bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 413: Hypothalamic Leptin Signaling And Blood Pressure Regulation In Obese Rats
Authors: Silva Carla G , Marin Rodrigo M , Katashima Carlos K , Marcondes Fernanda K , Saad Mario J 
Published: March 2022

The main function of Leptin is to inform the individual's nutritional status to hypothalamus, which in turn regulate food intake and energy expenditure. Such actions are orchestrated by phosphorylation of ObRb receptor on tyrosine 985 and 1138, the latter is related to metabolism and Stat3 pathway. Recently, it was demonstrated that high serum levels of leptin, which is seen in DIO, correlates strongly with hypertension. On the other hand, obese individuals have resistance to metabolic actions of leptin (satiety and thermogenesis).
To investigate the molecular hypothalamic pathways that characterize the selective activity of leptin on the effect of blood pressure (BP) increase, adults Sprague Dawley rats were fed with standard diet (SD) or HFD for three months and were submitted to chronic ICV injection of leptin (2μg/day) or saline (2μl) for 10 days. BP, food intake and energy expenditure were assessed before and after treatment.
SD+leptin group had reduced food intake from 109,48±8,48 to 57,3±7,04 kcal / day, increased energy expenditure from 85,6±1,87 to 94,4±0,58 kcal/day/kg^0,75 and consequently weight reduction of 15,25±3,54 g (P <0.001 all) which did not occur in HFD+leptin. However, both SD and HFD group, leptin increased BP of 10.44±0.12% (from 103,7±0,7 to 114,8±0,8 mmHg) and 14.22±1.9% (from 118,6±1,3 to 132,2±1,5 mmHg), respectively.
As expected, obese animals had elevated levels of serum leptin when compared to SD group (SD: 2,24±0,38 ng/dl and HFD: 9,88±1,82 ng/dl, p<0,05). Additionally, we evaluate the main activated signal pathways by leptin in hypothalamus. SD+leptin group showed a significant increase in activity of Stat3, Akt and in MAPK expression. However, HFD+leptin group manifested an increase only on the expression of MAPK pathway. Both SD and HFD leptin-treated groups had higher ObRb tyr985 phosphorylation, which was not observed with the pObRb tyr1138. It was possible to see that ObRb tyr985 dependent pathway is responsive to leptin in SD and HFD, and ObRb tyr1138 as well as the related protein Stat3 and Akt are reduced in obese animals. Therefore, it may be suggested that in HFD-induced obesity hypothalamic pathway ObRb tyr985 / MAPK, unlike the other pathways, is not resistent and can be related to cardiovascular actions of leptin.
Abstract 479: Ex vivo Equilibrium Analysis of the Renin-Angiotensin-System: Clinical Implications for Diagnosis and Treatment of Hypertension
Authors: Domenig Oliver , Schwager Cornelia , van Oyen Dunja , Poglitsch Marko 
Published: March 2022

The concentrations of angiotensins are maintained by equal rates of formation and degradation. The resulting steady-state angiotensin levels are affected by local molecular factors including tissue, endothelium or blood cell associated angiotensin receptors and processing enzymes as well as plasma soluble RAS components. The high concentration of the pro-hormone angiotensinogen in human plasma in combination with reported ranges for plasma renin activity result in a long-lasting and stable Ang I formation rate without significantly reducing angiotensinogen levels within several hours. This phenomenon can be utilized for the generation of an ex vivo situation that is characterized by significantly higher but stable angiotensin peptide levels. These ex vivo equilibrium angiotensin levels provide an integrated picture about plasma angiotensinase activities and therefore represent a powerful diagnostic tool for analyzing the systemic RAS in clinical samples. Moreover, these ex vivo levels remain stable over hours of incubation at 37°C and show a very high correlation (>90%) with angiotensin levels obtained by a state-of-the art sample collection procedure using complex inhibitor cocktails for stabilizing angiotensin peptides during blood collection.
The quantification of equilibrium angiotensin levels does not require any special sample collection procedures and can be applied to frozen serum and heparin plasma samples. It turned out that ex vivo angiotensin levels represent a measure for the consumption of angiotensin metabolites by the organism, therefore providing a powerful and versatile tool for assessing in vivo angiotensin signaling on the patient specific level enabling new diagnosis based rationales for anti-hypertensive therapies. The application of ex vivo RAS-Fingerprinting in clinical studies could substantially enhance our understanding of the regulation and physiology of the human RAS and could further lead to the development of powerful personalized approaches in the future treatment of hypertension.
Abstract 487: Cardiac Sympathetic Afferent Denervation Improves Cardiac Inflammation and Ameliorates Cardiac Remodeling in Post-MI Rats
Authors: Wang Hanjun , Mishra Paras K , Nandi Shyam S , Cornish Kurtis G , Zucker Irving H 
Published: March 2022

