Hypertensive Response Research Articles

Effects of White-coat Hypertension on Heart Rate Recovery and Blood Pressure Response during Exercise Test

Objectives White-coat hypertension is defined as high blood pressure (BP) on clinical assessment but normal BP elsewhere or on ambulatory measurement. Autonomic dysfunction may be one of the mechanisms causing white-coat hypertension. Slowed heart rate recovery and excessive BP response during exercise test are associated with autonomic dysfunction. The purpose of this study was to determine the association between white-coat hypertension and abnormal autonomic nervous system response. Methods We assessed 295 patients stratified into three groups via 24hr ambulatory BP monitoring, following 2017 ACC/AHA guidelines: normal BP group, white-coat hypertension group, and a hypertension group. We analyzed medical history, blood test, echocardiography, 24hr ambulatory BP monitoring, and exercise test data. Results There was no difference in basement characteristics and echocardiography among the groups. Blunted heart rate recovery of each group showed a significant difference. Control group had 0% blunted heart rate recovery, but 33.3% in white coat group and 27.6% in true hypertension group ( P < 0.001). Also, in the control group, 4.5% showed excessive BP response, but 31.5% in the white coat hypertension group and 29.3% in the true hypertension group ( P < 0.001). Excessive BP response during the exercise test or blunted heart rate recovery, which is an indicator of autonomic nervous system abnormality, was more common in the hypertensive group and white-coat hypertension group than in the normal BP group. Conclusions These results confirmed that white-coat hypertension has an autonomic nervous system risk. Therefore, white-coat hypertension can be a future cardiovascular risk factor.

Bioinformatics Study of Plasma Differentially Expressed Proteins in H-Type Hypertension with or without Acute Cerebral Infarction

Objective: To investigate the bioinformatics of differentially expressed proteins in plasma in patients with acute cerebral infarction associated with H-type hypertension. Methods: Gene chip public database (gene expression omnibus, GEO) GDS4521 chip data, in the chip in 30 cases of H patients with acute cerebral infarction with high blood pressure and age, gender, matching the 20 H hypertension patients as the research object, collects the mononuclear cells (PBMCs) is used to detect the gene chip, using the GO (gene Ontology, GO), protein function analysis tools such as KEGG, screening and analysis of enrichment of differentially expressed genes function and related signaling pathway. Results: 31 genes in PBMCs were significantly changed in h-type hypertension and H-type hypertension with acute cerebral infarction, 32 of which were increased and 2 of which were decreased. GO analysis showed that in terms of biological processes, the genes related to inflammatory response and neutrophil chemotaxis were the most. In terms of molecular function, chemokine activity-related genes are the most. KEGG signaling pathway analysis showed that the most differentially expressed genes were located in the TNF signaling pathway. Conclusion: H-type hypertension with acute cerebral infarction has a variety of functional proteins and signaling pathways changes, suggesting that inflammatory response in H-type hypertension with acute cerebral infarction recovery period may still play a role in the prognosis and reactivation of the disease.

Attenuation of hypertensive response with esmolol and labetalol in low doses in orotracheal intubation: A comparative study

Introduction: This was a prospective, randomized, double blind, comparative, clinical study to assess the efficacy of Esmolol and Labetalol, in low doses, for attenuation of sympathomimetic response to laryngoscopy and intubation. Materials and Methods: This study was conducted on 50 ASA 1 patients of either sex undergoing elective surgeries under general anaesthesia. Patients were randomized into two groups; group E who received intravenous Esmolol (0.5 mg/kg) or group L who received intravenous Labetalol (0.25 mg /kg) prior to induction and hemodynamic parameters were recorded as per designed protocol to assess stress response to laryngoscopy and intubation. Results: Both the study groups had similar demographic profile. Instat version 3.10 was used for statistical calculations. The study data were analyzed using statistical methods of mean, standard deviation. Esmolol (0.5 mg/kg), abetalol (0.25 mg/kg) significantly attenuated the rise in heart rate, systolic blood pressure, and RPP during laryngoscopy and intubation. However, the difference was not statistically significant among the values for DBP and MAP. Conclusion: From our clinical study it can be concluded that in lower doses, intravenous Labetalol (0.25 mg/kg) is a better agent than intravenous Esmolol (0.5 mg/kg) in attenuating the sympathomimetic response to laryngoscopy and intubation. Usual dose of esmolol used to obtund intubation response is 2-4mg/kg, while labetalol has been tried in all doses ranging from 0.25, 0.5, 0.75, and 1 mg/kg.17 Keywords: Esmolol, Labetalol, Stress response, Laryngoscopy and Intubation.

Nitric Oxide Production in Professional Skiers During Physical Activity at Maximum Load.

