Significant Elevation Of Blood Pressure Research Articles

Sacubitril/valsartan alleviates sunitinib-induced cardiac fibrosis and oxidative stress via improving TXNIP/TRX system and downregulation of NF-ĸB/Wnt/β-catenin/SOX9 signaling

We aimed in this study to investigate the possible cardioprotective effects of sacubitril/valsartan against sunitinib-induced cardiac fibrosis (CF) and oxidative stress via targeting thioredoxin-interacting protein/thioredoxin (TXNIP/TRX) system and nuclear factor-kappa B (NF-κB)/Wingless-related MMTV integration site (Wnt)/β-catenin/Sex-determining region Y box 9 (SOX9) signaling. CF was induced in male Wistar albino rats by cumulative dose of sunitinib (300 mg/kg, given over 4 weeks as: 25 mg/kg orally, three times a week), which were co-treated with sacubitril/valsartan (68 mg/kg/day, orally) for four weeks. Significant elevation in blood pressure, cardiac inflammatory and fibrotic markers besides cardiac dysfunction were observed. These alterations were associated with disruption of TXNIP/TRX system, upregulation of NF-κB/Wnt/β-catenin/SOX9 pathway along with marked increase in lysyl oxidase (LOX) and matrix metalloproteinase-1 (MMP-1) expressions and extensive deposition of collagen fibers in cardiac tissues. Luckily, sacubitril/valsartan was able to reverse all of the aforementioned detrimental effects in sunitinib-administered rats. These findings illustrate a potential role of sacubitril/valsartan in alleviating CF and oxidative stress induced by sunitinib via antioxidant, anti-inflammatory and antifibrotic properties. These remarkable effects of sacubitril/valsartan were mediated by its ability to improve TXNIP/TRX system and downregulate NF-κB/Wnt/β-catenin/SOX9 signaling in addition to decreasing LOX and MMP-1 expressions in cardiac tissues. In summary, this study highlights sacubitril/valsartan as a potential therapeutic agent in mitigating CF and oxidative stress especially in cancer cases treated with sunitinib.

The Role of Opioid Receptor Antagonists in Regulation of Blood Pressure and T-Cell Activation in Mice Selected for High Analgesia Induced by Swim Stress.

Opioid peptides and their G protein-coupled receptors are important regulators within the cardiovascular system, implicated in the modulation of both heart and vascular functions. It is known that naloxone-an opioid antagonist-may exert a hypertensive effect. Recent experimental and clinical evidence supports the important role of inflammatory mechanisms in hypertension. Since opioids may play a role in the regulation of both blood pressure and immune response, we studied these two processes in our model. We aimed to evaluate the effect of selective and non-selective opioid receptor antagonists on blood pressure and T-cell activation in a mouse model of high swim stress-induced analgesia. Blood pressure was measured before and during the infusion of opioid receptor antagonists using a non-invasive tail-cuff measurement system. To assess the activation of T-cells, flow cytometry was used. We discovered that the non-selective antagonism of the opioid system by naloxone caused a significant elevation of blood pressure. The selective antagonism of μ and κ but not δ opioid receptors significantly increased systolic blood pressure. Subsequently, a brief characterization of T-cell subsets was performed. We found that the blockade of μ and δ receptors is associated with the increased expression of CD69 on CD4 T-cells. Moreover, we observed an increase in the central memory CD4 and central memory CD8 T-cell populations after the δ opioid receptor blockade. The antagonism of the μ opioid receptor increased the CD8 effector and central memory T-cell populations.

A pharmacological and toxicological biochemical study of cardiovascular regulatory effects of hibiscus, corn silk, marjoram, and chamomile

Hypertension is one of the most typical causes of morbidity and mortality. The present study investigated the possible antihypertensive cardiovascular effects of an herbal mixture extract of Hibiscus, Corn silk, Marjoram, and Chamomile. HPLC analysis of the water extract prepared from the aerial parts of four plants and their mixture was done to detect the most predominant compounds. A safety study was done prior to the efficacy study to determine the dose and ensure the extract's safety in female rats. Hypertension was induced in ovariectomized and non-ovariectomized rats by oral administration of 50 mg/kg of LName for 30 days; the hypertensive rats were classified into non-ovariectomized and ovariectomized untreated groups, treated groups with high and low doses of the mixture(150,300 mg/kg) given to ovariectomized and non-ovariectomized hypertensive groups and a standard group treated with angiotensin-converting enzyme inhibitor. The untreated group showed significant elevation of blood pressure, heart rate, cholesterol, triglycerides, malondialdehyde, cyclic adenosine monophosphate, angiotensin-converting enzyme, C-reactive protein, and significantly lowered reduced glutathione, high-density lipoprotein, and endothelial nitric oxide synthase. Treatment significantly counteracted the effects of L Name. The mixture provides a promising natural cardiovascular regulating supplement owing to its high contents of flavonoids.

