Blood Pressure Rate Research Articles

Chronic Circadian Misalignment Increases Blood Pressure in Male and Female Bmal1‐KO Rats

Circadian misalignment, such as shift work, is an independent risk factor for the development of cardiovascular and renal disease. The molecular clock is ubiquitously expressed in all cell types and nearly 15% of all molecular transcripts are thought to be controlled by the molecular clock. However, it is unknown how environmental stress, such chronic circadian misalignment, can affect blood pressure and if the molecular clock is involved in this response. In this study, we test the hypothesis that chronic circadian misalignment will raise systolic and diastolic blood pressures in rats without a functional molecular clock. Male and female brain-and-muscle ARNTL-like 1 knockout rats (Bmal1-KO) and littermate controls were implanted with a telemetry catheter in the abdominal aorta to record blood pressure rhythms. Rats were allowed to recover from surgery for 10 days in a 12hr:12hr light/dark (LD) cycle. After recovery, animals were placed in the circadian misalignment protocol, wherein lights were phase advanced 6 hours weekly for five weeks. Food and water were available ad libitum for the duration of experiment. Prior to the circadian misalignment protocol, Bmal1KO rats display blood pressures lower than littermate controls with an intact diurnal rhythm. At the end of the protocol, systolic (SBP) and diastolic blood pressures (DBP) were significantly higher in both Bmal1-KO rats and littermate controls of both sexes (3-way ANOVAs, p>0.05 for inactive (7AM to 7PM) and active (7PM to 7AM) period SBP and DBP). Male control animals had an average active period SBP delta of 4.3±3.2 mmHg while male Bmal1-KO animals had an average active period SBP delta of 8.3±1.8 mmHg. Female control animals had an average active period SBP delta of 1.5±1.5 mmHg while female Bmal1-KO rats had an average active period SBP delta of 7.7±8.4 mmHg. This data suggests that circadian misalignment can raise SBP and DBP in rats after only 5 weeks and may provide insight into the mechanisms by which shift work can lead to the development of cardiovascular and renal disease. A functional molecular clock may mitigate the degree of increased blood pressures during circadian misalignment, as Bmal1-KO rats had larger absolute increases in BP after the misalignment protocol. Further studies will address the role of sex and the contribution of specific organs important to the control of BP during circadian misalignment in rats.

Integrative genomic analysis of blood pressure and related phenotypes in rats.

ABSTRACTDespite remarkable progress made in human genome-wide association studies, there remains a substantial gap between statistical evidence for genetic associations and functional comprehension of the underlying mechanisms governing these associations. As a means of bridging this gap, we performed genomic analysis of blood pressure (BP) and related phenotypes in spontaneously hypertensive rats (SHR) and their substrain, stroke-prone SHR (SHRSP), both of which are unique genetic models of severe hypertension and cardiovascular complications. By integrating whole-genome sequencing, transcriptome profiling, genome-wide linkage scans (maximum n=1415), fine congenic mapping (maximum n=8704), pharmacological intervention and comparative analysis with transcriptome-wide association study (TWAS) datasets, we searched causal genes and causal pathways for the tested traits. The overall results validated the polygenic architecture of elevated BP compared with a non-hypertensive control strain, Wistar Kyoto rats (WKY); e.g. inter-strain BP differences between SHRSP and WKY could be largely explained by an aggregate of BP changes in seven SHRSP-derived consomic strains. We identified 26 potential target genes, including rat homologs of human TWAS loci, for the tested traits. In this study, we re-discovered 18 genes that had previously been determined to contribute to hypertension or cardiovascular phenotypes. Notably, five of these genes belong to the kallikrein–kinin/renin–angiotensin systems (KKS/RAS), in which the most prominent differential expression between hypertensive and non-hypertensive alleles could be detected in rat Klk1 paralogs. In combination with a pharmacological intervention, we provide in vivo experimental evidence supporting the presence of key disease pathways, such as KKS/RAS, in a rat polygenic hypertension model.

Renal Alterations Induced by Chronic Testosterone Therapy in Adult Female Rats

Testosterone esters are used in clinical conditions such as male hypogonadism. Additionally, it has been used to improve sports performance, increasing muscle mass in both genders, and to affirm gender identity by transgender men. However, few experimental studies have been carried out to evaluate the repercussion of testosterone on female rodents on renal function and blood pressure. Thus, the present study aims to evaluate the blood pressure and renal function in female rats subjected chronically to testosterone therapy. Adult female Wistar rats weighing 200 ± 20 g were randomly assigned to receive testosterone (T) or vehicle (control group - C). Group T received testosterone cypionate (3.0 mg/kg, i.m.) and C received vehicle oil every 10 days for 4 months. Renal function and blood pressure were evaluated at 6 months of age. Urine was collected in metabolic cages for 24 h. Plasma and urine concentrations of urea, creatinine, sodium, potassium, osmolality, and glomerular filtration rate (GFR) were measured. The kidneys were weighed, paraffin-embedded, and histological sections were prepared to evaluate the glomerular area. When compared to C, the group T had higher values of BP [C: 119±1.0; T: 131±1.4; mmHg], lower GFR [C: 0.78±0.02; T: 0.67±0.03; ml/min/g kidney weight], increased proteinuria [C: 2.9±0.2; T: 6.2±0.9 mg/24 h], increased kidney weight [C: 1.8±0.04; T: 2.2±0.06; g] and glomerular hypertrophy [C: 7884±112.8; T: 8917±152.4; µm2]. Urinary osmolality and sodium and potassium excretion were similar in both groups. Testosterone therapy in female rats increased blood pressure and induced renal changes that may be related to adaptations caused by the hormonal treatment that carried female rats close to male physiological conditions.