The purpose of this study is to assess the production of nitric oxide in professional cross-country skiers with normotensive and hypertensive responses to physical activity at maximum load. The observation group included professional cross-country skiers (22.2 ± 7.1 years, = 107) who were current members of the national team of the Komi Republic. All the examined athletes performed the exercise test on a cycle ergometer “until exhaustion.” The following parameters were determined for each participant while they were sitting at rest, while at their anaerobic threshold level, during peak load, and during the recovery period (5th min): systolic blood pressure, diastolic blood pressure, heart rate, and the level of stable nitric oxide metabolites (nitrites, nitrates) in capillary blood samples. According to the blood pressure results, the cross-country skiers were divided into two groups. Group I included athletes with a normotensive response to stress. Group II was composed of individuals with a hypertensive response to stress. During the performance of the test “until exhaustion,” a significant (p < 0.05) increase in the amount of stable metabolites of nitric oxide was observed in the group of athletes with a normotensive response to the load compared with the group with a hypertensive response to the load. In athletes with a normotensive reaction to the load during exercise at maximum load and in the early recovery period, nitrate was prioritized in the regulation of vascular tone. The exercise test on a cycle ergometer “until exhaustion,” combined with the assessment of the levels of stable nitric oxide metabolites in plasma, can be considered a test for the early diagnosis of endothelial dysfunction in professional athletes.

Non-invasive blood pressure monitoring underestimates hypertensive response to exercise in suspected heart failure with preserved ejection fraction.

Non-invasive blood pressure monitoring underestimates hypertensive response to exercise in suspected heart failure with preserved ejection fraction.

Frequency of hypertensive response to dobutamine stress and diminished diagnostic value in patients with end-stage renal disease awaiting renal transplant.

Patients with end-stage renal disease (ESRD) have a cardiovascular mortality about 15-30 times the general population and this is reduced by about 70% with renal transplant. Dobutamine stress echocardiography (DSE) is commonly performed for preoperative cardiac evaluation before renal transplantation. Hypertensive response during DSE occurs in about 1%-5% of DSE studies. However, it seems to be more frequent in patients with ESRD. But its frequency and clinical implications are not known. Of the 249-consecutive adult ESRD patients undergoing DSE for pre-kidney transplant cardiac risk assessment at our dedicated clinic, 53 (21%) had a hypertensive response. Half of the patients with a hypertensive response had stress-induced segmental wall motion abnormalities, of whom only half had angiographically significant coronary artery disease by quantitative coronary angiography. The hypertensive response was not a predictor of survival. Stress-induced segmental wall motion abnormalities predicted poor survival in those with a normotensive response, but not in those with a hypertensive response. The main and independent predictor of a hypertensive response was higher baseline systolic blood pressure (P<.0001). Hypertensive response to dobutamine stress is common in ESRD patients and is not a predictor of survival. Stress-induced segmental wall motion abnormalities occur nearly thrice as frequently with a hypertensive response, but this is a poor predictor of angiographically significant coronary artery disease and does not predict survival.

Predator Scent-Induced Sensitization of Hypertension and Anxiety-like Behaviors.

Post-traumatic stress disorder (PTSD), ananxiety-related syndrome, is associated with increased risk for cardiovascular diseases. The present study investigated whether predator scent (PS) stress, a model of PTSD, induces sensitization of hypertension and anxiety-like behaviors and underlying mechanisms related to renin-angiotensin systems (RAS) and inflammation. Coyote urine, as a PS stressor, was used to model PTSD. After PS exposures, separate cohorts of rats were studied for hypertensive response sensitization (HTRS), anxiety-like behaviors, and changes in plasma levels and mRNA expression of several components of the RAS and proinflammatory cytokines (PICs) in the lamina terminalis (LT), paraventricular nucleus (PVN), and amygdala (AMY). Rats exposed to PS as compared to control animals exhibited (1) a significantly greater hypertensive response (i.e., HTRS) when challenged with a slow-pressor dose of angiotensin (ANG) II, (2) significant decrease in locomotor activity and increase in time spent in the closed arms of a plus maze as well as general immobility (i.e., behavioral signs of increased anxiety), (3) upregulated plasma levels of ANG II and interleukin-6, and (4) increased expression of message for components of the RAS and PICs in key brain nuclei. All the PS-induced adverse effects were blocked by pretreatment with either an angiotensin-converting enzyme antagonist or a tumor necrosis factor-α inhibitor. The results suggest that PS, used as an experimental model of PTSD, sensitizes ANG II-induced hypertension and produces behavioral signs of anxiety, probably through upregulation of RAS components and inflammatory markers in plasma and brain areas associated with anxiety and blood pressure control.

