 [24.9-48.5]), <0.0001), aldosterone-renin-ratio (ARR, 173.5 [92.2-229.6] ng/dl/ng/ml/h vs 144.3 [69.9-252.1], <0.0001), than the wtAPA patients. They were similar for blood pressure (BP) and need for antihypertensive medications. After adrenalectomy BP, PAC, ARR, and LVMI normalized in all groups, with no difference between mutAPA vs wtAPA.
Compared to the wild-type APA patients those with KCNJ5 mutations showed more prominent cardiovascular and renal damage, likely because of the higher PAC. However, the presence of these mutations did not compromise the chances of being cured from the hyperaldosteronism and the high blood pressure, or the regression of LVMI after adrenalectomy.
Abstract 399: Whole-Body Deletion of PPAR? in Mice Increases Sympathetic Nerve Activity
Authors: Yang Tianxin , Aoyagi Toshinori , Dowtown Maicy , Liu Mi , Whitehead Kevin , Jia Zhanjun 
Published: July 2021

PPARγ and sympathetic nerve activity (SNA) antagonistically regulate energy metabolism and cardiovascular function with the former promoting anabolism and vasorelaxation and the later favoring catabolism and vasoconstriction. However, the precise relationship between these two factors is not known. The present study examined the influence of PPARγ deletion on SNA. Systemic inactivation of PPARγ was
generated constitutively by using Mox2-Cre mice (MoxCre/flox) or inducibly by using the tamoxifen system (EsrCre/flox/TM). Radiotelemetry demonstrates consistent increases in resting daytime heart rate (HR) in both strains of null mice; this was associated a more than 10-fold increase in urinary epinephrine and norepinephrine levels. Subsequently, more detailed analysis of SNA was performed in Esr/flox/TM mice. In response to a bolus ip injection of the gangalion blocker pentolinium at 7.5 mg/kg, the decreases in HR and MAP were greater in the null mice than in the flox controls (delta HR:-254.2 vs. 92.3 beat/min; delta MAP: -67.8 vs. 33.4 mmHg). The HR decrease in response to the beta-blocker metaprolol (12 mg/kg, ip) was greater in the null mice than in the flox controls so was the MAP decease in response to the alpha1-blocker prazosin (1 mg/kg, ip). Baroreflex sensitivity (BRS) was assessed by the measurement of the HR responses to bolus injections of sodium nitroprusside (NP-BRS) or phenylephrine (PE-BRS). EsrCre/flox/TM mice displayed normal PE-BRS but blunted NP-BRS. Echocardiography under anesthesia demonstrated that the ejection fraction (EF) was 11% lower after administration of metaprolol contrasting to a drop of only 1.5% for the flox controls, in parallel with a greater reduction of HR in the KO mice. In contrast, the increase in HR following administration of the beta1 agonist dobutamine (0.8 mg/kg, ip) was less in the KO mice than in the flox controls. Together, we conclude: 1) PPARγ deletion causes the activation of SNA, 2) the parasympathetic nervous system may be unaffected, 3) the blunted response to dobutamine suggest suppressed beta1 receptor activity possibly as a result of compensatory response to sympathoactivation.
Abstract 453: Angiogenesis Inhibition-Induced Hypertension and Nephrotoxicity: Not All Antihypertensives are the Same
Authors: Lankhorst Stephanie , Kappers Mariëtte H , Van Esch Joep H , Smedts Frank M , Sleijfer Stefan , Danser Jan A , van den Meiracker Anton H 
Published: July 2021

