bluuebunny/crossref_metadata_2025_split huggingface dataset:
ANTI-HYPERTENSIVE EFFECT OF THE DIPEPTIDE, TYROSYL-PROLINE, IN RVLM; A MICROINJECTION STUDY
Authors: Zahid Hasan Md. , Fujikawa Koichi , Ohara Hiroki , Okamoto Kenji , Nabika Toru 
Published: April 2021

Objective:
Oligo-peptides were shown to have various physiological effects in-vivo. In this study, we evaluated antihypertensive activity of a dipeptide, tyrosyl-proline (YP), which was found in fermented milk at high concentration.

Design and method:
To evaluate effects of YP in CNS, YP was micro-injected into the rostral ventrolateral medulla (RVLM), the nucleus in the brainstem regulating blood pressure (BP), and changes in intra-arterial BP were monitored directly with a catheter inserted in the femoral artery in anesthetized rats. This study was supported by the Research Program on Development of Innovative Technology of the Bio-oriented Technology Research Advancement Institution, NARO.

Results:
YP microinjection into RVLM reduced BP in a dose-dependent manner. BP reduction at 100 pmole of YP was 41 ± 3 mmHg in SHRSP, which was as strong as that of LVY and IPP, both of which were known to have a potent anti-hypertensive effect. BP decrease was much smaller in WKY (7 ± 2 mmHg). Different sequences of dipeptide composed of tyrosine and proline (PY, YY and PP) showed much less effect on BP, excluding a possibility that the effect of YP on BP was non-specific. Naloxone (a non-specific inhibitor of opioid receptors) and nor-binaltorphimine (a selective inhibitor of kappa opioid receptor) antagonized the effect of YP, whereas naltrindole (a selective inhibitor of delta opioid receptor) failed to block it. This result implied that the effect of YP in RVLM was mediated by kappa opioid receptor.

Conclusions:
YP might play an important role in regulation of BP in RVLM through opioid receptors.
CHANGES IN MUSCLE-SPECIFIC MICRORNAS ACCOMPANY TERMINAL STAGES OF MONOCROTALINE-INDUCED PULMONARY HYPERTENSION IN RAT
Authors: Kmecova Zuzana , Veteskova Jana , Zirova Katarina , Pivackova Lenka Bies , Doka Gabriel , Malikova Eva , Krenek Peter , Passakova Nina , Paulis Ludovit , Luknar Milan , Goncalvesova Eva , Klimas Jan 
Published: April 2021

Objective:
Importance of muscle-specific microRNAs (miR-1/miR-133a/miR-208/miR-499) has been identified in various cardiovascular pathologies, including their potential of being biomarkers in these diseases. Pulmonary arterial hypertension (PAH) is an incurable disease progressing into right ventricular (RV) failure as the leading cause of death. Here, we hypothesised that muscle-specific microRNAs influence RV damage in PAH and their plasma levels might be used also as indicators of disease severity.

Design and method:
12-weeks old male Wistar rats were administered either monocrotaline (MCT group) or vehicle (CON group) and the animals were sacrificed 4 weeks after this treatment. Certain animals from MCT group, in which the condition of pulmonary hypertension (PH) developed more severely, were terminated prematurely (ptMCT group), since they displayed signs of serious clinical worsening and so represented the terminal stage of PH. Additionally, plasma samples of patients diagnosed with PAH were obtained from a PAH referral centre. Expression of microRNAs, both in rats and humans, was determined by RT-qPCR.

Results:
Fulton index of MCT and ptMCT animals was gradually increased by 47% (p < 0.05 vs CON) and by 110% (p < 0.05 vs CON and MCT) respectively. Expression of muscle-specific microRNAs in RV was not significantly altered in MCT group, but we noted decrease in ptMCT group (-52% for miR-1, -61% for miR-133a, -64% for miR-208, -57% for miR-499 vs CON, all p < 0.05). In human plasma samples, only miR-1 and miR-133a expressions were reliably determinable by RT-qPCR, nevertheless, we noted no significant correlations with mean pulmonary arterial pressure, pulmonary vascular resistance, RV cardiac output or NT-proBNP levels.

Conclusions:
The decrease of muscle-specific microRNAs in ptMCT group suggests that they might not be responsible for RV modifications in earlier stages of developed PH, but their downregulation in RV tissue mirrors the severity of terminal stages of this experimental model. On the other hand, based on our results, the use of muscle-specific microRNAs as clinical biomarkers of PAH remains elusive and the attention should be directed to other miRNA candidates.
A HIGH SALT DIET ALTERS THE DAILY RHYTHM OF BLOOD PRESSURE IN C57BL6/J MICE
Authors: Ivy Jessica , Ralph Ailsa , Costello Hannah , Celine Grenier , Stewart Kevin , Dhaun Neeraj , Bailey Matthew 
Published: April 2021

Objective:
Abnormal blood pressure (BP) rhythms precede and predict cardiovascular disease and are often linked with salt-sensitivity. The mechanisms underlying these rhythms are unknown. High dietary salt intake can cause phase shifts in the intrinsic circadian clocks within peripheral organs but the implications for BP rhythm are unclear. We investigated the effect of a high salt diet on the rhythms of BP, heart rate (HR) and activity.