Abstract 13065: Blood Pressure Response to Treadmill Cardiopulmonary Exercise Testing in Children With Normal Hearts

Background: Blood pressure (BP) response to the treadmill cardiopulmonary exercise test (CPET) has yet been studied with no standard criteria for abnormal BP responses in children. Our hypothesis was that the reference values of BP responses to the treadmill CPET should be defined by gender and age in children. Objectives: The objective of our study was to describe the BP responses to the treadmill CPET and propose the criteria for abnormal BP responses in children. Methods: The treadmill CPET data were retrospectively analyzed to evaluate the BP responses to exercise during the period of 8 years (2011-2018). Children aged &lt;18 years with normal hearts were included for the analysis. Results: Our cohort consisted of 1,085 children (males 59%) aged 7-17 years. The analysis of variance for Systolic BP at peak exercise (peak SBP) and change (Δ) of SBP showed significant age and gender effects and age-gender interaction effect ( p &lt;0.01). In the multiple linear regression model ( p &lt;0.001), peak SBP (mmHg) was predicted as 100.39 + 4.68 x age (years) for males; 132.27 + 1.37 x age (years) for females. The following criteria for abnormal BP responses in children were proposed. Hypertensive BP response were defined by peak SBP &gt;90% confidence interval upper limit of reference values based on age and gender. Blunted BP response was defined by 1) ΔSBP &lt;10 mmHg for age 7-11 years and &lt;20 mmHg for age 12-17 years in males; and ΔSBP &lt;10 mmHg in females. Conclusion: Blood Pressure response to the treadmill CPET was dependent on age and gender in children with normal hearts. The proposed criteria for abnormal BP responses in children should prove useful in interpreting BP responses in children during the CPET.

Abstract 17191: Left Atrial Volume Index and E/E’ Predict Predominance of Post-Capillary Pulmonary Hypertension With Exercise Hemodynamics

Introduction: Post-capillary pulmonary hypertension (PH) is diagnosed with rest hemodynamics and requires management of left heart disease. However, in subclinical PH and mixed PH (mixed pre- and post-capillary), it is imperative to identify a predominant post-capillary phenotype with exercise (aka. Pulmonary venous hypertension). Hypothesis: In suspected subclinical and mixed PH, greater left atrial volume index (LAVI; &gt;35) and E/E’ (&gt;8) on echocardiogram can reliably predict a predominant post-capillary PH with exercise, assessed with invasive cardiopulmonary exercise testing (iCPET). Methods: We reviewed clinical, echocardiographic and iCPET data for 37 patients undergoing exercise right heart catheterization and then analyzed the data with receiver operator curve (ROC) and area under the curve (AUC) analysis to estimate the different echo parameters to identify post-capillary PH. Results: Within the cohort, mean age (± SD) was 63.6±11.3 years, and 19 subjects were female (51%). On ROC analysis, LAVI and E/E’ had high predictive ability to identify a pulmonary venous hypertension response with exercise (AUC=0.860, p=0.003 for LAVI, and AUC=0.788, p=0.014) with optimal cut-offs identified as: LAVI &gt;35 and E/E’ &gt;8. These variables also notably had a significant association with PCWP/CO&gt;2. To understand the hemodynamics associated with these differentiable echo features, we divided the overall cohort (n=37) into 2 groups: group 1 ( Abnormal-LA group ) =LAVI&gt;35 and/or E/E’ &gt;8, group 2 ( Normal-LA group )=LAVI≤ 34 and E/E’≤8. The LAVI in group 1 vs group 2 was: 44.3±15.2 vs 23.1±4.4 (p&lt;0.001) and E/E’ was: 15.8±9.9 vs 7.7±1.95 (p&lt;0.01). Results are summarized in Table 1. Conclusions: Among individuals with suspected PH, LAVI&gt;35 and E/E’ &gt;8 are reliable non-invasive markers to identify post-capillary PH. In a patient with a new diagnosis of PH based on screening echocardiogram, LAVI≤ 34 and E/E’≤8 may identify a patient who is likely to benefit from PH drugs.

Activation of the Sympathetic Nervous System Promotes Blood Pressure Salt-Sensitivity in C57BL6/J Mice.