A recent study from our laboratory demonstrated that chronic and
selective cardiac sympathetic afferent denervation at the time of myocardial infarction (MI) by epicardial application of resiniferatoxin (RTX), a neuronal toxin capable of inducing rapid degeneration of transient receptor potential vanilloid 1 (TRPV1)-expressing afferent neurons and fibers, largely prevented the deleterious cardiac remodeling process 9-11 weeks post-MI. This included reduced cardiac hypertrophy, fibrosis and apoptosis. Here, we further investigated the effect of epicardial application of RTX during MI on cardiac extracellular matrix (ECM) remodeling at 10 weeks post-MI. Echocardiographic and morphologic data demonstrated that, compared to MI+vehicle, MI+RTX exhibited a significantly slower LV chamber dilation (6-week echocardiographic data: left ventricular end-diastolic diameter, 10.7 ± 0.2 vs. 9.6 ± 0.3 mm; left ventricular end-systolic diameter: 8.8 ± 0.2 vs. 7.8 ± 0.3 mm; MI+vehicle vs. MI+RTX, n=18, P<0.05). To further explore its molecular mechanism, we used zymography to evaluate the effect of RTX application on the matrix metalloproteinase (MMP) activity, which is responsible for degrading ECM and cardiac dilation after MI. Our preliminary data show that MMP9 activity was increased by 3.9 times in the peri-infarct myocardium post-MI compared to sham. This was largely abolished by RTX application (peri-infarct area: 3.9 ± 0.5 vs. 1.7 ± 0.4, MI+vehicle vs. MI+RTX, n=3, p=0.03). We further investigated the effect of RTX application on MI-induced cardiac inflammation, which has been reported as an upstream mechanism triggering MMP activation post-MI. Our data show that cardiac TNF alpha levels are markedly increased in the peri-infarct or remote myocardium of post-MI rats, which was largely abolished by RTX application during MI (TNF alpha levels in peri-infarct area: 214.2 ± 13.1 vs. 647.5 ± 45.1 vs. 357.3 ± 25.4 pg/mg protein, sham+vehicle vs. MI+vehicle vs. MI+RTX, n=5/each, p<0.05). These data suggest that cardiac sympathetic afferent denervation during MI exerts a local anti-inflammatory effect and reduces the ECM remodeling by preventing excessive MMP activation in post-MI rats.
Abstract 505: Effects of Etamicastat, a Selective Peripheral Dopamine-β-Hydroxylase Inhibitor, Upon Stress-induced Changes in Blood Pressure in the SHR
Authors: Igreja Bruno , Pires Nuno , Wright Lyndon C , Soares-da-Silva Patricio 
Published: March 2022

Stressors induce an overactivation of the sympathetic nervous system (SNS) that triggers several changes in the body as a response to stress. These changes include vasoconstriction and increase in heart rate, which results in raised blood pressure (BP). Etamicastat is a selective dopamine-β-hydroxylase (DβH) inhibitor that decreases norepinephrine levels in peripheral sympathetically innervated tissues.
Cardiovascular parameters were measured after a single oral administration of etamicastat (30 mg/kg) 9 h post-administration in male spontaneously hypertensive rats (SHR) by radio-telemetry or tail-cuff recording. Telemetered recording was performed in both restrained and unrestrained animals.
Etamicastat treatment had no effect on heart rate (HR, beats/min) in any recording method. HR measured in unrestrained SHR instrumented with radio-telemetry probes (305±5) consistently yielded HR values significantly lower than restrained animals (362±11) or those recorded by tail-cuff (393±7). On the other hand, single-dose oral etamicastat treatment decrease in mean arterial pressure (MAP, mm Hg) was -14.0±2.0 from 153.3±4.0 in telemetered unrestrained animals, -26.1±5.1 from 182.8±6.4 in telemetry-implanted restrained SHR and -47.9±7.0 from 183.4±9.5 recorded by tail-cuff method. In addition, a power spectral analysis was performed to evaluate BP variability (BPV), in SHR implanted with radio-telemetry probes, at high frequency (HF: 1-2 Hz), low frequency (LF: 0.2-0.6 Hz) and very low frequency (VLF: 0.02-0.2 Hz). The stressor (i.e., cage restrainement) increased the ratio LF/HF-BPV in untreated SHR from 5.23±1.24 to 10.03±1.75, which results from the activation of the SNS. Treatment with etamicastat decreased the ratio LF/HF-BPV in stressed SHR from 10.03±1.75 to 4.46±0.68 and in non-stressed SHR from 5.23±1.24 to 2.23±0.39.
In conclusion, etamicastat treatment reduces (1) high BP in SHR, (2) the stress-induced increase in SNS drive and (3) the stress-induced increase in BP.
Abstract 526: Blood Pressure in the SHR Following Renal Denervation or Etamicastat, a Novel Dopamine-β-Hydroxylase Inhibitor
Authors: Pires Nuno , Igreja Bruno , Moura Eduardo , Wright Lyndon C , Serrão Paula , Soares-da-Silva Patricio 
Published: March 2022