B Cell Depletion During Pregnancy Improves Hypertension, Natural Killer Cell Activation, and May Not Worsen Fetal Outcomes in Response to Placental Ischemia

Preeclampsia (PE), new onset hypertension during pregnancy, is the leading cause of death and morbidity world-wide for the mother and fetus. Women with PE have elevated inflammatory cytokines, cytolytic natural killer (cNK) cells, and B cells producing agonistic antibodies to the angiotensin II type I receptor (AT1-AA). The Reduced Uterine Perfusion Pressure Rat Model of PE (RUPP) exhibits many characteristics of PE. We have shown Rituximab, a chimeric monoclonal antibody used clinically for B cell depletion, lowers blood pressure, AT1-AA, and cytokines in RUPP rats. However, we don't know the effect of maternal B cell depletion on placental cNK cells, or offspring survival and growth. Moreover, recent studies have touted that Rituximab doesn't work in rodents nor are B cells important for hypertension in RUPP rats. Therefore, we hypothesize that Rituximab will deplete circulating B cells and lower AT1-AA stimulated cNK cells and blood pressure in response to placental ischemia in RUPP rats. Rituximab (250 mcg/kg) was given on gestation day (GD) 14 via mini-osmotic pump. Blood and tissues were collected, blood pressure (MAP), pup weight, and NK cells were measured by flow cytometry in the blood and placenta on GD 19. A separate group of dams were allowed to deliver and birth weight of pups were recorded within 12 hours. Weights were measured weekly until 12 weeks. A one-way ANOVA was used for statistical analysis. On GD19, circulating B cells were 15.67±2.28 % gate (n=14) in RUPP rats which was elevated compared to NP rats, 7.04±2.3 % gate (n=6, p<0.05), and was normalized with Rituximab (4.21±0.61 % gate (n=3, p<0.05)). MAP increased in RUPP 123±2 mmHg (n=19, p<0.05) compared to NP controls 101±1 mmHg (n=18) and was normalized with Rituximab 106±3 mmHg (n=8, p<0.05). Circulating and placental cNK cells were 0.22±0.14, 0.64±0.48 % gate in NP rats (n=9, n=6), 1.36±0.32, 1.83±0.49 % gate in RUPP rats (n=16 p<0.05, n=10), which was decreased to 0.01±0.01, 0.81±0.50 % gate with Rituximab (n=5, p<0.05, n=5). RUPP pup weight, 1.78±0.06 g (n=19), was reduced compared to NP pup weight, 2.29±0.14 g (n=18, p<0.05) and was unchanged by Rituximab, 1.82±0.16 g (n=7). RUPP and Rituximab male and female offspring were smaller at birth than NP offspring. Although there no differences among the female offspring, RUPP and Rituximab male offspring remained smaller at 12 weeks of age compared to NP offspring. Our findings indicate that Rituximab indeed lowers maternal circulating B cells, cNK cells and blood pressure in response to placental ischemia in pregnant dams and may not exacerbate adverse fetal outcomes in response to placental ischemia.

Sex‐Specific Influence of Broad‐Spectrum Antibiotic Treatment on Dahl Salt‐Sensitive Hypertension

Our laboratory has previously demonstrated through fecal microbiota transfer studies that the gut microbiota importantly contributes to the development of hypertension, renal damage, and renal inflammation in the Dahl Salt-Sensitive (SS) rat fed a 4.0% high salt diet (HS). We have furthermore provided evidence that female SS rats are significantly protected from salt-induced hypertension, renal injury, and renal immune cell infiltration compared to males. One potential explanation for this sex difference is the substantial divergence we have observed in gut microbiota composition between male and female SS rats. Given the established role of the gut microbiota, we hypothesized that gut microbiota ablation via broad-spectrum antibiotic treatment would modulate the hypertensive response to high salt in both male and female SS rats. SS rats were treated with a broad-spectrum antibiotic cocktail of bacitracin and streptomycin (Bac/Strep, 2 g/L in drinking water) throughout the 3-week duration of HS challenge. SS males treated with Bac/Strep resulted in a significant reduction in mean arterial pressure (170.8±5.1 vs 156.0±4.1 mmHg, Vehicle vs Bac/Strep, n=12-13/group, p=0.001), proteinuria (365.0±39.7 vs 254.1±23.2 mg/day, p=0.002), and albuminuria (207.6±24.4 vs 124.3±10.3 mg/day, p<0.001) compared to male vehicle-treated rats after 3 weeks of HS. Due to the immunological nature of Dahl SS hypertension, we analyzed the infiltrating immune cell profile in the kidneys of Bac/Strep-treated males and found a specific decrease in B cells (40.7% reduction, p=0.012) as compared to vehicle-treated male SS kidneys, with no change in the number of T cells or monocytes/macrophages. These data altogether indicate that Bac/Strep treatment eliminated gut bacteria responsible for driving the hypertensive and renal injury phenotype in male Dahl SS rats. However, these protective effects of Bac/Strep were not observed in female SS rats. There was no significant difference in mean arterial pressure (134.6±3.1 vs 134.7±2.7 mmHg, Vehicle vs Bac/Strep, n=7-9/group, p= 0.974), proteinuria (39.5±3.8 vs 45.6±8.5 mg/day, p=0.408), or albuminuria (16.7±2.3 vs 18.7±3.7 mg/day, p=0.572) between vehicle- and Bac/Strep-treated female SS rats after 3 weeks of HS. Interestingly, despite the lack of an effect on the salt-induced hypertensive phenotype in females, there was still a significant decrease in renal B cells (38.5% reduction, p=0.05) in Bac/Strep-treated female SS rats compared to vehicle, perhaps indicating a specific effect of antibiotic treatment as opposed to a consequence of reduced blood pressure and renal damage. In conclusion, broad-spectrum antibiotic treatment reduced hypertension, renal damage, and renal inflammation in male Dahl SS rats, providing further evidence for the contribution of the gut bacteria in the response to HS. However, it appears that salt-induced elevations in blood pressure in female rats occur independent of Bac/Strep-sensitive gut bacteria.