Protocolo diagnóstico y terapéutico de las crisis hipertensivas en urgencias

Hypertensive urgencies and hypertensive emergencies (HE) are categorized as hypertensive crises. They are different because in the first, there is a significant elevation in blood pressure (BP) without target organ damage (heart, brain, kidney, retina, and arteries) and in the second there is. The cardiovascular risk in a hypertensive urgency is not particularly high whereas in an HE, it is life-threatening and requires a more aggressive decline in BP figures, inpatient management, and intravenous medication.Hypertensive urgencies can be managed on an outpatient basis in most cases; the treatment route of administration is oral and the aim is achieving a reduction in BP below 160/100mm Hg over hours or days. A correct diagnosis that suitably fits each case is key in order not to underdiagnose cases of HE and also to avoid iatrogenesis in hypertensive crises.

Abstract 086: Examining The Role Of Bacterial Extracellular Vesicles In Host Blood Pressure Regulation

We have demonstrated that disruption of the normal gut microbiota, termed gut dysbiosis, is an underlying cause of hypertension (HT). However, the mechanisms by which the microbiota influences host blood pressure (BP) are largely unknown. We hypothesized that extracellular vesicles (EVs) released by gut microbiota gain access to the circulation, deliver cargo to host tissues involved in BP regulation, inducing inflammation and ultimately HT. Bacterial EVs (bEVs) were isolated from cecal content of spontaneously hypertensive stroke prone rats (SHRSP) or Wistar-Kyoto rats (WKY) by size exclusion chromatography. BEV cargo including small RNAs, LPS, and 16s rRNA, was assessed. To directly examine the role of bEVs on BP, purified WKY and SHRP bEVs were transplanted to recipient rats of the same and opposite strain by oral gavage (1.5x10 10 EVs/rat) every other day for 4 weeks. The inflammatory status of ileum and brain were assessed by flow cytometry. Global analysis of small RNA cargo of bEVs was found to be significantly different between WKY and SHRSP (n=6, p=0.001). BEVs from SHRSP contained significantly greater LPS as compared to those from WKY (49 vs 38 EU/ml, n=6, p=0.01). EVs isolated from plasma of both strains contained bacterial 16s rRNA, demonstrating bEVs gain access to host circulation. Finally, as compared to WKY rats receiving WKY bEVs, WKY rats transplanted with SHRSP bEVs had 1) significant elevations in BP at 4 weeks (176 mmHg vs 150 mmHg, n=6, p<0.01), 2) significant reduction of T regulatory cells in ileum (49% vs 58%, n=6, p<0.05) and brain (9% vs 18%, n=6, p<0.05), and 3) significant increases in macrophages in ileum (39% vs 6%, n=6, p<0.001) and microglia in brain (24% vs 8%, n=6, p<0.05). SHRSP rats transplanted with WKY bEVs had significantly lower BP at 4 weeks (160 mmHg vs 175 mmHg, n=6, p<0.05), reduced macrophages in ileum (5% vs 42%, n=6, p<0.001) and microglia in brain (5% vs 29%, n=6, p<0.01), as compared to SHRSP receiving SHRSP bEVs. In conclusion, BEVs originating from the dysbiotic gut of hypertensive SHRSP rats carry distinct cargo, reach the host circulation, and are involved in host gut- and neuroinflammation and HT. These studies identify bEVs as a previously unrecognized mechanism for microbiota-host interaction involved in BP regulation.

Chronic Effects of Apelin on Cardiovascular Regulation and Angiotensin II-Induced Hypertension.