Angiogenesis inhibition with the VEGF inhibitor sunitinib is an established anti-cancer therapy inducing hypertension and nephrotoxicity. Here we compared the effects of the endothelin antagonist (ET-R) macitentan (30 mg/kg/day, p.o; n=8), the calcium channel blocker (CCB) amlodipine (3 mg/kg/day, p.o; n=9), or the ACE-inhibitor captopril (3 or 12 mg/kg/day, s.c.; n=9) vs. no treatment (n=14) in sunitinib (26.7 mg/kg/day, p.o)-exposed hypertensive WKY rats. Treatment lasted 8 days; mean arterial pressure (MAP) was monitored telemetrically. At the end of the treatment period, 24-hour urine samples for protein and endothelin-1 (ET-1) measurements, and blood samples and kidneys for histological evaluation were collected.
With sunitinib, MAP increased from 94.7±0.9 mmHg to 125.8±1.5 mmHg (Δ31.1±0.9 mmHg, p<0.001). Co-administration of macitentan (Δ12.3±1.5 mmHg, p<0.001) or amlodipine (Δ11.4±1.7 mmHg, p<0.001) attenuated the sunitinib-induced MAP rise, whereas low and high captopril doses did not (Δ28.1±2.0 and Δ27.2±1.1 mmHg). With sunitinib, serum creatinine increased from 8.0±2.7 to 29.9±4.6 μmol/l (p<0.01) and proteinuria from 7.5±1.3 to 33.3±4.8 mg/day, p<0.05. Although no agent could prevent the sunitinib-induced rise in creatinine, the induced proteinuria was attenuated by 62% (p<0.01) with macitentan and by 88% with low and 114% (p<0.001) with high dose of captopril, while proteinuria increased by 56% (p=NS) with amlodipine. With sunitinib, urinary ET-1 increased from 3.3±0.5 to 4.8±1.0 pg/day (p<0.05). Macitentan and captopril abolished this increase. Renal histology revealed extensive glomerular ischemia and endothelial cell swelling. Concomitant with the decrease in proteinuria, glomerular intra-epithelial protein deposition decreased with macitentan and captopril.
In conclusion, ET-R antagonism and CCB effectively reduced the sunitinib-induced hypertension, whereas ACE-inhibition did not. Both ET-R antagonism and ACE inhibition diminished the sunitinib-induced proteinuria. Since ET-R antagonists are not yet available as anti-hypertensive agents, CCBs are preferred in angiogenesis inhibition-induced hypertension, while adding an ACE-inhibitor might be considered when proteinuria is also present.
Abstract 454: Hypertension Control by Decrease of Sympathetic Hyperactivity in SHR Rats: Comparison Between Renal Denervation and Dopamine ß-hydroxylase Inhibition
Authors: Pires Nuno , Igreja Bruno , Wright Lyndon , Soares-da-Silva Patrício 
Published: July 2021

Activation of the sympathetic nervous system has been described in the development and progression of systemic hypertension. Recently, catheter-based renal nerve ablation for treatment of drug-resistant hypertension has been developed. An alternative strategy for modulation of sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH), the enzyme that catalysis the conversion of dopamine (DA) to NE in sympathetic nerves.
Renal denervation was assessed in the rat by transient (90 sec) ischemia of renal tissues. Bilateral renal artery occlusion (RAO) was assessed in spontaneously hypertensive rats (SHR) to evaluate the effect of renal denervation on NE levels and blood pressure throughout a 28-day period. Oral treatment with the selective peripheral DβH inhibitor etamicastat (30 mg/Kg body weight) was performed in a second cohort of SHR and NE levels and blood pressure was assessed.
Renal denervation resulted in marked depletion of NE levels, selective for the renal sympathetic innervations, 5 days after RAO in renal cortex (16.5±7.7% of control values, P<0.0001). Decreased NE levels persisted up to 28 days after RAO (40.8±19.4% of control values, P<0.0001). No differences in left ventricle NE levels were observed. Renal denervation significantly decreased systolic blood pressure (SBP) 5 days (165±6 vs. 187±2 mmHg, P<0.05) and 14 days post-surgery (194±3 vs. 204±2 mmHg, P<0.05), but had no effect on heart rate. Systolic blood pressure recovered to basal values 28 days post-surgery. Likewise, etamicastat treatment resulted in a depletion of NE levels in both renal cortex (70.9±9.1% of control values, P<0.05) and left ventricle (55.8±3.9% of control values, P<0.01). Etamicastat treatment decreased SBP (228±7 vs. 174±9 mmHg, P<0.001) without effects on heart rate.
In conclusion, these results suggest that renal denervation and DβH inhibition similarly decreases sympathetic hyperactivity and high blood pressure in the SHR. Downregulation of sympathetic drive with DβH inhibitors may be useful in the treatment of hypertension.
Abstract 458: Relaxin Did Not Improve Angiotensin II-induced Target Organ Damage
Authors: Haase Nadine , Hupfer Stefan , Golic Michaela , Herse Florian , Qadri Fatimunnisa , Müller Dominik N , Dechend Ralf 
Published: July 2021