Neutralization of Natural Killer Cell Associated Cytokines Improves Vascular Function and Reduces Blood Pressure in Placental Ischemic Rats

Women with preeclampsia (PE) have increased cytolytic NK cells (cNKs), interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) in the circulation and placenta. In previous studies, adoptive transfer of placental cNKs from the Reduced Uterine Perfusion Pressure (RUPP) model of PE into normal pregnant Sprague Dawley (SD) rats caused increased IFNγ and TNFα, and induced vascular dysfunction, hypertension (HTN), and restricted fetal growth (IUGR) similar to what is observed in PE patients. The purpose of this study was to examine the roles of IFNγ and TNFα in RUPP and PE pathophysiology. We hypothesized that neutralization of IFNγ or TNFα would attenuate PE-associated pathophysiology in RUPP rats. Pregnant SD rats underwent RUPP or Sham procedure on Gestation Day (GD) 14. On GD 15 and 18, a subset of Sham and RUPP rats received vehicle or 10μg/kg anti-IFNγ monoclonal antibody (IFNy-ab; n=9/group) i.p. On GD18, Uterine Artery Resistance Index (UARI) was measured via Doppler Ultrasound and on GD19, mean arterial pressure (MAP), fetal and placental weight were measured, and blood and tissues were processed for analysis. MAP was 105±2 mmHg and 108±2 mmHg in Sham and Sham+IFNγ-ab respectively, was elevated to 125±1 mmHg in RUPP (p<0.05 vs Sham), and reduced to 112±2 mmHg in RUPP+ IFNγ-ab (p<0.05 vs RUPP). Fetal and placental weights were significantly reduced in RUPP and remained so in RUPP+IFNγ-ab (p<0.05 vs Sham). UARI was 0.6±0.02 in Sham and Sham+ IFNγ-ab, was elevated to 0.73±0.02 in RUPP (p<0.05 vs Sham), and was normalized to 0.6±0.02 in RUPP+ IFNγ-ab (p<0.05 vs RUPP). Both placental ROS and plasma soluble Fms-like Tyrosine kinase 1 (sFlt-1) were elevated in RUPP (p<0.05 vs Sham) and were normalized in RUPP+IFNγ-ab (p<0.05 vs RUPP). In separate experiments, pregnant SD rats underwent RUPP or Sham procedure on GD 14. On GD 15 and 18, a subset of Sham and RUPP rats received vehicle or 0.4 mg/kg of Etanercept (ETA), a soluble TNFα receptor (n=10/group) i.p. Analyses were performed as described above. MAP was elevated in RUPP (127±2 mmHg) compared to Sham (105±3 mmHg) and Sham+ETA (109±2 mmHg, p<0.05) and was normalized to 109±3 mmHg in RUPP+ETA (p<0.05 vs RUPP). Both fetal and placental weights were significantly reduced in RUPP rats (p<0.05 vs Sham) and were normalized in RUPP+ETA (p<0.05 vs RUPP). UARI was 0.6±0.02 in Sham and 0.6±0.01 in Sham+ETA. UARI was elevated in RUPP (0.72±0.02, p<0.05 vs Sham) and was normalized to 0.61±0.02 in RUPP+ETA (p<0.05 vs RUPP). Plasma total nitrate was significantly reduced in RUPP (p<0.05 vs Sham) and was normalized in RUPP+ETA (p<0.05 vs RUPP). Placental ROS was elevated in RUPP (p<0.05 vs Sham) and remained so in RUPP+ETA (p>0.05 vs RUPP). Plasma sFlt-1 was 92±34 pg/mL in Sham and 53±9 pg/mL in Sham+ETA, was elevated to 1039±211 pg/mL in RUPP (p<0.05 vs Sham), and was normalized to 145±33 pg/mL in RUPP+ETA (p<0.05 vs RUPP). The results of this study suggest that increased secretion of IFNγ and TNFα by cNKs mediate vascular dysfunction to cause maternal HTN and IUGR in RUPP and PE pathophysiology. IFNγ and TNFα are potential therapeutic targets for treatment in PE.