Overactivity of the sympathetic nervous system plays an important role in the development and progression of hypertension. Catheter-based renal nerve ablation for treatment of drug-resistant hypertension has been recently 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 to NE in sympathetic nerves.
Renal denervation (RDN) was performed in spontaneously hypertensive rats (SHR) to evaluate the effect of RDN on NE levels and blood pressure throughout a 28-day period. Chronic oral treatment with the peripheral selective DβH inhibitor etamicastat (30 mg/kg/day) was performed in another cohort of SHR.
RDN and chronic oral treatment with etamicastat did not affect renal function, as assessed by urinary protein, creatinine and urea levels. RDN significantly decreased mean arterial blood pressure (MAP, in mm Hg) 7 days post-surgery (139±6, P<0.01) versus baseline values (158±6). A gradual MAP return to high baseline levels was observed overtime; 139±7 at day 14, 151±12, at day 21 and 155±12 at day 28 after RDN. Treatment with etamicastat decreased baseline MAP (150±5) in a sustained and significant (P<0.01) manner at all-time points: 141±5 at day 7, 139±5 at day 14, 138±5 at day 21 and 143±5 at day 28. At day 28, NE levels (in pmol/mg tissue) in renal tissue were significantly decreased in both RDN (0.12±0.08, P=0.001) and etamicastat-treated group (0.48±0.04, P=0.01) as compared to vehicle group (0.88±0.13). On the other hand, left ventricle NE levels were decreased only after treatment with etamicastat (1.24±0.12, P=0.04) but not in the RDN group (2.53±0.24, P=0.9) when compared to controls (2.59±0.58).
It is concluded that RDN produces transitory decreases in MAP, whereas prolonged down regulation of sympathetic drive with the DβH inhibitor etamicastat results in sustained decreases in MAP.
Abstract 666: RNAi Therapeutics Targeting Human Angiotensinogen (hAGT) Ameliorate Preeclamptic Sequelae in an Established Transgenic Rodent Model for Preeclampsia
Authors: Haase Nadine , Foster Don , Bercher Julia , Milstein Stuart , Golic Michaela , Charisse Klaus , Rugor Julianna , Kuchimanchi Satya , Przybyl Lukasz , Bettencourt Brian , Müller Dominik N , Hinkle Greg , Dechend Ralf 
Published: March 2022

Preeclampsia, a disorder with the hallmark features of new-onset hypertension and proteinuria beginning after 20 weeks of gestation, affects 5% of pregnancies in industrialized nations. It is a major cause of fetal and maternal morbidity/mortality. Several studies have demonstrated that angiotensinogen is involved in the pathogenesis of the disease; however, treatment with ACE Inhibitor or AT1 Receptor blocker is contraindicated due to fetal toxicity.
RNAi therapeutics are highly potent mediators of gene-specific silencing. We tested a human angiotensinogen (hAGT)-specifc siRNA, conjugated to triantennary GalNAc, for the ability to ameliorate symptoms of preeclampsia in an established rat model, without affecting the fetus. Transgenic rats expressing hAGT and human renin (hREN) were crossed to produce a model of preeclampsia (PE rat) in the dams. Beginning on day 3 of gestation, transgenic hAGT dams were dosed subcutaneously with 10 mg/kg siRNA every third day through gestation day 15. Mean blood pressure was continuously recorded by radiotelemetry and 24 hour urine samples were collected in metabolic cages at day 18 of gestation. Rats were euthanized at day 21 of gestation.
Treatment with the GalNAc-conjugated siRNA reduced the spike in blood pressure seen on gestation day 13 and lasted through study termination (MAP on day 16 of gestation: 155.1 ± 1.4 mmHg untreated vs. 138.4 ± 1.8 mmHg treated). Proteinuria was ameliorated (21.7 ± 3.1 mg/d untreated vs. 2.7 ± 0.6 mg/d treated) and levels of agonistic autoantibodies against the angiotensin receptor AT1 were reduced below the limit of detection. Fetal and uteroplacental unit weights increased with RNAi therapy, demonstrating a reduction in intra-uterine growth restriction (brain to liver ratio (0.95 ± 0.04 untreated vs. 0.73 ± 0.02 treated). mRNA levels of hAGT were reduced to background levels in the liver, but were not affected in the placenta, which is of fetal origin.
Our data show that an RNAi therapeutic targeting hAGT ameliorates the clinical sequelae of preeclampsia in a transgenic rat model and improves the outcome of the fetus.
Abstract 003: Selective Splenic Denervation Inhibits the Egression of T Cell From Spleen, Induced by Angiotensinii, and Protects From Hypertension
Authors: Carnevale Daniela , Perrotta Marialuisa , Pallante Fabio , Fardella Valentina , Iacobucci Roberta , Cutrone Antonella , Lembo Giuseppe 
Published: March 2022