We investigated whether or not Relaxin ameliorates the hypertension induced damage to heart and kidney. We used double transgenic rats harboring both human renin and angiotensinogen genes (dTGRs). These rats develop moderately severe Hypertension but die of end-organ cardiac and renal damage by week 7. Untreated dTGRs had an around 50% mortality rate at 7 weeks. The heart shows necrosis and fibrosis, whereas the kidneys esemble the hemolytic-uremic syndrome vasculopathy.
We started Relaxin-treatment on four weeks old dTGR in low (26 μg/kg/d) and high dose (240 μg/kg/d) and age-matched SD rats. Blood-pressure- and albuminuria-measurements were monitored during the treatment period (three weeks). Seven weeks old animals were killed, hearts and kidneys were isolated and used for histochemical and quantitative TaqMan RT-PCR analysis. Systolic blood pressure increased progressively in untreated dTGRs from 161.6 ± 3.02 mmHg in week 5 to 225.3 ± 4.48 mmHg in week 7. Relaxin treatment had no significant influence on blood pressure (low dose 208.0 ± 5.51 mmHg and high dose 222.2 ± 5.60 mmHg at week 7 ) whereas SD rats were normotensive (106.3 ± 1.15 mmHg). Untreated (5.38 ± 0.13 mg/g) and Relaxin treated dTGRs (low dose 5.20 ± 0.18 mg/g and high dose 5.33 ± 0.29 mg/g) had similar cardiac hypertrophy indices (heart-to-body weight ratio), which were significantly higher compared with nontransgenic SD rats (2.90 ± 0.08 mg/g). BNP and CTFG mRNA expression in the hearts was significant higher in untreated dTGRs compared to SD rats. There were no differences in BNP and CTFG expression between untreated and Relaxin treated dTGRs. Relaxin treatment (low dose 78502 ± 16848 μg/day and high dose 43642 ± 10852
μg/day at week 7) did not ameliorate albuminuria compared with untreated dTGRs (57937 ± 6122 μg/day at week 7). Furthermore the treatment with Relaxin did not prevent matrix deposition in the heart and kidney of d TGRs. Finally, Relaxin treatment did not reduce mortality. Although survival was 52 %, in untreated dTGRs 36 % in low dose and 54 % high dose Relaxin treated dTGRs at week 7.
These data demonstrate that Relaxin did not improve angiotensin II-induced target organ damage.
Abstract 532: BIA 5-1058, Beyond Blood Pressure, Improves Cardiometabolism and Decrease End-organ Damage
Authors: Igreja Bruno , Pires Nuno M , Wright Lyndon C , Soares-da-Silva Patrício 
Published: July 2021

The sympathetic nervous system (SNS) can alter blood pressure (BP) by modulation of cardiac output, peripheral vascular resistance and renal function. One strategy for controlling sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH). BIA 5-1058 is a new peripheral DβH inhibitor that decreases NE levels in sympathetically innervated tissues and slows down the drive of SNS.
In order to evaluate the cardiometabolic effects of BIA 5-1058 in aged spontaneously hypertensive rats (SHR), 12 male SHR 50-week-old were randomized into two groups and one group was treated with BIA 5-1058 (30 mg/Kg/day) mixed in the diet for 9 weeks. During week 8 of treatment, blood pressure (BP) and heart rate (HR) were measured by tail cuff. At the end of the study, 24-hour urine and plasma was collected and organs weight was recorded.
BIA 5-1058 treatment reduced systolic BP (224±5 vs 183±8 mmHg, p<0.05) with no significant effect on HR. The heart/body weight ratio was decreased in animals treated with BIA 5-1058 (3.66±0.08 vs 3.45±0.04 mg/g, p<0.05), while the ratio kidney/body weight was unchanged. BIA 5-1058 significantly decreased plasma levels of the inflammatory markers CRP (447.3±7.1 vs 401.2±7.1 μg/ml, p<0.05), MCP-1 (90.3±10.5 vs 58.2±9.0 pg/ml, p<0.05) and ASAT (91.7±8.0 vs 67.3±4.0 U/l, p<0.05) but no significant effect on ALAT was observed. Concerning lipid metabolism, there was a decrease in plasma triglycerides (0.94±0.05 vs. 0.70±0.05 mmol/l, p<0.05) and free fatty acids levels (0.23±0.03 vs 0.11±0.01 mmol/l, p<0.05) induced by BIA 5-1058, while total cholesterol plasma levels was similar in both groups. BIA 5-1058 significantly reduced the 24-hour urine excretion (13.5±1.6 vs 8.9±1.2 ml, p<0.05), but had no significant effect in the amount of protein excreted in urine nor in the creatinine clearance rate.
In conclusion, the new DBH inhibitor, BIA 5-1058, presents cardiometabolic benefits in aged SHR.
Abstract 95: Glucagon Like Peptide-1 (GLP-1) Does Not Cause Vasodilation Even When Dipeptidyl Peptidase 4 (DPP4) is Inhibited
Authors: Devin Jessica K , Pretorius Mias , Billings Frederic T , Nian Hui , Brown Nancy J 
Published: July 2021