Apelin, by stimulation of APJ receptors, induces transient blood pressure (BP) reduction and positive inotropic effects. APJ receptors share high homology with the Ang II type 1 receptor; thus, apelin was proposed to play a protective role in cardiovascular disease by antagonizing the actions of Ang II. In this regard, apelin and apelin-mimetics are currently being studied in clinical trials. However, the chronic effect of apelin in cardiovascular regulation has not been fully investigated. In the current study, blood pressure (BP) and heart rate (HR) were recorded using a telemetry implantation approach in conscious rats, before and during chronic subcutaneous infusion of apelin-13, using osmotic minipumps. At the end of the recording, the cardiac myocyte morphology was examined using H&E staining, and cardiac fibrosis was evaluated by Sirius Red in each group of rats. The results demonstrated that the chronic infusion of apelin-13 did not change either BP or HR. However, under the same condition, the chronic infusion of Ang II induced significant BP elevation, cardiac hypertrophy, and fibrosis. Co-administration of apelin-13 did not significantly alter the Ang II-induced elevation in BP, changes in cardiac morphology, and fibrosis. Taken together, our experiments showed an unexpected result indicating that the chronic administration of apelin-13 did not alter basal BP, nor did it change Ang II-induced hypertension and cardiac hypertrophy. The findings suggest that an APJ receptor biased agonist could be a better therapeutic alternative for treatment of hypertension.

Excess Global Blood Pressure Associated With Fine Particulate Matter Air Pollution Levels Exceeding World Health Organization Guidelines

Excess Global Blood Pressure Associated With Fine Particulate Matter Air Pollution Levels Exceeding World Health Organization Guidelines

Blood pressure patterns of hypertensive disorders of pregnancy in first and second trimester and contributing factors: a retrospective study

We aimed to investigate the blood pressure (BP) patterns of hypertensive disorders of pregnancy (HDP) in the first and second trimesters and its contributing factors, which may help us understand its pathogenesis and identify this group of diseases in a timely manner. SPSS 21.0 was used to describe the BP patterns of 688 HDP as well as 2050 normotensive pregnancies respectively before 28 gestational weeks, and the repeated measurements and two-way ANOVA was used to decide the significant difference of blood pressure in the same period. The results revealed blood pressure in HDP underwent a mid-pregnancy drop as normal while the drop was unremarkable in advanced-age or obesity pregnancies. Besides, we found blood pressure was significantly higher in patients during first and second trimesters, not just after 20 weeks. In conclusion, our study indicated a significant elevation of blood pressure had appeared before 20 weeks in HDP pregnancies, we should pay more attention to monitoring blood pressure before 20 weeks, especially for advanced age and obese women. IMPACT STATEMENT What is already known on this subject? Gestational hypertension, preeclampsia as well as eclampsia were supposed to have the similar pathogenesis and their time of onset was strictly defined after 20 gestational weeks, while the reason for the time point was not clear. On the other hand, higher blood pressure in the first trimester was associated with increasing risk of developing HDP, while the blood pressure(BP) pattern of normal as well as HDP pregnancy was still controversial, especially for the existence of mid-trimester drop. What do the results of this study add? Firstly, we found blood pressure in HDP underwent a mid-pregnancy drop as normal while the BP drop was unremarkable in advanced-age or obesity pregnancies. Secondly, we noticed the blood pressure in HDP was significantly higher than the normal before 20 weeks, which had not been proved before. What are the implications of these findings for clinical practice and/or further research? On one hand, both the abnormal elevation of BP and the development of the placenta happened in the first trimester suggested toxic substances caused by the defective placenta played a vital role in the onset and aggravation of HDP, which guides us to pay more attention to monitor blood pressure before 20 weeks, especially for advanced age and obesity pregnancies. On the other hand, our results about BP patterns in HDP help us identify this group of diseases in time which can contribute to a better outcome.

PS-BPB05-1: DUAL DISRUPTION OF ENDOTHELIAL NITRIC OXIDE SYNTHASE AND APOE GENE ACCELERATES KIDNEY FIBROSIS AND AGING AFTER INJURY