Global salt intake averages >8 g/person per day, over twice the limit advocated by the American Heart Association. Dietary salt excess leads to hypertension, and this partly mediates its poor health outcomes. In ≈30% of people, the hypertensive response to salt is exaggerated. This salt-sensitivity increases cardiovascular risk. Mechanistic cardiovascular research relies heavily on rodent models and the C57BL6/J mouse is the most widely used reference strain. We examined the effects of high salt intake on blood pressure, renal, and vascular function in the most commonly used and commercially available C57BL6/J mouse strain. Changing from control (0.3% Na+) to high salt (3% Na+) diet increased systolic blood pressure in male mice by ≈10 mm Hg within 4 days of dietary switch. This hypertensive response was maintained over the 3-week study period. Returning to control diet gradually reduced blood pressure back to baseline. High-salt diet caused a rapid and sustained downregulation in mRNA encoding renal NHE3 (sodium-hydrogen-exchanger 3) and EnaC (epithelial sodium channel), although we did not observe a suppression in aldosterone until ≈7 days. During the development of salt-sensitivity, the acute pressure natriuresis relationship was augmented and neutral sodium balance was maintained throughout. High-salt diet increased ex vivo sensitivity of the renal artery to phenylephrine and increased urinary excretion of adrenaline, but not noradrenaline. The acute blood pressure-depressor effect of hexamethonium, a ganglionic blocker, was enhanced by high salt. Salt-sensitivity in commercially sourced C57BL6/J mice is attributable to sympathetic overactivity, increased adrenaline, and enhanced vascular sensitivity to alpha-adrenoreceptor activation and not sodium retention or attenuation of the acute pressure natriuresis response.

The generation of fluorometholone nanocrystal eye drops, their metabolization to dihydrofluorometholone and penetration into rabbit eyes

Fluorometholone is a widely used anti-inflammatory ophthalmic formulation, which elicits a lower ocular hypertensive response than other glucocorticoid medications. This serves to mitigate against the risk of steroid-induced glaucoma. Based on the hypothesis that an improved corneal permeability can increase the bioavailability of a drug, we sought to obtain fluorometholone in suspension with a small particle size. Accordingly, we describe the formulation of fluorometholone nanocrystal eye drops, which have a mean particle size of 201.2 ± 14.1 nm (standard deviation (s.d.)) when measured by dynamic light scattering. Scanning electron microscopy further indicates that fluorometholone nanocrystals are predominantly rectangular in shape. Fluorometholone microcrystals, on the other hand, with a mean particle size of 9.24 ± 4.51 µm (s.d.), tend to have a rod-like morphology. Powder x-ray diffraction revealed that fluorometholone microcrystal and nanocrystal formulations have the same crystal structure, with the main diffraction peaks at 2θ = 10.4 and 15.3°. The nanocrystal formulation was found to be stable, long-term, when stored at 10 °C for up to 6-months. High pressure liquid chromatography (HPLC) of the aqueous humor of rabbit eyes 15–240 mins after the in vivo application of fluorometholone eye drops to the ocular surface revealed that the molecule had been converted to 20α-dihydrofluorometholone (with no evidence of a 20β-dihydrofluorometholone fraction), and that penetration was 2–6 fold higher and longer lasting with the nanocrystal, rather than the microcrystal, formulation. In current study we show how newly generated fluorometholone nanocrystals when administered as eye drops enter the anterior chamber of the eye and become metabolized to dihydrofluorometholone.

Alkaline Phosphatase Is Associated with Red Cell Alloimmunization in the Pulmonary Hypertension and Hypoxic Response (PUSH) Sickle Cell Disease Cohort