Neonatal maternal separation decreases mean arterial blood pressure in adult female rats

Introduction The prevalence of depression is higher in adult women than in men. Interestingly, a decrease in arterial blood pressure is commonly observed in patients affected by this mood disorder. This association raises the possibility that low blood pressure could distinguish a subgroup of the population that are at higher risk to develop this psychiatric disorder. In rats, exposure to neonatal maternal separation (NMS) leads to depressive-like behaviors in adult animals, thus offering a simple translational model for pre-clinic studies. In addition, a variety of studies showed that during the premenstrual period a high number of women at reproductive-age present symptoms of irritability, emotional hypersensitivity, increased anxiety as well as depression. The impact of hormonal fluctuations on psychiatric disorders is well established, yet there are only a few studies regarding blood pressure control during different phases of the menstrual cycle. While the link between stress (including NMS) and hypertension has been well documented in males, the effects of hormonal fluctuations in pre-clinical studies in female animals have not been explored. Based on that, we developed two main hypotheses: 1) by comparison with undisturbed (control) rats, NMS decreases arterial blood pressure in adult females. 2) NMS will increase the impact of the estrous cycle on blood pressure. Methodology Rat pups were either undisturbed (control) or subjected to NMS during which pups were placed in individual spaces into a temperature-controlled incubator 3h/day from postnatal day 3 to 12. Once they reached adulthood, (8 weeks of age) cardiovascular parameters were measured in females using the tail cuff method. To cover all phases of the estrous cycle, we did our measurements once a week during 7 weeks, (between 8-14 weeks of animal's life), during the morning (9-12h) period. The data were analyzed using the two-way ANOVA test, comparing the treatment (CTRL vs NMS) and the phases of the estrous cycle. Results We showed that the diastolic and systolic pressures of NMS females were 5% less than controls (diastolic: CTRL: 84 mmHg, NMS: 79 mmHg, p=0.0015, systolic: CTRL: 121 mmHg, NMS: 116 mmHg, p=0.02). This resulted in a significant drop in mean arterial pressure (CTRL: 96 mmHg, NMS: 91 mmHg, p=0.02). The heart rate was similar between the groups. Surprisingly, we observed no effects of the estrous cycle on the blood pressure neither in NMS nor in control animals. Discussion This demonstrates that the NMS decreases the blood pressure of our female animals in adult life as observed in humans with anxiety and depressive behaviors. This observation further validates our model and justifies new studies exploring the mechanisms by which early life stress leads to physiological and psychiatric changes in adulthood. Ultimately, this research can help us develop more precise therapies for specific groups. For instance, Licht et al 2009 demonstrated that the use of antidepressant from patients that exhibited decreased blood pressure increases their risk to present hypertension.

The Influence of Anesthesia on the Cardiovascular Effects of Centrally Administered Clonidine

The α2 adrenergic receptor (α2AR) agonists are known to induce hypotensive responses when administered via intracerebroventricular (icv) route in normotensive rats anesthetized with either pentobarbital or urethane. However, the icv injection of α2AR agonists such as clonidine (CLO) produces hypertensive responses in normotensive conscious rats. To date, the effects icv administration of CLO in normotensive rats under ketamine/xylazine anesthesia, a commonly used anesthetic combination in experimental studies, is still unknown. We hypothesized that anesthetic drugs differentially modulate cardiovascular responses to centrally administered CLO. To evaluate this hypothesis, we assessed blood pressure (BP) and heart rate (HR) of normotensive male rats anesthetized with pentobarbital or ketamine/xylazine, both under mechanical ventilation. These animals received CLO (10 μg/5 μL) or dexmedetomidine (DEX; 0.6 μg/5 μL) by icv route. In additional experiments, yohimbine (5 μg/5 μL), a selective α2AR antagonist, was given by icv route 15 min before a second injection of CLO or DEX in ketamine/xylazine anesthetized rats. As widely described, the icv microinjection of CLO decreased the mean arterial pressure (MAP) and HR by 40.73 ± 6.3 mmHg and 134 ± 15 bpm in pentobarbital anesthetized rats (n = 5). On the other hand, in ketamine/xylazine anesthetized rats (n = 6) CLO increased MAP by 29.4 ± 5.1 mmHg and decreased HR by 34 ± 5 bpm, a less pronounced effect when compared with the pentobarbital group (p < 0.0001). Similarly, the icv microinjection of DEX in ketamine/xylazine anesthetized rats (n = 6) increased MAP by 20.8 ± 3.2 mmHg and decreased HR by 51 ± 16 bpm. Notably, yohimbine generated a pattern of hypotensive responses comparable to CLO and DEX. Additionally, after yohimbine administration, both CLO- and DEX-increased MAP were reduced to 9.9 ± 2.3 mmHg and 6.7 ± 1.1 mmHg, respectively (n = 6, p < 0.05), despite the lack of influence of yohimbine in the bradycardia induced by these α2AR agonists in ketamine/xylazine anesthetized rats. This study discloses that in normotensive rats under ketamine/xylazine anesthesia, central administration of CLO produces a hypertensive effect, opposing the findings obtained in pentobarbital-anesthetized rats and resembling the vascular responses described in conscious animals. This data was reproduced by DEX and reduced by yohimbine, suggesting that stimulation of central α2AR takes a preponderant role in this effect. Our results reinforce the relevance regarding the influence of anesthetic choice for studies involving cardiovascular parameters.