Glucagon-like peptide 1 (GLP-1) causes direct vasodilation in animal models. Dipeptidyl peptidase 4 (DPP4) inhibitors improve glycemic control in diabetic patients by preventing the degradation of GLP-1. The direct effect of GLP-1 in the human vasculature, and how it is altered by DPP4 inhibition, has not been reported. This study tested the hypothesis that intra-arterial infusion of GLP-1 causes dose-dependent vasodilation, and that DPP4 inhibition potentiates the forearm blood flow (FBF) response to GLP-1 by decreasing its degradation.

Eight healthy, non-obese (BMI<30 kg/m
2
) subjects, age 28-54 years old (3 female) participated in this double-blind, placebo-controlled crossover study. On study days separated by at least one week subjects received DPP4 inhibitor (sitagliptin 200 mg p.o.) or placebo, followed by infusion of GLP-1 in the brachial artery at graded doses (0.45-3.60 pmol/min) for 5 minutes per dose.

Sitagliptin significantly decreased plasma DPP4 activity (p<0.001 vs. placebo). Sitagliptin did not significantly affect baseline heart rate or baseline FBF. Baseline mean arterial pressure was significantly higher during sitagliptin than during placebo [87.13 ± 2.10 mmHg versus 84.75 ± 3.28 mmHg, p=0.037]. GLP-1 concentrations were significantly higher after sitagliptin (Left Figure; N=5). There was no effect of GLP-1 on FBF either in the presence or absence of sitagliptin. Moreover, there was no interactive effect of GLP-1 and sitagliptin on FBF (Right Figure).
GLP-1 does not cause vasodilation in healthy humans even when its degradation is inhibited. These data have implications for the cardiovascular effects of DPP4 inhibitors and GLP-1 receptor agonists.
Abstract 076: Urinary Exosomal Epithelial Sodium Channel And Sodium-chloride Cotransporter Measurement In Humans
Authors: MUSTAPHA TAOPHEEQ A , NWAZUE VICTOR , SCHEY KEVIN , SATISH RAJ , LUTHER JAMES M 
Published: July 2021

Sodium reabsorption in the distal nephron is tightly regulated in part by epithelial sodium channel (ENaC) and sodium chloride cotransporter (NCC), although non-invasive measure of these proteins in humans has not previously been feasible. We recently analyzed the urinary exosomal proteome and identified candidate targets for quantification of ENaC and NCC using targeted mass spectrometry.
To test the hypothesis that urinary exosomal ENaC and NCC are altered during renin-angiotensin-aldosterone system activation, we activated the endogenous RAAS using a low sodium diet (LS) in two separate studies. We provided 8 subjects LS diet (10mmol/day for 7days) to assess urinary protein excretion at 7 days (study 1) and longitudinally over the course of 1 week (study 2). Daily 24-hour urine was collected to monitor sodium balance, and spot urine samples were obtained each morning on days 0, 2, 4, and 6 of LS diet. Urinary exosomal ENaC-α, ENaC-γ, and NCC peptides were analyzed using targeted multiple-reaction-monitoring analysis quantified with stable-isotope peptide standards, and results were normalized to urine creatinine concentration.
In study 1, urinary ENaCγ increased after 8 days of LS diet (Figure A). In study 2, urinary exosomal ENaCγ (Figure B) and NCC peptides (Figure C) increased in a time-dependent manner during LS diet. These measures of urinary sodium channel expression may provide further insight into distal sodium reabsorption in human hypertension.
Abstract 088: Angiotensin Converting Enzyme 2 (ACE2) in the Kidney: Soluble ACE2 Restores Blood Pressure Regulation
Authors: Gurley Susan , Ortiz Melo David , Ortiz Natalie M , Prescott Jessica , Xu Katherine , Griffiths Robert , Burns Kevin 
Published: July 2021

Angiotensin converting enzyme 2 (ACE2) is a carboxypeptidase that metabolizes angiotensin II (AngII) to Ang(1-7). ACE2 can be cleaved by metalloproteinases to generate soluble ACE2 (sACE2), which remains catalytically active. The objective of this study is to determine if sACE2, acting in the kidney, could modulate the BP response to AngII infusion.Data from our kidney cross-transplant study using male (129/SvEv x C57BL/6)F
1
ACE2 KO and WT mice suggest that sACE2 can reach the urinary compartment even when not expressed in kidney cells. For these experiments, we generated 4 experimental groups: 1) WT, 2) Kidney ACE2KO, 3) Systemic ACE2KO, and 4) Total ACE2KO. Mean arterial pressures (MAP) were measured with radiotelemetry. AngII was infused chronically at 1ug/kg/min. Enzymatic activity was determined using an

ACE2-specific quenched fluorescent substrate assay. ACE2 protein in the urine was confirmed by western blots using a specific N-terminus antibody.