Objective: Advances in medical science have made it possible to control diseases such as cancer, autoimmune diseases, and infectious diseases, extending the lifespan of affected people around the world. On the other hand, the number of patients with Chronic Kidney Disease (CKD) is increasing worldwide, and hypertension is a key factor. Suppression of CKD is important for extending healthy life expectancy. In this study, we will clarify the effects of the interaction between hypertension and atherosclerosis on renal fibrosis and aging. Design and method: Wild type (WT) mouse, apolipoprotein E-/- (ApoE KO) mouse, and endothelial nitric oxide synthase (eNOS)-/- ; ApoE-/- (DKO) mouse were obtained by crossing eNOS+/- mouse and ApoE+/- mouse. Unilateral ureteral obstruction (UUO) was performed on 8–10 weeks old male mice after blood pressure and lipid profile were measured. Mice were sacrificed 10 days after UUO. The degree of renal tubular injury, fibrosis and kidney senescence were evaluated. Results: DKO mice exhibited the most pronounced blood pressure and lipid abnormalities among the three groups, with a significant elevation of blood pressure, total cholesterol, and low HDL cholesterol compared to WT mice. DKO mice manifested elevated blood pressure, higher total cholesterol and lower HDL than WT mice. Compared with WT mice, ApoE KO and DKO mice showed sustained kidney injury molecule-1 expression and kidney fibrosis was significantly higher in ApoEKO and DKO mice. mRNA expression of genes related to kidney fibrosis was the highest in DKO mice. The mRNA expression of Zinc alpha2 Glycoprotein and heme oxygenase-1 were significantly decreased in DKO mice. Furthermore, mRNA expression of p53, p21 and p16 were increased both in ApoEKO and DKO mice, with DKO mice being the highest. Senescence associated beta-gal positive tubule area was significantly increased in DKO. Increased DNA damage and target of rapamycin autophagy spatial coupling compartments (TASCCs, Sci Transl Med. 2019;11(476):eaav4754. J Clin Invest. 2019;129(11):4797- 4816.) formation was found in DKO mice. Conclusion: Mice at high risk for cardiovascular disease developed kidney fibrosis and aging even in the young mice after injury. Vulnerability to oxidative stress due to endothelial cell dysfunction promotes fibrosis and aging. Managing lifestyle-related diseases including hypertension from a young age is important for CKD prevention.

Abstract P248: Estrogen Replacement Mitigated Blood Pressure Elevation Via Suppression Of Sodium Cotransporter In Angiotensin Ii-infused Ovariectomized Female Rats

Introduction: Female rats with lower proximal sodium transporters are known to excrete natriuresis faster than male rats. However, it is not sure whether the protective effect would be conserved in menopausal rats. Hypothesis: We assessed the hypothesis that ovariectomy would change renal sodium transporters in female rats and the estrogen supplementation could reverse angiotensin II (ANGII)-induced changes in renal sodium transporters and natriuresis. Methods: Six-week female Sprague Dawley rats (n=22) were ovariectomized, and half of them (n=11) were treated with estradiol 2 weeks later for 4 weeks, and then ANGII (n=14) or vehicle (n=8) was infused via osmotic minipumps for 2 weeks. Blood pressure (BP) was measured by the tail-cuff sphygmomanometer. Blood, urine, and kidney samples were collected. Results: The ANGII induced significant BP elevation in ovariectomized (OVX) and OVX with estradiol (OVX+E) rats. OVX affected elevating BP even in the sham rats. Albuminuria significantly increased in ANGII-infused OVX rats and did not change in ANGII-infused OVX+E rats. Urine sodium was significantly decreased in ANGII-infused OVX rats, while it increased in ANGII-infused OVX+E rats. Sodium transporters in the proximal tubule (sodium-hydrogen exchange 3, sodium phosphate cotransporter) were not different between OVX and OVX+E irrespective of ANGII infusion. Among the distal tubule transporters (α/β/γ-epithelial sodium channel (α/β/γENaC), sodium chloride cotransporter (NCC), phosphorylated NCC (pNCC)), pNCC were markedly augmented in ANGII-infused OVX rats, whereas not changed in ANGII-infused OVX+E rats. ANGII infusion affected increasing ANGII type 2 receptor (AT 2 R) in OVX+E rats but did not influence AT 2 R levels in OVX rats. Conclusions: Estradiol has the protective effect from elevating BP in ANGII-infused OVX rats. It was achieved via augmentation of natriuresis, which was connected to the suppression of NCC.

Self-reported fraud victimization and objectively measured blood pressure: Sex differences in post-fraud cardiovascular health.