ET B Receptor Mediated Increases in Vasomotor Sympathetic Activity

Dysfunctional autonomic balance is a hallmark of many forms of hypertension. Endothelin B receptors (ETB-Rs) are present throughout the autonomic nervous system, but their role in modulating autonomic balance remains unclear. We have previously demonstrated that acute activation of ETB-Rs on sympathetic nerves increases blood pressure via a-1 adrenoceptor-mediated vasoconstriction. ETB-R deficient (ETB-def) rats lack functional ETB-Rs except on adrenergic tissues where functional ETB-Rs are expressed via transgene and have elevated vasomotor sympathetic tone compared to transgenic control (TG) rats, which express functional ETB-Rs and possess the transgene. We hypothesized that selective ETB-R blockade lowers blood pressure and sympathetic tone in ETB-def rats but raises blood pressure and sympathetic tone in TG controls. We anticipated that ETB-R blockade would create an intermediate blood pressure and sympathetic tone phenotype where ETB-def and TG controls would meet in the middle. We implanted male and female ETB-def rats and controls with telemetry to monitor freely-moving, conscious blood pressure, heart rate, and frequency domain parameters. Following baseline recordings, we implanted osmotic minipumps to deliver 10 mg/kg/d of A-192621, a selective ETB-R antagonist. We also injected 1.0 mg/kg chlorisondamine to directly measure vasomotor sympathetic tone both during baseline and drug infusion periods. All statistical comparisons were evaluated by 2-way RM ANOVA followed by Sidak's post hoc test. Following 3-4 days of A-192621 treatment, systolic blood pressure (SBP) did not change from baseline in ETB-def rats (+ 0.1 ± 3.2 mmHg; p = 0.99); however, SBP rose dramatically in TG controls (+ 18.0 ± 1.4 mmHg; p < 0.001). During A-192621 infusion, SBP in ETB-def and TG controls were similar (150.1 ± 2.7 vs 148.5 ± 2.3 mmHg, respectively, p = 0.85). In essence, TG controls became like ETB-def rats following ETB-R antagonism. At baseline, ETB-def exhibited higher vasomotor sympathetic tone as demonstrated by a greater decline in SBP following ganglionic blockade from chlorisondamine relative to TG controls (-61.0 ± 2.7 vs. -47.1 ± 2.1 mmHg, respectively; p = 0.01). A-192621 did not alter this response in ETB-def rats (- 64.6 ± 3.3 mmHg; p = 0.61 vs. baseline) but increased vasomotor tone in TG controls (- 56.8 ± 3.0; p = 0.03 vs. baseline). Frequency domain analysis also indicated that TG controls had increased sympathetic to parasympathetic vasomotor balance following A-192621 as measured by the low frequency to high frequency ratio (LF/HF) of SBP variability (+ 0.43 ± 0.11 LF/HF; p = 0.02) whereas ETB-def did not have a significant difference between baseline and treatment periods (-0.04 ± 0.18 LF/HF; p = 0.96). Taken together, these results indicate that selective ETB-R antagonism had no effect on blood pressure or vasomotor sympathetic tone in ETB-def animals but increased both parameters in TG controls to levels comparable to ETB-def. Contrary to our hypothesis, these results suggest that ETB-Rs on efferent sympathetic nerves may not influence blood pressure of vasomotor autonomic tone under normal physiological conditions; however, blockade or absence of ETB-Rs on sensory pathways may be responsible for the elevation of sympathetic tone and blood pressure.

High carbohydrate high fat diet induces the production of connective tissue growth factors, increased blood pressure, and changes in the aortic wall in aged rats

Age and diabetes are a risk factor for arterial hypertension. In the presented work, the morphological basis of an increase in blood pressure under the influence of a high-carbohydrate high-fat diet in old rats was investigated. It was determined the connective tissue growth factor levels and morphological changes in the aortic wall. A study was carried out in male Wistar rats weighing 350–400 g, 140 day old and rats weighing 530-620 g, 540 day old at the end of research. All procedures conformed to the Directive 2010/63/EU of the European Parliament and FASEB Statement of Principles for the use of Animals in Research and Education. Ethical approval was granted by the Ethical Committee of Research Institute of Cardiology, Tomsk National Research Medical Center. The high carbohydrate high fat diet (HCHFD) consisted from proteins 16%, fats 21%, carbohydrates 46%, including 17% fructose, 0.125% cholesterol, 90 days. Control group rats were fed a standard rat diet. It was found that the severity of arterial hypertension (Fig. 1), histological changes in the aortic wall (Fig. 2), and the level of connective tissue growth factors (TGFbeta, CTGF, fibronectin; Fig. 1) were significantly increased in elderly rats kept on a high-carbohydrate high-fat diet than young animals. In young rats kept on a high-carbohydrate, high-fat diet, arterial hypertension has a transient hypervolumic hallmark and does not cause changes in the aortic wall. The rise in blood pressure has a positive correlation with CTGF and fibronectin content (Fig. 1). These findings indicate that the formation of increased blood pressure in old rats when kept on a high carbohydrate high fat diet is associated with changes in the morphological structure of the aorta and is due to increased production of connective tissue growth factors.