Background: Blood transfusion is a common therapy for sickle cell disease (SCD). Although, highly effective, a major limitation is development of alloantibodies to minor blood group antigens on donor red cells. Alloimmunization has a prevalence of 2-5% for transfusions in the general population, but it is significantly higher in SCD. Risk factors for alloimmunization have been poorly characterized, although number of lifetime transfusions is an important risk factor. Alloimmunization has been clinically observed in children with a prevalence of about 7%. With development of each antibody, blood donor matching becomes increasingly difficult and expensive with an increased risk for transfusion reactions and diminished availability of compatible red cell units for treatment of SCD. The ability to identify risk factors for developing alloantibodies would be beneficial for clinicians. To identify markers for alloimmunization in SCD, we have analyzed children and adults who developed this complication. Methods: We analyzed The Pulmonary Hypertension and Hypoxic Response in Sickle Cell Disease (PUSH) study, which enrolled n=468 pediatric and n=59 adult SCD subjects. In both children and adults, alloimmunization cases were defined as a history of at least 1 alloantibody. Controls in both cohorts were defined as subjects with no history of alloantibodies and receipt of more than 10 lifetime red cell transfusions. All others within the study who did not meet these criteria were assigned to a third comparison group. To identify differences between cases, controls and all others, we performed univariate analyses (using ANOVA or Kruskal Wallace where appropriate) for clinical parameters and laboratories. Case control comparisons were also performed for selected variables and plasma levels for 11 cytokines. Results were further analyzed using regression modeling. Results: The overall prevalence of alloimmunization was 7.3% among children (34/468 subjects; median age 12, range 3-20 years) compared to 28.8% in adults (17/59 subjects; median age 37, range 18-73 years). When only considering those with &amp;gt;10 lifetime transfusions, the prevalence was considerably higher at 29.3% and 54.8% in children and adults, respectively. At the same time, 8 pediatric (23.5%) and 5 adult (29.4%) alloimmunization cases had received fewer than 10 transfusions. In a 3-way pediatric cohort comparison (cases, controls and all others), risk factors associated with alloimmunization included SS genotype, older age and markers of more severe disease (higher ferritin, WBCs, platelets and total bilirubin). Comparison of cases to controls showed alkaline phosphatase (P=0.05) was significantly lower in cases, whereas AST (P=0.02) was significantly higher even with adjustment for age. Levels of plasma cytokines MCP-1 (P=0.01) and IFNgamma (P=0.08) were lower in cases from a subset of the pediatric cohort. In adults, only 4/59 (6.8%) subjects had never received a lifetime transfusion (all non-SS). In the adult 3-way comparisons, only SS genotype and higher ferritin were associated with alloimmunization. The adult case control analysis showed higher absolute monocyte count (P=0.02), absolute eosinophil count (P=0.04) and absolute basophil count (P=0.008) in association with alloimmunization cases. In addition, alkaline phosphatase was again significantly lower among cases (P=0.02) as seen in the pediatric cohort. There were no significant differences in cytokine levels among adults. Conclusions: When considering only transfused SCD patients, the prevalence of alloimmunization is higher than 30%. As seen in prior studies, higher lifetime red cell transfusions are an important risk factor especially among adults where most patients have received transfusions. Children who develop alloantibodies appear to have laboratory markers of more severe disease, but this is not observed in adults. A novel association observed across both pediatric and adult subjects is a significantly lower serum alkaline phosphatase in those with alloantibodies. The results of this study suggest a need for improved tracking of red cell transfusion therapy in the US for SCD patients due to a high prevalence of alloimmunization. Further study is also needed to elucidate the significance of the alkaline phosphatase association. Disclosures Gordeuk: CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Ironwood: Research Funding; Imara: Research Funding.

Editing of the myosin phosphatase regulatory subunit suppresses angiotensin II induced hypertension via sensitization to nitric oxide mediated vasodilation.

Alternative splicing of exon 24 (E24) of the myosin phosphatase regulatory subunit (Mypt1) tunes smooth muscle sensitivity to NO/cGMP-mediated vasorelaxation and thereby controls blood pressure (BP) in otherwise normal mice. This occurs via the toggling in or out of a C-terminal leucine zipper (LZ) motif required for hetero-dimerization with and activation by cGMP-dependent protein kinase cGK1α. Here we tested the hypothesis that editing (deletion) of E24, by shifting to the LZ positive isoform of Mypt1, would suppress the hypertensive response to angiotensin II (AngII). To test this, mice underwent tamoxifen-inducible and smooth muscle-specific deletion of E24 (E24 cKO) at age 6 weeks followed by a chronic slow-pressor dose of AngII (400 ng/kg/min) plus additional stressors. E24 cKO suppressed the hypertensive response to AngII alone or with the addition of a high salt diet. This effect was not a function of altered salt balance as there were no differences in intake or renal excretion of sodium. This effect was NO dependent as L-NAME in the drinking water caused an exaggerated hypertensive response in the E24cKO mice. E24cKO mouse mesenteric arteries were more sensitive to DEA/NO-induced vasorelaxation and less responsive to AngII- and α-adrenergic-induced vasoconstriction at baseline. Only the latter two effects were still present after 2 weeks of chronic AngII treatment. We conclude that editing of Mypt1 E24, by shifting the expression of naturally occurring isoforms and sensitizing to NO-mediated vasodilation, could be a novel approach to the treatment of human hypertension.

Empagliflozin treatment does not affect the hypertensive response to Ang II administration to rats but decreases oxidative stress in the arterial wall, and endothelial and cardiac dysfunction