It has been elucidated that immunity plays a role in both etiology and target organ damage of hypertension (HTN) induced by different stimuli (AngII, salt, etc.). In the very last year, we found that AngII activates a neuroimmune pathway, passing through the celiac ganglion (CG). Here, we aimed at dissecting this neuroimmune drive, in order to examine the specific role of splenic sympathetic nerve activity (SSNA) in the onset of HTN.
We tested the hypothesis that chronic AngII infusion activates SSNA, in order to recruit T cells. In splenic nerve bundles, we recorded SSNA with a bipolar electrode in mice infused with AngII for 3 days (before BP increase) or with vehicle. SSNA was higher in AngII mice, as compared to vehicle (355±18 vs 141±24 spikes/10min) (p<0.001). We next selectively denervated splenic nerve (SDN) by thermoablation, in order to evaluate whether the AngII-induced increase in SSNA could be detrimental for activation of immunity and onset of HTN. We confirmed the efficacy of SDN by injecting a retrograde neurotracer in the spleen, which was effective in labeling the CG neurons only in sham mice and not in SDN. Furthermore, the tyrosine hydroxylase innervation in the splenic artery of SDN mice was reduced as compared to sham, as well as noradrenaline content in the spleen (sham: 1000±274 vs SDN: 172±44 pg/mg tissue, p<0.01). After 28 days from AngII infusion, SDN mice were protected from HTN as compared to sham (SBP: 107±2 vs 129±3 mmHg) and vehicle treated mice (veh-sham 110±1 vs veh-SDN 106±1 mmHg) (p<0.001). Moreover, SDN hampered the T cell egression from splenic reservoir, evaluated as CD3+ cell content, induced by AngII. In the end, we assessed the amount of T cells infiltration, finding that AngII-SDN mice were significantly protected in aorta (CD8+/mm2: veh-sham 197±17; veh-SDN 143±14; AngII-sham 293±36*; AngII-SDN 156±8) and kidney (CD8+/mm2: veh-sham 40±4; veh-SDN 34±4; AngII-sham 231±27*; AngII-SDN 29±5), *p<0.01 vs all other groups. Similar results were found for CD4+ infiltrates.
Our results demonstrate that the neuroimmune drive activated by chronic AngII infusion is mediated by the activation of the SSNA, converging into T cells activation in the spleen and their egression toward target organs, where they contribute to the onset of HTN.
Abstract 024: The Direct Renin Inhibitor Aliskiren Improves Vasodilation and Endothelial Function in Resistance Arteries from Diabetic and Hypertensive Patients
Authors: Savoia Carmine , De Ciuceis Carolina , Arrabito Emanuele , Paini Anna , Sada Lidia , Nicoletti Carmine , Carletti Raffaella , Rizzoni Damiano , Muiesan Maria Lorenza , Di Giioia Cira , Agabiti Rosei Enrico , Volpe Massimo 
Published: March 2022