Design and method:
BP was monitored by radiotelemetry in male C57BL6/J mice. After 1 week of 0.25% Na+ chow (baseline), mice received 3% Na+ diet for 3 weeks followed by 0.25% Na+ for a further 2 weeks (Na+ washout). Systolic BP (SBP), HR and activity data was analysed by cosinor analysis. Sympathetic nervous system activity was estimated by measuring 12 h urinary catecholamine spillover and plasma aldosterone was measured following a week of 3% Na+ diet.

Results:
Mesor (circadian mean) SBP increased by 7mmHg after week 1 of 3% Na+ diet. This was maintained over 3 weeks but reduced to baseline after Na+ washout. BP amplitude increased from 9mmHg (baseline) to 14mmHg within 1 week of 3% Na+ feeding. This was maintained for the 3 weeks of 3% Na+ but reduced to 8mmHg following Na+ washout. This reflected elevated active-phase BP rather than enhanced dip in sleep-phase BP. A ∼4.5-hour phase delay in SBP was observed in the second week of 3% Na+ diet. HR mesor did not change throughout the experiment but amplitude was elevated at 3 weeks of 3% Na+. Activity amplitude increased during the first week of 3% Na+ intake but was not maintained at week 2. Plasma aldosterone was appropriately suppressed but day and night urinary adrenaline levels were increased after 1 week on 3% Na+ diet.

Conclusions:
C57BL6/J mice exhibit salt-sensitive BP. A 3% Na+ diet altered BP rhythm by increasing amplitude and inducing a modest phase shift. Further studies are needed to investigate the role of the sympathetic system and intrinsic molecular clocks in the induction of these rhythms. This may give insights into mechanisms underlying the relationship between salt-sensitivity and abnormal BP rhythms.
ECTOPIC TWEAKR EXPRESSION IN TYPE I FIBER OF STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS IS RELATED TO SLOW MUSCLE-SPECIFIC HYPOTROPHY THROUGH MURF1 OVEREXPRESSION
Authors: Inoue Takao , Hagiyama Man , Maenishi Osamu , Kimura Masatomo , Mizuguchi Nobuyuki , Mine Yoshihiro , Kimura Ryuichiro , Chikugo Takaaki , Itoh Tatsuki , Satou Takao , Ito Akihiko 
Published: April 2021

Objective:
The maintenance of muscle strength and mass is important for body homeostasis. Stroke-prone spontaneously hypertensive rats (SHRSP) show significantly higher blood pressure and lower body weight than normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In addition, blood pressure and body weight show an inverse correlation among the rats. We hypothesized that skeletal muscle hypotrophy in hypertensive rats is related to hypertension-related diseases and is useful as a therapeutic target for hypertension and hypertension-related diseases. We aimed to investigate the pathophysiological characteristics of muscle hypotrophy in SHRSP to determine the therapeutic target molecule(s).

Design and method:
First, the difference in skeletal muscles in the lower leg between WKY and SHRSP was evaluated mainly through weight/tibial length and histological analysis. Further experiments were carried out based on gene expression using microarray, protein expression, and immunohistochemistry analyses.

Results:
SHRSP had a significantly lower weight/tibial length in the soleus and gastrocnemius, but not in the plantaris and tibialis anterior. This suggests that muscles with a relatively high amount of slow muscle fiber (type I fiber) show hypotrophy. Histological analysis of the soleus, showing that type I fibers mainly decreased the fiber size, corresponded to the result of weight/tibial length. Microarray and protein expression analyses showed that the muscle-specific ubiquitin ligase, muscle RING finger 1 (MuRF1), but not atrogin-1, was highly expressed in the soleus, but not in the plantaris, in SHRSP. TNF-like weak inducer of apoptosis receptor (TWEAKR) was predicted as a MuRF1 up-regulator in the Ingenuity Pathway Analysis. There was no significant difference in TWEAKR expression level in the soleus between WKY and SHRSP. However, immunofluorescence revealed that WKY had only type II fiber staining, but SHRSP had both type I and II fiber staining.