Total ACE2KO mice had an enhanced hypertensive response to AngII compared to WT (152±6 vs.144±7 mmHg;
p
=0.03). The presence of ACE2 in either kidney or systemic tissues restored MAPs to levels similar to WT (kidney ACE2KO 140±7mmHg, systemic ACE2 KO 140±5 mmHg, p<0.01 vs. total ACE2KO). However, Kidney ACE2KO mice had similar urinary ACE2 activity as systemic ACE2KO (76±32 and 108±52 RFU/ul/hr, respectively, p=NS). We confirmed this was ACE2 with immunoblotting of urine samples. As expected, we detected a 92kDa band in WT and systemic KO mice, which represents full length ACE2. A smaller band (70kDa) was present in the WT, systemic KO,
and
kidney KO groups, and absent in total KO mice. This likely represents sACE2. Moreover, the presence of the smaller band correlated with urine ACE2 activity and was associated with attenuated BPs.

Our studies demonstrate that the exaggerated hypertensive
phenotype seen in total ACE2 deficiency can be rescued when ACE2 is restored either in the kidney or in systemic tissues. Since the Kidney KO group demonstrated ACE2 activity and protein in the urine, we suggest that soluble ACE2 can be filtered in hypertensive renal injury and may provide an additional source of balance against upregulation of the RAS within the kidney, with the overall goal of regulating BP.
Abstract 200:

Low Dose Spironolactone Treatment Prevents Cardiac Diastolic Dysfunction, Oxidant Stress and Fibrosis in a Female Model of Obesity in Concert with a Modulation of Inflammation
Authors: Bostick Brian , Habibi Javad , McKarns Susan C , Ma Lixin , Rehmer Nathan T , Bender Shawn , Garro Mona , Meuth Alex , Nistala Ravi , Jia Guanghong , Sowers James R 
Published: July 2021

Obesity is a global epidemic with 1.5 billion overweight or obese people worldwide. The association of obesity and a high-fat/high-fructose Western diet (WD) markedly increases cardiovascular disease (CVD) particularly diastolic dysfunction in women. Few treatments exist for diastolic heart disease but, recent work implicates the mineralocorticoid receptor (MR) in inflammation, fibrosis and oxidant stress. We thus hypothesized that low-dose spironolactone (LDSp) could prevent diastolic dysfunction by reducing fibrosis, oxidant stress and inflammation. To test this hypothesis, we developed a female model of obesity induced diastolic dysfunction and examined preventative treatment with LDSp.
Four week-old C57BL6/J female mice were fed a WD with/without 1.0mg/kg/day of Sp (n=7 for each group). This dose of LDSp exerts no effect on blood pressure. After 16 weeks, we conducted detailed phenotypic analysis and assessed diastolic function by cardiac MRI. Immunohistochemistry was also done for cardiac oxidant stress, fibrosis, collagen content and insulin receptor (IRS-1) expression. Flow cytometry of heart tissue was utilized to examine inflammatory mechanisms.
We found WD feeding caused diastolic dysfunction that was prevented by LDSp (LV diastolic relaxation time 33.4 ± 1.2ms for WD, 20.6 ± 1.5ms for control and 24.3 ± 0.9ms for WD+LDSp, p <0.01). 3-nitrotyrosine staining showed significant cardiac oxidant stress with WD feeding that was ameliorated by LDSp. Cardiac fibrosis and the collagen 1:3 ratio were markedly increased with WD but prevented by LDSp. IRS-1 expression and phosphorylation were markedly reduced by WD feeding but not improved by LDSp. Flow cytometry showed evidence towards reduced M2 macrophage polarization with lower CD11b/CD301 double positive cells in WD fed hearts with trend toward improvement with LDSp.
These findings suggest WD induces cardiac diastolic dysfunction in females by increasing oxidant stress and fibrosis potentially mediated by deficiency in anti-inflammatory M2 macrophages. MR antagonism with spironolactone may prevent the decrease in M2 macrophage polarization reducing oxidant stress and fibrosis. This work supports a novel mechanism for spironolactone in treatment of WD induced heart disease.