We previously demonstrated that the direct renin inhibitor aliskiren (ALK) significantly reduced the remodeling of subcutaneous resistance arteries of hypertensive patients as compared to the angiotensin-converting enzyme inhibitor ramipril (RAM). Here we questioned whether endothelial function of resistance arteries would improve after 1 year of blood pressure (BP) control with ALK or RAM.
Sixteen diabetic patients with mild essential hypertension were randomized to ALK (150-300 mg once daily, n=9) or RAM (5-10 mg once daily, n=7). Subcutaneous resistance arteries were dissected from gluteal biopsy and mounted on a pressurized micromyograph. Endothelium-dependent and -independent relaxations were assessed by concentration-response curves to acetylcholine (1 nM to 100 μM) and sodium nitroprusside (10 nM to 1 mM) respectively, in arteries pre-contracted with norepinephrine (10 μM). Carotid-femoral pulse wave velocity (PWV) was assessed by applantion tonometry. Forearm flow mediated dilation (FMD) was assessed by ultrasounds. The expression of P-eNOS/e-NOS and the markers of oxidative stress nitrotyrosine and LOX-1 were assessed by immunohistochemistry in resistance arteries.
Patients were similar for age, sex, BMI and glycemic and metabolic control. Systolic BP was significantly and equally reduced by both ALK and RAM (153±8.9 mmHg reduced to 128±7.3 mmHg and 151±10.6 mmHg reduced to 121±12.1, respectively, P<0.01) whereas diastolic BP was significantly reduced only in ALK-treated but not in RAM-treated patients (94.2±7.17 mmHg reduced to 81.4±6.31 mmHg, P<0.01; and 84.7±12.22 reduced to 78.6±7.48, NS, respectively). PWV and FMD were similar in both groups before and after treatment.
Endothelium-dependent vasodilation was improved only by ALK (max dilation 92.5±3.8% vs 50.5±14%, P<0.05) but not by RAM (max dilation 72.9±5.6% vs 61.8±14.5%, NS). Endothelium-independent vasodilation was similar in all the groups. Only ALK increased P-eNOS/eNOS expression (+44% vs before treatment, p<0.05). The markers of oxidative stress were similar in both groups before and after treatment.
In conclusion ALK improved endothelial function and induced vasodilation in resistance arteries from diabetic and hypertensive patients.
Abstract 136: Mineralocorticoid Receptor Activation In Macrophages Mediates High Fat/high Sucrose Induced Vascular Stiffness in Female Mice
Authors: Manrique Camila , Sowers James , Aroor Annayya , Jia Guanghong , Habibi Javad , Mortensen Richard M , Lastra Guido 
Published: March 2022

Enhanced mineralocorticoid receptor (MR) activation promotes vascular dysfunction and remodeling. We studied the role of MR activation in perivascular adipose tissue (PVAT) macrophages in the development of high-fat/high-fructose diet (“Western Diet”, WD) induced vascular stiffness in female mice.
Myeloid MR KO mice (MyMRKO) were fed a WD for 8 weeks (n=3). MyMRKO female mice (n=2) were infused with aldosterone (Aldo) for 3 weeks. Aortic stiffness was assessed in vivo by pulse wave velocity and ex vivo by atomic force microscopy. Vascular reactivity was studied in aortic rings.
MyMRKO mice were protected from Aldo and WD induced aortic stiffness and had greater endothelial-dependent and independent vasodilation compared to littermates (Fig. 1, 2).
Immunohistochemistry suggested decreased peri-aortic fibrosis and macrophage infiltration in Aldo infused MyMRKO (Fig.1).
We conclude that MR KO in myeloid cells protects against WD and Aldo-induced vascular stiffness in female mice. Our data support a role for MR activation in PVAT macrophages in the pathogenesis of WD-induced vascular dysfunction.
Abstract P065: Pacemaker Tapping Maneuver in the Treatment of Orthostatic Hypotension
Authors: Ashangari Chandralekha , Suleman Amer 
Published: March 2022

A 77 year old man was referred to us with fainting spells especially after standing/walking few steps. Initially he went to a neurologist and ENT specialist where the cause could not be determined and symptoms continued. During annual physical, he noticed that his blood pressue dropped when he stood up suddenly. He had severe fainting spells and was placed pacemaker in him.However,pacemaker did not make a huge difference.Blood Pressure monitoring was done and noticed 50 mmHg drop upon standing. Pacemaker was changed to constant pacing where his dizziness continued but he had no falls. He had periodic vision problems, numbness in fingers and legs, digestive problems, stomach issues and balance problems. His tilt table test showed orthostatic hypotension.
Medical management (florinef, mestinone, midodrine) did not relieve his symptoms .Pacemaker sensor was turned on and made more sensitive that after he taps on the pacemaker, heart rate increases for 10 minutes. We told him to tap on pacemaker whenever he is dizzy and see if there is any improvement in orthostatic symptoms. The later treatment had made a huge difference; he is practically asymptomatic and was very much satisfied with his current health. He is using the tapping maneuver 4-5 times a day and his fainting disappeared and no syncope.
First time our case report on Pacemaker tapping demonstrated significant improvement in treating symptoms of orthostatic hypotension.