Conclusions:
TWEAKR is a type II-specific receptor in the skeletal muscle. Ectopic TWEAKR expression in type I fibers of SHRSP is most likely involved in slow muscle-specific hypotrophy through MuRF1 overexpression. The TWEAKR-MuRF1 pathway may be a useful therapeutic target for slow muscle hypotrophy.
SEX DIFFERENCES IN RESPONSE TO STRESS IN MALE AND FEMALE HYPERTENSIVE SCHLAGER MICE
Authors: Gueguen Cindy , Jackson Kristy L. , Le-Pham Phuong-Nhan , Head Geoffrey A. 
Published: April 2021

Objective:
The inbred hypertensive mouse strain (BPH/2) and a normotensive strain (BPN/3) are thought to be a neurogenic form of hypertension. The aim of the current study was to compare the cardiovascular characteristics of male and female hypertensive and normotensive mice to determine any sex differences in the underlying mechanisms.

Design and method:
12-week-old hypertensive BPH/2J and normotensive BPN/3J male and female mice were implanted with telemetry probes to record blood pressure (BP), heart rate and activity. Cardiovascular responses to restraint, dirty cage swap, feeding, enalaprilat and pentolinium were measured in conscious mice.

Results:
Mean, systolic, diastolic BP, heart rate and activity were similar in males and females but higher in BPH/2 than BPN/3 (n = 5–7). Day night differences in BP were 3 times higher in BPH/2 compared to BPN/3 (17 vs 6 mmHg respectively) but similar in male and female mice. The depressor responses to enalaprilat reduced BP by -11 ± 1 mmHg and was similar in both male strains but greater in female BPH/2 mice (-17 ± 1 mmHg). Blocking the sympathetic nervous system activity produced a 5-fold greater reduction in BP in male and female BPH/2 mice. The pressor response to restraint stress was higher in BPH/2 than BPN/3 but similar in the males and females of each strain. While the pressor response to dirty cage swap was greater in BPH/2 than BPN/3 mice, it was also greater in males than females. Treatment with a synthetic neurosteroid ganaxolone (5 mg/kg/day) for 2 weeks attenuated the pressor response to cage swap only in male BPH/2 mice and not in females. The percentage of time spent in a dark area compared to the light (indicating anxiety) was similar in males and females of both strains.

Conclusions:
While hypertension is similar in male and female BPH/2 mice the differential response to behavioral stress tests and their susceptibility of attenuation by ganaxolone in males and females suggests important differences in the central pathways controlling the adverse response to stress. Understanding these differences may be relevant to the higher cardiovascular risk observed in males.
A SELECTIVE UPREGULATION OF GABAA RECEPTOR SUBUNIT EXPRESSION IS ASSOCIATED WITH THE HYPOTENSIVE EFFECTS OF GANAXOLONE IN MALE HYPERTENSIVE SCHLAGER MICE
Authors: Gueguen Cindy , Le-Pham Phuong-Nhan , Jackson Kristy L , Paterson Madeleine R , Esler Murray , Marques Francine Z , Lambert Elisabeth , Head Geoffrey A 
Published: April 2021

Objective:
Ganaxolone is a synthetic form of allopregnanolone, an allosteric modulator of gamma aminobutyric acid type A receptors (GABAAR). Allopregnanolone reduced blood pressure (BP) in male BPH/2J mice with neurogenic hypertension (Stevenson et al., 2017), which suggests that a lack of tonic inhibition in the forebrain mediates the hypertension. The hypotensive effect of allopregnanolone was associated with an upregulation of the GABAAR alpha4 and delta-subunit mRNA in the hypothalamus and medial amygdala of BPH/2J mice. The objective of this study was to investigate the temporal association of the antihypertensive effects of ganaxolone and the alteration in the different GABAAR subunits in the forebrain of BPH/2J mice.

Design and method:
12-week-old hypertensive BPH/2J and normotensive BPN/3J male mice were implanted with a telemetry probe to record BP and heart rate. Cardiovascular responses to stress tests and pentolinium were measured before and after administering vehicle or ganaxolone (5 mg/kg/day, subcutaneous minipumps) for 2 weeks. The mRNA expression of the GABAAR subunits was measured by real-time PCR 1 to 2 weeks after the beginning of the treatment in vehicle or ganaxolone-treated BPH/2J mice.

Results:
After 2 weeks, ganaxolone reduced BP by 10.7 mmHg (P < 0.001) in male BPH/2J mice and reduced the pressor responses during restraint (-8.2 mmHg, P < 0.001) and dirty-cage switch (-12.4 mmHg, P < 0.001) stresses compared with pre-treatment. One-week treatment with ganaxolone or vehicle had no effect on cardiovascular parameters on either strain. Ganaxolone-treated BPH/2J mice had increased mRNA expression of alpha4-subunit and showed a trend towards increased delta-subunit of hypothalamic GABAAR compared to vehicle-treated BPH/2J. None of these effects were seen at 1-week post-treatment and in BPN/3J mice.