Over 5 million older Americans are victims of financial exploitation, schemes, and/or scams per year. Such victimization is associated with increased hospitalizations, admittance to skilled nursing facilities, and lower 5-year all-cause mortality survival rates. Despite this, associations with medical comorbidities like elevated blood pressure (BP) have not been examined. We investigated the association of self-reported fraud victimization (presence/absence) with objectively measured BP metrics leveraging cross-sectional and longitudinal data from over 1200 non-demented adults (75% female; age ~81 years) from the Rush Memory and Aging Project. We first examined cross-sectional associations between baseline fraud victimization and BP, then used longitudinal data to test the hypothesis that fraud victimization is associated with increases in BP after incident fraud. During up to 11 years of annual observation, participants were queried for fraud victimization and underwent serial BP measurements to calculate per visit averages of systolic and diastolic BP, mean arterial pressure (MAP), and pulse pressure. Cross-sectional analyses established that fraud victimization at baseline was associated with higher BP values. Next, using longitudinal changepoint analyses, we showed that fraud victimization was associated with elevations in BP among men but not women. Specifically, men who reported incident fraud exhibited increases in all BP metrics post-fraud. Results suggest an important link between fraud victimization and BP, particularly among men. Older men showed significant elevations in BP after incident fraud that, compounded over time, may portend other adverse health outcomes.

Cardiovascular symptom phenotypes of post-acute sequelae of SARS-CoV-2

BackgroundAcute COVID-19 infection has been shown to have significant effects on the cardiovascular system. Post-acute sequelae of SARS-CoV-2 (PASC) are being identified in patients; however, the cardiovascular effects are yet to be well-defined. The Post-COVID Cardiology Clinic at Washington University evaluates and treats patients with ongoing cardiovascular PASC. ObjectivesThis investigation aims to describe the phenotypes of cardiovascular symptoms of PASC in patients presenting to the Post-COVID Cardiology Clinic, including their demographics, symptoms, and the clinical phenotypes observed. MethodsThis was a retrospective analysis of symptoms, clinical findings, and test results from the first 100 consecutive adult patients who presented to the Post-COVID Cardiology Clinic at Washington University in St. Louis, between September 2020 to May 2021 with cardiovascular symptoms following COVID-19 infection. ResultsThe population (n = 100) had a mean age of 46.3 years and was 81% female. Most patients had mild acute illness, with only 23% of patients requiring hospitalization during acute COVID-19 infection. The most commonly reported PASC symptoms were chest pain (66%), palpitations (59%), and dyspnea on exertion (56%). Of those presenting with these symptoms, 74/98 patients (75.5%) were found to have a significant blood pressure elevation, considerable sinus tachycardia burden, reduced global longitudinal strain, increased indexed left-ventricular end-diastolic volume (LVEDVi) by echocardiogram, and/or cMRI findings consistent with possible active or healing myocarditis. ConclusionsOur findings highlight clinical phenotypes of the cardiovascular manifestations of PASC. Further studies are needed to evaluate the pathophysiology, treatment options and long-term outcomes for these patients.

The Role of Prehospital REBOA for Hemorrhage Control in Civilian and Military Austere Settings: A Systematic Review

Despite the success of prehospital resuscitative endovascular balloon occlusion of the aorta (REBOA) in combat and civilian settings, the prevalence of complications and the lack of conclusive evidence has led to uncertainty and controversy. Therefore, this systematic review aimed to evaluate the role of prehospital REBOA for hemorrhage control in trauma populations. We systematically searched Cochrane, Ovid MEDLINE, EMBASE and Google Scholar for all relevant studies that investigated the efficacy of prehospital REBOA on trauma patients with massive hemorrhage. Primary outcome was evaluated by blood pressure elevation and secondary outcome was measured by 30-day mortality and complications. Our search identified 546 studies, but only six studies met the inclusion and exclusion criteria. Included studies were low to moderate quality due to limitations within the studies. However, all of the studies reported significant elevation of blood pressure and survival, demonstrating the potential benefits of REBOA. For example, the 30-day mortality rate reduced significantly after REBOA, but studies lacked long-term outcome assessments across the continuum of care. Due to the heterogeneity of the results, a meta-analysis was not possible. We conclude that prehospital REBOA is a feasible and effective resuscitative adjunct for shock patients with lethal non-compressible torso hemorrhage. However, due to the unclear causes of complications and the lack of high quality and homogeneous data, the effects of prehospital REBOA were not truly reflected and comparison between groups was not feasible. Thus, further high-quality studies are required to attest the causality between prehospital REBOA and outcomes.