Abstract Background Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown cardiovascular protection in type 2 diabetes patients with established cardiovascular disease independently of glycemic control. Angiotensin II (Ang II) and H2O2 have been shown to be strong inducers of the expression of SGLT2 and 1 in endothelial cells promoting oxidative stress and endothelial dysfunction. Purpose This study examined the cardiovascular protective effect of empagliflozin (empa) in a normoglycemic experimental model of hypertension in the rat. Methods Male Wistar rats received empa (30 mg/kg/day) provided in the diet for 5 weeks. After 1 week, rats underwent sham surgery (sham rats) or surgery with implantation of an osmotic mini-pump infusing Ang II (0.4 mg/kg/d) for 4 weeks. Systolic blood pressure (SBP) was assessed by sphygmomanometry, the cardiac function using echocardiography, the expression level of target proteins by immunofluorescence staining, and the level of oxidative stress using dihydroethidium staining. Results Angiotensin II administration increased systolic blood pressure from about 130 to 180 mmHg, which was not affected by the empa treatment. The 4-week Ang II treatment did not significantly affect the systolic cardiac function (cardiac output, left ventricle ejection fraction) but impaired the diastolic function as indicated by a reduced E' and IVRT values, and an increased E/E' value. The Ang II treatment increased significantly the heart and right ventricle weight whereas the left ventricle + septum weight was slightly but not significantly increased. No such functional and structural changes were observed in the Ang II + empa treatment group. An increased immunofluorescence eNOS signal in the endothelium, and a higher level of ROS throughout the aorta wall were observed in the Ang II-treated group, both of which were significantly reduced in the empa + Ang II-treated group. In the Ang II-treated group, the high level of oxidative stress in the aorta was significantly reduced by the AT1 receptor antagonist losartan, the NADPH oxidase inhibitor VAS-2871, the eNOS inhibitor NG-nitro-L-arginine and also to a greater extent by the selective SGLT2 inhibitor empa compared to the dual SGLT1/2 inhibitor sotagliflozin. Conclusion(s) The present findings indicate that although the empa treatment did not affect the hypertensive response of rats to Ang II, the SGLT2 inhibitor prevented the deleterious impact of Ang II on the diastolic cardiac function and remodeling, and the upregulation of eNOS expression and oxidative stress in the aorta wall. Thus, these findings highlight the protective potential of empa on the cardiovascular system in a normoglycemic hypertensive experimental model. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Boehringer Ingelheim Pharma GmbH &amp; Co KG (Biberach an der Riss, Germany)

Blocking of interleukin-1 suppresses both angiotensin II-induced renal inflammation and hypertension

Abstract Background Clinical hypertension is associated with renal inflammation and elevated circulating levels of proinflammatory cytokines. IL-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines and plays a crucial role in inflammation. Inhibition of IL-1 may contribute to modulation of the Angiotensin II (AngII)-induced hypertension response. This study aimed to elucidate the effects of IL-1Ra and anti-IL-1beta antibody (01BSUR) on AngII-induced hypertension and renal inflammation. Methods and results To determine the contribution of IL-1Ra to AngII-induced renal inflammation, male wild-type (WT) and IL-1Ra-deficient (IL-1Ra−/−) mice were infused with AngII (1000ng/kg/min) using subcutaneous osmotic pumps for 14 days. We checked blood pressure, histological change, and several mRNA expressions 14 days after infusion. Fourteen days after infusion, systolic blood pressure (197±5 vs 169±9 mmHg, p&amp;lt;0.05) in IL-1Ra−/− mice significantly increased compared with WT mice. Furthermore, on day 14 of AngII infusion, plasma IL-6 was 5.9-fold higher in IL-1Ra−/− versus WT mice (p&amp;lt;0.001); renal preproendothelin-1 mRNA expression was also significantly higher in IL-1Ra−/− mice (p&amp;lt;0.05). To examine renal function, we analyzed 24-hour urinary protein excretion and serum levels of blood urea nitrogen, creatinine, and uric acid in IL-1Ra−/− and WT mice. On day 14 of Ang II infusion, all levels increased significantly in IL-1Ra−/− mice compared with WT mice, suggesting that IL-1Ra deficiency reduced renal function following Ang II infusion. In addition, renal histology revealed that glomerular injury (Figure upper panels: PAS staining) and tubulointerstitial fibrosis (Figure lower panels: Elastica Masson staining) increased significantly in Ang II-infused IL-1Ra−/− versus Ang II-infused WT mice. Finally, we administrated 01BSUR to both IL-1Ra−/− and WT mice, and 01BSUR treatment decreased AngII-induced hypertension (162±17 vs 204±6 mmHg, p&amp;lt;0.05) and renal damage (glomerular injury and fibrosis of the tubulointerstitial area) in both IL-1Ra−/− and WT mice compared with IgG2a treatment. These findings suggest that 01BSUR suppresses Ang II-induced inflammation and renal injury. Conclusions Inhibition of interleukin-1 by both endogenous IL-1Ra and exogenous 01BSUR decreased AngII-induced hypertension and renal damage in mice, suggesting suppression of IL-1 may provide an additional strategy to protect against renal damage in hypertensive patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI

Effects of propofol on intracranial pressure and prognosis in patients with severe brain diseases undergoing endotracheal suctioning