Effect of music intervention during hemodialysis: a comprehensive meta-analysis.

Aggravating disease and the accompanying increase in the frequency of hemodialysis interventions worsen the quality of life of patients leading to poor physical and psychological outcomes. Music-based interventions have been suggested to improve both the physical and psychological prognoses for patients undergoing hemodialysis. Two meta-analyses on the impact of music-based interventions on anxiety in patients undergoing hemodialysis failed to evaluate the impact of these interventions on other physiological outcomes. Therefore, in this study, we gather evidence on the effects of music-based interventions on physical and psychological outcomes in patients with chronic kidney disease undergoing hemodialysis. To determine the influence of music-based interventions on anxiety, pain, heart rate, and blood pressure (systolic, diastolic) in patients with chronic kidney disease undergoing hemodialysis, we performed a systematic literature search adhering to PRISMA guidelines on the EMBASE, CENTRAL, Scopus, and MEDLINE academic databases. We performed meta-analyses to consolidate the evidence on the influence of music-based interventions on the physical and psychological outcomes of patients with chronic kidney disease undergoing hemodialysis. From 1,402 studies, we found eight eligible studies with 597 (264 women, 287 men) patients with chronic kidney disease undergoing hemodialysis (mean age, 56.9 ± 10.8 years). Among these patients, 298 received the music-based intervention and 299 were included as controls. Our meta-analysis revealed a small-to-medium effect of the music-based intervention to reduce pain levels (Hedge's g, -0.75), anxiety (-0.16), heart rate (-0.15), and systolic (-0.14) and diastolic blood pressure (-0.11) in patients with chronic kidney disease receiving hemodialysis as compared to the values of the same variables in the control group. The evidence from our analyses supports the beneficial impact of music-based interventions to alleviate anxiety and pain, and to reduce heart rate and blood pressure in these patients.

Nitric Oxide Alleviated High Salt-Induced Cardiomyocyte Apoptosis and Autophagy Independent of Blood Pressure in Rats.

The present study aimed to explore whether high-salt diet (HSD) could cause cardiac damage independent of blood pressure, and whether nitric oxide (NO) could alleviate high-salt–induced cardiomyocyte apoptosis and autophagy in rats. The rats received 8% HSD in vivo. H9C2 cells or primary neonatal rat cardiomyocytes (NRCM) were treated with sodium chloride (NaCl) in vitro. The levels of cleaved-caspase 3/caspase 3, cleaved-caspase 8/caspase 8, Bax/Bcl2, LC3 II/LC3 I, Beclin-1 and autophagy related 7 (ATG7) were increased in the heart of HSD rats with hypertension (HTN), and in hypertension-prone (HP) and hypertension-resistant (HR) rats. Middle and high doses (50 and 100 mM) of NaCl increased the level of cleaved-caspase 3/caspase 3, cleaved-caspase 8/caspase 8, Bax/Bcl2, LC3 II/LC3 I, Beclin-1, and ATG7 in H9C2 cells and NRCM. The endothelial NO synthase (eNOS) level was increased, but p-eNOS level was reduced in the heart of HSD rats and H9C2 cells treated with 100 mM NaCl. The level of NO was reduced in the serum and heart of HSD rats. NO donor sodium nitroprusside (SNP) reversed the increases of cleaved-caspase 3/caspase 3, cleaved-caspase 8/caspase 8, Bax/Bcl2 induced by NaCl (100 mM) in H9C2 cells and NRCM. SNP treatment attenuated the increases of cleaved-caspase 3/caspase 3, Bax/Bcl2, LC3 II/LC3 I, Beclin-1, and ATG7 in the heart, but had no effect on the blood pressure of HSD rats with HR. These results demonstrated that HSD enhanced cardiac damage independently of blood pressure. Exogenous NO supplementarity could alleviate the high salt–induced apoptosis and autophagy in cardiomyocytes.

Admission lactate level and the GRACE 2.0 score are independent and additive predictors of 30-day mortality of STEMI patients treated with primary PCI - preliminary results of a real-world registry

Abstract Funding Acknowledgements Type of funding sources: None. Background In many of the current risk estimation algorithms for patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI), heart rate and systolic blood pressure are key predictors. Yet, these parameters may also be influenced by the actual medical treatment / circulatory support, thereby decreasing the discriminatory power of the models. Purpose We aimed to investigate whether venous lactate level, a marker of microcirculatory failure, may have an added prognostic value beyond conventional predictors. Methods In a pilot real-world registry, 174 cases were studied. Venous blood gas analysis was performed in all patients at hospital admission. Nested logistic regression models were built using the extensively validated "Global Registry of Acute Coronary Events" (GRACE) 2.0 score alone (base model) or with the addition of venous lactate level (expanded model) using 30-day all-cause mortality as outcome measure. Independence of predictors (lack of collinearity) was evaluated by the variance inflation factor (VIF). Instead of the insensitive c-statistic, difference in performance of the nested models was analyzed by the likelihood ratio test and the integrated discrimination improvement (IDI). Results The VIF was 1.0684, indicating independence of the measured lactate values from the calculated GRACE 2.0 scores. Both base and expanded models showed high discriminatory power: c-statistic = 0.88 and 0.89, respectively, p = 0.68). Nevertheless, addition of venous lactate level to the GRACE 2.0 score improved predictions of 30-day mortality significantly as assessed by both likelihood ratio test (chi-square = 8.97, p = 0.0027) and IDI (IDI = 0.1029, 95% CI: 0.0002-0.2055, p = 0.0494). Conclusions Venous lactate level may be an independent predictor of 30-day mortality of STEMI patients treated with primary PCI. The addition of this marker to the GRACE 2.0 model may improve mortality prediction of these patients. Abstract Figure.