Association Between Obstructive Sleep Apnea and Stroke and Contributory Risk Factors

Obstructive sleep apnea (OSA), a common comorbidity in patients with stroke, has shown increasing prevalence over the past few decades. OSA is an important risk factor for stroke in addition to other well-known contributors, including hypertension, hyperlipidemia, atrial fibrillation, and diabetes mellitus. Moreover, OSA is an independent predictor of neurological outcomes and mortality. The pathological mechanisms underlying the association between OSA and stroke include autonomic dysfunction, hypertension, cardiac arrhythmia, dyslipidemia, impaired glucose tolerance, hypoxia, and inflammation. Continuous positive airway pressure (CPAP) therapy has proven clinical utility in improvement of neurological symptoms in patients with stroke. Findings from a CPAP withdrawal model have shown increased sympathetic activity in OSA with a consequent significant elevation in blood pressure, relevant cerebral hypoxia, and disturbed cardiac repolarization. In this review, we present an overview of the literature that describes an association between OSA and stroke in addition to the vascular risk factors, including hypertension, hyperlipidemia, atrial fibrillation, and diabetes mellitus. This study highlights the importance of early and accurate diagnosis and management of OSA for stroke prevention and care and will benefit physicians in clinical practice.

Deletion of Orphan G Protein-Coupled Receptor GPR37L1 in Mice Alters Cardiovascular Homeostasis in a Sex-Specific Manner.

GPR37L1 is a family A orphan G protein-coupled receptor (GPCR) with a putative role in blood pressure regulation and cardioprotection. In mice, genetic ablation of Gpr37l1 causes sex-dependent effects; female mice lacking Gpr37l1 (GPR37L1−/−) have a modest but significant elevation in blood pressure, while male GPR37L1−/− mice are more susceptible to cardiovascular dysfunction following angiotensin II-induced hypertension. Given that this receptor is highly expressed in the brain, we hypothesize that the cardiovascular phenotype of GPR37L1−/− mice is due to changes in autonomic regulation of blood pressure and heart rate. To investigate this, radiotelemetry was employed to characterize baseline cardiovascular variables in GPR37L1−/− mice of both sexes compared to wildtype controls, followed by power spectral analysis to quantify short-term fluctuations in blood pressure and heart rate attributable to alterations in autonomic homeostatic mechanisms. Additionally, pharmacological ganglionic blockade was performed to determine vasomotor tone, and environmental stress tests were used to assess whether cardiovascular reactivity was altered in GPR37L1−/− mice. We observed that mean arterial pressure was significantly lower in female GPR37L1−/− mice compared to wildtype counterparts, but was unchanged in male GPR37L1−/− mice. GPR37L1−/− genotype had a statistically significant positive chronotropic effect on heart rate across both sexes when analyzed by two-way ANOVA. Power spectral analysis of these data revealed a reduction in power in the heart rate spectrum between 0.5 and 3 Hz in female GPR37L1−/− mice during the diurnal active period, which indicates that GPR37L1−/− mice may have impaired cardiac vagal drive. GPR37L1−/− mice of both sexes also exhibited attenuated depressor responses to ganglionic blockade with pentolinium, indicating that GPR37L1 is involved in maintaining sympathetic vasomotor tone. Interestingly, when these mice were subjected to aversive and appetitive behavioral stressors, the female GPR37L1−/− mice exhibited an attenuation of cardiovascular reactivity to aversive, but not appetitive, environmental stimuli. Together, these results suggest that loss of GPR37L1 affects autonomic maintenance of blood pressure, giving rise to sex-specific cardiovascular changes in GPR37L1−/− mice.

Vascular endothelial growth factor inhibitor induced hypertension: Retrospective analysis of the impact of blood pressure elevations on outcomes.