BackgroundTo investigate whether the administration of intravenous propofol before endotracheal suctioning (ES) in patients with severe brain disease can reduce the sputum suction response, improve prognosis, and accelerate recovery.MethodsA total of 208 severe brain disease patients after craniocerebral surgery were enrolled in the study. The subjects were randomly assigned to the experimental group (n = 104) and the control group (n = 104). The experimental group was given intravenous propofol (10 ml propofol with 1 ml 2% lidocaine), 0.5–1 mg/kg, before ES, while the control group was subjected to ES only. Changes in vital signs, sputum suction effect, the fluctuation range of intracranial pressure (ICP) before and after ES, choking cough response, short-term complications, length of stay, and hospitalization cost were evaluated. Additionally, the Glasgow Outcome Scale (GOS) prognosis score was obtained at 6 months after the operation.ResultsAt the baseline, the characteristics of the two groups were comparable (P > 0.05). The increase of systolic blood pressure after ES was higher in the control group than in the experimental group (P < 0.05). The average peak value of ICP in the experimental group during the suctioning (15.57 ± 12.31 mmHg) was lower than in the control group (18.24 ± 8.99 mmHg; P < 0.05). The percentage of patients experiencing cough reaction- during suctioning in the experimental group was lower than in the control group (P < 0.05), and the fluctuation range of ICP was increased (P < 0.0001). The effect of ES was achieved in both groups. The incidence of short-term complications in the two groups was comparable (P > 0.05). At 6 months after the surgery, the GOS scores were significantly higher in the experimental than in the control group (4–5 points, 51.54% vs. 32.64%; 1–3 points, 48.46% vs. 67.36%; P < 0.05). There was no significant difference in the length of stay and hospitalization cost between the two groups.ConclusionsPropofol sedation before ES could reduce choking cough response and intracranial hypertension response. The use of propofol was safe and improved the long-term prognosis.The study was registered in the Chinese Clinical Trial Registry on May 16, 2015 (ChiCTR-IOR-15006441).

Surfactant Attenuates Air Embolism-Induced Lung Injury by Suppressing NKCC1 Expression and NF-\u03baB Activation

Excessive amounts of air can enter the lungs and cause air embolism (AE)-induced acute lung injury (ALI). Pulmonary AE can occur during diving, aviation, and iatrogenic invasive procedures. AE-induced lung injury presents with severe hypoxia, pulmonary hypertension, microvascular hyper-permeability, and severe inflammatory responses. Pulmonary AE-induced ALI is a serious complication resulting in significant morbidity and mortality. Surfactant is abundant in the lungs and its function is to lower surface tension. Earlier studies have explored the beneficial effects of surfactant in ALI; however, none have investigated the role of surfactant in pulmonary AE-induced ALI. Therefore, we conducted this study to determine the effects of surfactant in pulmonary AE-induced ALI. Isolated-perfused rat lungs were used as a model of pulmonary AE. The animals were divided into four groups (n = 6 per group): sham, air embolism (AE), AE + surfactant (0.5 mg/kg), and AE+ surfactant (1 mg/kg). Surfactant pretreatment was administered before the induction of pulmonary AE. Pulmonary AE was induced by the infusion of 0.7 cc air through a pulmonary artery catheter. After induction of air, pulmonary AE was presented with pulmonary edema, pulmonary microvascular hyper-permeability, and lung inflammation with neutrophilic sequestration. Activation of NF-κB was observed, along with increased expression of pro-inflammatory cytokines, and Na-K-Cl cotransporter isoform 1 (NKCC1). Surfactant suppressed the activation of NF-κB and decreased the expression of pro-inflammatory cytokines and NKCC1, thereby attenuating AE-induced lung injury. Therefore, AE-induced ALI presented with pulmonary edema, microvascular hyper-permeability, and lung inflammation. Surfactant suppressed the expressions of NF-κB, pro-inflammatory cytokines, and NKCC1, thereby attenuating AE-induced lung injury.

Oral nitrite treatment increases S-nitrosylation of vascular protein kinase C and attenuates the responses to angiotensin II

Nitrate and nitrite supplement deficient endogenous nitric oxide (NO) formation. While these anions may generate NO, recent studies have shown that circulating nitrite levels do not necessarily correlate with the antihypertensive effect of oral nitrite administration and that formation of nitrosylated species (RXNO) in the stomach is critically involved in this effect. This study examined the possibility that RXNO formed in the stomach after oral nitrite administration promotes target protein nitrosylation in the vasculature, inhibits vasoconstriction and the hypertensive responses to angiotensin II. Our results show that oral nitrite treatment enhances circulating RXNO concentrations (measured by ozone-based chemiluminescence methods), increases aortic protein kinase C (PKC) nitrosylation (measured by resin-assisted capture SNO-RAC method), and reduces both angiotensin II-induced vasoconstriction (isolated aortic ring preparation) and hypertensive (in vivo invasive blood pressure measurements) effects implicating PKC nitrosylation as a key mechanism for the responses to oral nitrite. Treatment of rats with the nitrosylating compound S-nitrosoglutathione (GSNO) resulted in the same effects described for oral nitrite. Moreover, partial depletion of thiols with buthionine sulfoximine prevented PKC nitrosylation and the blood pressure effects of oral nitrite. Further confirming a role for PKC nitrosylation, preincubation of aortas with GSNO attenuated the responses to both angiotensin II and to a direct PKC activator, and this effect was attenuated by ascorbate (reverses GSNO-induced nitrosylation). GSNO-induced nitrosylation also inhibited the increases in Ca2+ mobilization in angiotensin II-stimulated HEK293T cells expressing angiotensin type 1 receptor. Together, these results are consistent with the idea that PKC nitrosylation in the vasculature may underlie oral nitrite treatment-induced reduction in the vascular and hypertensive responses to angiotensin II.