Cooperation of augmented calcium sensitization and increased calcium entry contributes to high blood pressure in salt-sensitive Dahl rats.

Salt hypertensive Dahl rats are characterized by sympathoexcitation and relative NO deficiency. We tested the hypothesis that the increased blood pressure (BP) response to fasudil in salt hypertensive Dahl rats is due to augmented calcium sensitization in the salt-sensitive strain and/or due to their decreased baroreflex efficiency. BP reduction after acute administration of nifedipine (an L-type voltage-dependent calcium channel blocker) or fasudil (a Rho kinase inhibitor) was studied in conscious intact rats and in rats subjected to acute NO synthase inhibition or combined blockade of the renin-angiotensin system (captopril), sympathetic nervous system (pentolinium), and NO synthase (L-NAME). Intact salt-sensitive (SS) Dahl rats fed a low-salt diet had greater BP responses to nifedipine (-31 ± 6 mmHg) or fasudil (-34 ± 7 mmHg) than salt-resistant (SR) Dahl rats (-16 ± 4 and -17 ± 2 mmHg, respectively), and a high-salt intake augmented the BP response only in SS rats. These BP responses were doubled after acute NO synthase inhibition, indicating that endogenous NO attenuates both calcium entry and calcium sensitization. Additional pentolinium administration, which minimized sympathetic compensation for the drug-induced BP reduction, magnified the BP responses to nifedipine or fasudil in all groups except for salt hypertensive SS rats due to their lower baroreflex efficiency. The BP response to the calcium channel blocker nifedipine can distinguish SS and SR rats even after calcium sensitization inhibition by fasudil, which was not seen when fasudil was administered to nifedipine-pretreated rats. Thus, enhanced calcium entry (potentiated by sympathoexcitation) in salt hypertensive Dahl rats is the abnormality that is essential for their BP increase, which was further augmented by increased calcium sensitization in salt-sensitive Dahl rats.

Effects of S1PR2 antagonist on blood pressure and angiogenesis imbalance in preeclampsia rats.

Preeclampsia (PE), a hypertensive multisystem disorder, can lead to increased maternal and fetal mortality and morbidity. Sphingosine‑1‑phosphate (S1P) plays various roles, depending on the cell type, by binding to S1P receptors (S1PR). The present study evaluated the changes of S1PRs and investigated the potential role of S1PRs in pregnancy‑induced hypertension. PE rats were established by reduced uterine perfusion pressure. The involvement of S1PR2 was evaluated using JTE‑013, a specific S1PR2 antagonist, in PE rats. After the treatment, inflammatory cytokines were evaluated using enzyme linked immunosorbent assay, and the expression of vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS) activation and endothelial nitric oxide synthase (eNOS) were evaluated by reverse transcription‑quantitative PCR and western blotting. Results showed that S1PR2, but not S1PR1 and S1PR3, was significantly increased in the serum and placenta tissues of PE rats. Notably, JTE‑013 significantly decreased blood pressure, attenuated infiltration of inflammatory cells and decreased inflammation, as indicated by the decreased expression of inflammatory cytokines, including tumor necrosis factor‑α, interleukin‑1β (IL‑1β) and IL‑6, in placental tissues. Mechanistic studies demonstrated that JTE‑013 significantly increased the expression of VEGF and decreased the expression of fms‑like tyrosine kinase1 in placental tissue. Furthermore, JTE‑013 prevented iNOS activation and increased eNOS in placental tissue. In summary, the present study demonstrated that S1PR2 contributed to hypertension and angiogenesis imbalance in PE rats.

Endotheliumprotectiv and antihypoxic properties of quercetin in elderly patients with metabolic syndrome

Aim: To investigate the effectiveness of course quercetin in improving functional state of the microvascular endothelium and to determine the possibility of using quercetin to increase body resistance to hypoxia in the elderly. Materials and methods. The effectiveness of quercetin in improving the functional state of the endothelium and increasing body resistance to hypoxia was studied in 110 elderly patients with metabolic syndrome, who were divided equally into the main and control groups. Patients in the main group received quercetin at a daily dose of 240 mg for 3 months, and patients in the control group received placebo for the same period. Before and after treatment, the microvascular endothelial function was studied by laser Doppler flowmetry using the post-occlusive hyperemia test. Acute hypoxic test was performed under isocapnicnormobaric hypoxia, during which the followings were recorded: blood saturation (SpO2), heart rate and diastolic blood pressure (BP). Results. In the group of patients receiving quercetin, there was an improvement in blood flow to the skin, as evidenced by a statistically significant increase in the maximum volumetric rate of cutaneous blood flow and the duration of the recovery period of OSHSK to baseline in the post-occlusive hyperaemia. The course of quercetin also led to a less significant decrease in SpO2 during hypoxic test and to a decrease in the absolute values of systolic and diastolic blood pressure, while reducing an increase of the systolic blood pressure on the 20th min of the hypoxic test. Conclusions. In elderly patients with metabolic syndrome (within a 3 month course) the use of quercetin has improved the microvascular endothelium functional status and increased the resistance to hypoxia.