Vascular endothelial growth factor (VEGF) inhibitors are known to cause hypertension. The purpose of this study was to assess the impact of blood pressure (BP) elevations on outcomes in patients receiving VEGF inhibitors. This retrospective chart review analyzed patients receiving treatment with VEGF inhibitors. The primary endpoint was time to progression (TTP) in those with or without significant increase in BP (increase in systolic BP greater than 20 mm Hg or greater than 10 mm Hg increase in diastolic BP). Secondary endpoints included treatment interruption, therapy discontinuation due to documented adverse effect, and time to BP elevation. Subgroup analyses were completed in those receiving bevacizumab and oral tyrosine kinase inhibitors. A total of 155 patients were included and 93 patients (60%) experienced a significant increase in BP. Median time to development of an elevated BP was 47 days. Patients with significant increases in BP had a longer median TTP compared to patients without (8.1 months vs 4.4 months, p = 0.002). No differences were present between groups in treatment interruption or discontinuation due to a documented adverse effect and outcomes were similar in those receiving bevacizumab and oral tyrosine kinase inhibitors. In the analysis of the impact of severity of BP elevations, those with severe BP elevations were more likely to have treatment interrupted but discontinuation rates were similar across groups. Development of significant BP elevations may be a marker of therapeutic response to VEGF inhibitors and does not limit treatment duration, even in those with severe elevations.

Effects of audio and visual distraction on patients\u2019 vital signs and tolerance during esophagogastroduodenoscopy: a randomized controlled trial

BackgroundEsophagogastroduodenoscopy (EGD) provides an indispensable and unambiguous inspection allowing the discovery upper gastrointestinal lesions. However, many patients are anxious about undergoing EGD. Few studies have investigated the influence on patients’ vital signs and tolerance during EGD using subjective and objective assessments. This study was a prospective randomized controlled study that investigated the influence of audio and visual distraction on EGD.MethodsWe randomly divided 289 subjects who underwent EGD into 4 groups (control group, audio group, visual group, combination group) and examined their vital signs, heart rate variability (HRV), psychological items, and acceptance of distraction.ResultsPulse rate (PR) at post-distraction and post-EGD in the 3 distraction groups were significantly lower than those of control group (p < 0.001 and p < 0.01, respectively). Blood pressure (BP) during and post-EGD was significantly higher than that at pre-EGD in control group (p < 0.05), but no significant elevation of BP was observed during the latter half of EGD and post-EGD in the 3 distraction groups. BP at post-distraction improved significantly compared to pre-distraction in the 3 distraction groups (p < 0.05). There was a significant difference in the low-frequency (LF) power/ high-frequency (HF) power at post-distraction and post-EGD among the 4 groups (p < 0.001 and p < 0.001, respectively). The LF power/HF power at post-distraction and post-EGD in the 3 distraction groups was significantly lower than that in control group (p < 0.05). Several items of profile of mood states (POMS) and the impression of EGD at post-distraction improved significantly compared to those at pre-distraction among the 3 distraction groups (p < 0.05). Visual analog scale (VAS) of willingness for the next use of distraction in the 3 distraction groups was excellent because VAS was more than 70.ConclusionsDistractions effectively improved psychological factors, vital signs and some of HRV at pre and post-EGD. Distractions may suppress BP elevation during the latter half of EGD and lead to stability of HRV on EGD.Trial registrationThis prospective trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000029637. Registered on 20 October 2017.

Angiotensin AT2 receptors in the solitary tract nucleus lower blood pressure via inhibition of GABA signaling