Hypertensive Cardiotoxicity in Cancer Treatment-Systematic Analysis of Adjunct, Conventional Chemotherapy, and Novel Therapies-Epidemiology, Incidence, and Pathophysiology.

Cardiotoxicity is the umbrella term for cardiovascular side effects of cancer therapies. The most widely recognized phenotype is left ventricular dysfunction, but cardiotoxicity can manifest as arrhythmogenic, vascular, myocarditic and hypertensive toxicities. Hypertension has long been regarded as one of the most prevalent and modifiable cardiovascular risk factors in the general population, but its relevance during the cancer treatment journey may be underestimated. Hypertensive cardiotoxicity occurs de novo in a substantial proportion of treated cancer patients. The pathology is incompletely characterized—natriuresis and renin angiotensin system interactions play a role particularly in conventional treatments, but in novel therapies endothelial dysfunction and the interaction between the cancer and cardiac kinome are implicated. There exists a treatment paradox in that a significant hypertensive response not only mandates anti-hypertensive treatment, but in fact, in certain cancer treatment scenarios, hypertension is a predictor of cancer treatment efficacy and response. In this comprehensive review of over 80,000 patients, we explored the epidemiology, incidence, and mechanistic pathophysiology of hypertensive cardiotoxicity in adjunct, conventional chemotherapy, and novel cancer treatments. Conventional chemotherapy, adjunct treatments, and novel targeted therapies collectively caused new onset hypertension in 33–68% of treated patients. The incidence of hypertensive cardiotoxicity across twenty common novel therapies for any grade hypertension ranged from 4% (imatinib) to 68% (lenvatinib), and high grade 3 or 4 hypertension in <1% (imatinib) to 42% (lenvatinib). The weighted average effect was all-grade hypertension in 24% and grade 3 or 4 hypertension in 8%.

Fibroblast Nox2 (NADPH Oxidase-2) Regulates ANG II (Angiotensin II)-Induced Vascular Remodeling and Hypertension via Paracrine Signaling to Vascular Smooth Muscle Cells.

The superoxide-generating Nox2 (NADPH oxidase-2) is expressed in multiple cell types. Previous studies demonstrated distinct roles for cardiomyocyte, endothelial cell, and leukocyte cell Nox2 in ANG II (angiotensin II)-induced cardiovascular remodeling. However, the in vivo role of fibroblast Nox2 remains unclear. Approach and Results: We developed a novel mouse model with inducible fibroblast-specific deficiency of Nox2 (fibroblast-specific Nox2 knockout or Fibro-Nox2KO mice) and investigated the responses to chronic ANG II stimulation. Fibro-Nox2KO mice showed no differences in basal blood pressure or vessel wall morphology, but the hypertensive response to ANG II infusion (1.1 mg/[kg·day] for 14 days) was substantially reduced as compared to control Nox2-Flox littermates. This was accompanied by a significant attenuation of aortic and resistance vessel remodeling. The conditioned medium of ANG II-stimulated primary fibroblasts induced a significant increase in vascular smooth muscle cell growth, which was inhibited by the short hairpin RNA (shRNA)-mediated knockdown of fibroblast Nox2. Mass spectrometric analysis of the secretome of ANG II-treated primary fibroblasts identified GDF6 (growth differentiation factor 6) as a potential growth factor that may be involved in these effects. Recombinant GDF6 induced a concentration-dependent increase in vascular smooth muscle cell growth while chronic ANG II infusion in vivo significantly increased aortic GDF6 protein levels in control mice but not Fibro-Nox2KO animals. Finally, silencing GDF6 in fibroblasts prevented the induction of vascular smooth muscle cell growth by fibroblast-conditioned media in vitro. These results indicate that fibroblast Nox2 plays a crucial role in the development of ANG II-induced vascular remodeling and hypertension in vivo. Mechanistically, fibroblast Nox2 may regulate paracrine signaling to medial vascular smooth muscle cells via factors, such as GDF6.