Chronic Blockade of NMDAR Subunit 2A in the Hypothalamic Paraventricular Nucleus Alleviates Hypertension Through Suppression of MEK/ERK/CREB Pathway

N-methyl-D-aspartate Receptor (NMDAR) in the hypothalamic paraventricular nucleus (PVN) plays critical roles in regulating sympathetic outflow. Studies showed that acute application of the antagonists of NMDAR or its subunits would reduce sympathetic nerve discharges. However, little is known about the effect of long-term management of NMDAR in hypertensive animals. PEAQX, the specific antagonist of NMDAR subunit 2A (GluN2A) was injected into both side of the PVN of two-kidney, one clip (2K1C) renal hypertensive rats and control (normotensive rats) for three weeks. Three weeks of PEAQX infusion significantly reduced the blood pressure of the 2K1C rats. It managed to resume the balance between excitatory and inhibitory neural transmitters, reduce the level of pro-inflammatory cytokines and reactive oxygen species in the PVN, and reduce the level of norepinephrine in plasma of the 2K1C rats. PEAQX administration also largely reduced the transcription and translation levels of GluN2A and changed the expression levels of NMDAR subunit 1 and 2B (GluN1 and GluN2B). In addition, NMDAR was known to function through activating the extracellular regulated protein kinases (ERK) or phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways. In our study we found that in the PVN of 2K1C rats treated with PEAQX, the phosphorylation levels of mitogen-activated protein kinase kinase (MEK), ERK1/2 and cAMP-response element binding protein (CREB) significantly reduced, while the phosphorylation level of PI3K didn't change significantly. Chronic blockade of GluN2A alleviates hypertension through suppression of MEK/ERK/CREB pathway.

Molecular Mechanism of Palmitic Acid on Myocardial Contractility in Hypertensive Rats and Its Relationship with Neural Nitric Oxide Synthase Protein in Cardiomyocytes.

Objective It is aimed at investigating the mechanism of palmitic acid (PA) on myocardial contractility in hypertensive rats and its relationship with myocardial neural nitric oxide synthase (nNOS) protein. Methods The rats were randomly divided into sham operation group and hypertensive group, with thirty rats in each group, to prepare angiotensin II-induced hypertensive model rats. The blood pressure of rats was measured by the multianimal multichannel tail cuff noninvasive blood pressure system of Kent Coda, USA. The Ionoptix single-cell contraction detection system was used to detect myocardial cells. ATP level of left ventricular cardiomyocytes was determined by luminescence method, and protein was measured by Western blot. Results Compared with the sham group, systolic blood pressure and diastolic blood pressure were increased in the hypertensive group over 4 weeks; PA increased the contractility of left ventricular cardiomyocytes in normal rats, but not in hypertensive rats, and PA increased the intracellular ATP level of rats in the sham group but not in the hypertension group. In the hypertension group, the expression of nNOS in the cardiomyocytes was significantly increased, and specific nNOS inhibitor S-methyl-L-thiocitrulline (SMTC) was found to restore the positive inotropic effect of PA in the myocardium of the hypertension group. PA was supplemented after using CPT-1 inhibitor etomoxir (ETO); it was found that ETO inhibited the positive inotropic effect of PA on left ventricular cardiomyocytes in the sham group, and PA was supplemented after using SMTC and ETO, it was found that SMTC + ETO could inhibit the positive inotropic effect of PA on left ventricular cardiomyocytes in myocardium of hypertensive rats. Conclusion PA could increase the contractility of healthy cardiomyocytes, but had no obvious positive effect on the cardiomyocytes of hypertensive rats, PA enhanced the contractility of cardiomyocytes by increasing ATP level in them, and the inhibitory effect of PA on myocardial contractility in hypertensive rats may be related to the increased nNOS and CPT-1 in cardiomyocytes.

Design and Evaluation of User Interface Design of Mobile Heart Monitoring Application

Many mobile health applicationsincluding mobile heart monitoring applications are available on Apple App Store, and Google Play Store. However, when the user feels dissatisfied with the user interface design of the mobile heart monitoring application, it impacts user satisfaction level to the extent that the users do not use it anymore. User satisfaction level isa very important factor in usability to identify a mobile heart monitoring application whichis pleasant and comfortable forcontinuous use. This study recruited four cardiologists in a hospital in Palembang, Indonesia for evaluatingtheuser interface design ofa mobile heart monitoring prototype called HeartM. The prototype has several features including measuringpatient’s heart rate and blood pressurerate, treatment record, forum, and chat to ease communication between heart patients and their cardiologist. The focus of the user interface design evaluation are oncontent, visual and navigation aspects.This paper contributes to user interface design knowledge and design recommendations particularly for mobile heart monitoring applications.

Statement of Retraction: Effects of isoflurane on arterial blood pressure, heart rate, and phrenic nerve discharge in the decerebrate rat

Statement of Retraction: Effects of isoflurane on arterial blood pressure, heart rate, and phrenic nerve discharge in the decerebrate rat