Chronic CNS administration of angiotensin AT2 receptor (AT2R) agonists lowers blood pressure (BP) in normal and hypertensive rodents, but the location(s) and mechanism(s) of action are unknown. One locus may be the intermediate solitary tract nucleus (intNTS). Our previous studies demonstrated a high density of AT2R located on GABA neurons in the intNTS (de Kloet et al, Brain Struct. Func., 2016, 22:891–912), and decades of research have established increased GABA signaling in the intNTS as a pathophysiological mechanism contributing to increased BP and hypertension. These studies reveal that reductions in BP (~8 mmHg) induced by 2‐week intracerebroventricular (icv) infusion of the AT2R agonist C21 (7.5 ng/kg/h) in normotensive mice is associated with significant decreases in gene expression of GABA synthetic enzymes (GAD‐1 &amp; GAD‐2) in the intNTS. Based on this, we developed the hypothesis that the depressor action of C21 is mediated through AT2R located on intNTS GABA neurons and a reduction of GABA signaling. To test this, we engineered a novel mouse line that has Cre‐recombinase expression directed to the AT2R gene (AT2R‐Cre), and demonstrated that Cre recombinase activity mirrors AT2R mRNA expression within the NTS. Next, we used the Cre‐LoxP system and virally (AAV)‐mediated gene transfer to direct expression of the light‐sensitive excitatory opsin channelrhodopsin‐2 (ChR2) and/or eYFP specifically to neurons in the intNTS that synthesize AT2R. Using these mice, we performed electrophysiological‐ or cardiovascular recordings during optogenetic manipulations (blue light) that selectively excite AT2R‐expressing neurons in the intNTS. For the electrophysiological studies, optical stimulation produced a strong inward current in voltage clamp (611.80 ± 78.55 pA; n=9), and robust frequency dependent firing of action potentials in current‐clamp, validating functional opsin expression within AT2R‐expressing neurons. Optical activation of the Chr2/eYFP‐containing AT2R‐expressing neurons in brain slices resulted in activation of adjacent (non‐eYFP‐labeled) neurons, as indicated by light‐evoked currents (n=31), an effect blocked by GABA receptor antagonists (PTX and CGP). Cardiovascular studies revealed that (i) Optogenetic stimulation of the AT2R intNTS neurons expressing ChR2 in isoflurane anesthetized mice elicited significant elevations in BP compared with control mice that express only eYFP; (ii) The AT2R‐containing neurons that were activated by light stimulation are GABAergic, as indicated by increased expression and co‐localization of c‐Fos mRNA with GAD‐1 mRNA and eYFP; (iii) Chronic icv infusion of C21 as above significantly blunted the light‐induced increases in BP, an effect that persisted across all patterns of optical stimulation. Collectively, these data indicate that AT2R‐mediated decreases in BP involve a blunting of GABA signaling in the intNTS, and suggest that neurons expressing AT2R in the intNTS may be an access point for cardiovascular control.Support or Funding InformationNIH grants HL‐125805 (AdK), HL‐145028 (AdK), HL‐136595 (EGK/CS)

Clinical utility of midodrine and methylene blue as catecholamine-sparing agents in intensive care unit patients with shock

Shock is common in the intensive care unit, affecting up to one third of patients. Treatment of shock is centered upon managing hypotension and ensuring adequate perfusion via administration of fluids and catecholamine vasopressors. Due to the risks associated with catecholamine vasopressors, interest has grown in using catecholamine-sparing agents such as midodrine and methylene blue. Midodrine is an orally administered alpha-1 adrenergic agonist while methylene blue is an intravenously administered blue dye used to restore vascular tone and increase blood pressure. Separate MEDLINE, Scopus, and Embase database searches were conducted to assess literature revolving around these agents. Examples of search terms included "midodrine", "methylene blue", "critically ill", "shock", and "catecholamine-sparing." Several studies have evaluated their use in patients with shock and found potential benefits in terms of causing significant elevations in blood pressure and hastening catecholamine vasopressor discontinuation with few adverse effects; however, robust evidence is lacking for these off-label indications. Because of the variety of dosing strategies used and the incongruences between patient populations, it is also challenging to define finite recommendations. This review aims to summarize current evidence for the use of midodrine and methylene blue as catecholamine-sparing agents in critically ill patients with resolving or refractory shock.

Therapeutic role of taurine as antioxidant in reducing hypertension risks in rats

AimThe current investigation focused on the therapeutic role of the administration of taurine on hypertensive rats to reduce or cure the hazard effects of hypertension problems. MethodologyThis research included 2 experiments; 1st was done to survey the variations that might occur in blood pressure (BP) of male rats because of the fed 8% NaCl diet for 4 weeks. 2nd experiment, it contains normal control rats', hypertensive rats were served as hypertension recovery group and hypertensive rats were took orally by the help of gastric tube 50 mg taurine/100 g b.wt/day for four weeks and served as taurine group. Results1st experimental, clarified a significant elevation in BP, body weight, serum cholesterol, triglycerides, LDL, activities of serum cardiac enzymes, endothelin-1, ADMA, MDA and TNF-α in hypertensive rats' group. On contrary, there is a significant reduction in serum level of TNO and antioxidant enzymes level in relation to the control group. A numerical variation but not statistically significant was happened in HDL in hypertensive rats' group as compared to their matching results in control rats' group. 2nd experimental taurine significantly reduced the BP as compared with hypertensive control. Furthermore, a significant improvement occurred in the mean value of most investigation parameters in hypertensive animal group which treated with taurine. ConclusionThe previous data could be concluded that, there is an obvious amelioration effects of taurine on hypertensive rats by reducing the hazard effects of hypertension problems. The primary mechanisms were discussed according to existing published investigations.