Conclusions:
Ganaxolone reduced hypertension and the cardiovascular response to stress in male BPH/2J mice but only when upregulated alpha4 and delta-subunit mRNA expression of the GABAAR was observed. Therefore, it is likely that the main mechanism of the delayed antihypertensive effects of ganaxolone in neurogenic hypertensive mice is dependent on upregulation of specific GABAAR subunits.
ARYL HYDROCARBON RECEPTOR ANTAGONISTS - A NEW ENTRY IN ANTIHYPERTENSIVE ARMAMENTARIUM OF OBSTRUCTIVE SLEEP APNEA?
Authors: Pereira Sofia Azeredo , Coelho Nuno R. , Tomkiewcz Céline , Correia Maria João , Pimpao Antonio B. , Barouki Robert , Coumoul Xavier , Monteiro Emilia C 
Published: April 2021

Objective:
To investigate aryl hydrocarbon receptor (AhR) metabolic circuitry as a druggable target in chronic intermittent hypoxia (CIH) induced hypertension (HTA).

Design and method:
This study was approved by Nova Medical School's Ethics Committee and followed national and international regulations. We used a rat model of CIH-induced HTA to disclose the hypothesis that the aryl hydrocarbon receptor (AHR) is activated by IH, once it shares the same binding partner of HIF-1alpha and promotes pro-oxidant, pro-inflammatory (NF-kB) and pro-fibrotic events in common with CIH. AhR activation was measured by the mRNA and protein levels of its hallmark target gene Cyp1a1. Blood pressure, heart rate and locomotor activity were measured daily by radiotelemetry. A CIH paradigm of 21% to 5% of O2, 5.6 cycles/h, 10.5 h/day was used in their inactive/sleep period.

Results:
Upon established hypertension (21 days exposure to IH), we observed an increase in Cyp1a1 mRNA (hallmark of AhR activation) in kidney cortex (6-fold), kidney medulla (3-fold) and liver (3-fold), but not in other tissues. Increased renal expression of Ahr and markers of inflammation (Rela), epithelial to mesenchymal transition markers, the rate-controlling step of gluconeogenesis, Pepck1, and members of HIF-pathway, namely, Hif-3alpha were also observed. The ratio kynurenin/tryptophan (inflammatory index) was also increased in the kidney. The chronicity of IH increased the protein levels of cyp1a1 protein (western blot). Daily administration (14 days) of AHR antagonist, CH-223191 (5 mg.kg-1.day-1, gavage), simultaneously to CIH prevented the increase in systolic blood pressure (SBP) by 53 ± 12% and in diastolic blood pressure (DBP) by 44 ± 16%. Moreover, this AhR antagonist administration upon already established HTN reversed the increase in SBP by 52 ± 12%. Despite the antihypertensive effect seen in the rats’ active phase, in the inactive period, CH22319 did not revert the non-dipping blood pressure profile associated to CIH.

Conclusions:
CIH caused an activation of AHR signaling particularly in the kidney and its pharmacological blockade had a significant impact reverting already established HTN. This first evidence inspires innovative research opportunities for the understanding and treatment of this particular type of HTN.
PREVALENCE AND PREDICTORS OF ADVERSE DRUG REACTIONS IN OLDER HYPERTENSIVE ADULTS
Authors: Turrin Giada , Coscarelli Antonio , D’andria Maria Flora , Tortu Virginia , Giuliani Evelina , Ungar Andrea , Rivasi Giulia 
Published: April 2021

Objective:
Polipharmacy is common in older people, thus increasing the risk of adverse drufg reactrions. This study aimed to analyse prevalence and predictors of the most relevant adverse drug reactions in older hypertensive adults.

Design and method:
We retrospectively analysed data on antihypertensive- and statin-related adverse drug reactions in adults aged 65 or older evaluated at the Hypertension Clinic of Careggi Hospital, Florance, Italy, between January 2018 and December 2019. Predictors were investigated using multivariate logistic regression.

Results:
Of 262 participants (mean age 75.9 years, 55.3% female), the 19% of the patients taking ACE-inhibitors reported cough while 33.6% of the patients taking calcium channel blockers (CCB) reported peripheral edema, occuring more frequently of amlodipine. The prevalence of statin-related myalgia was 23.5%. At multivariate analysis SNRI antidepressants and gastroesophageal reflux disease (GERD) were predictive of ACE-inibitors induced cough (OR 16.220, 95% CI 1.243 – 211.621; OR 4.207, 95% CI 1.249 – 4.171, respectively) and angiotensin-receptor antagonists were associated with an increased risk of peripheral edema on CCB (OR 2.500, 95% CI 1.095 - 5.710). GERD was predictive for statin-induced myalgia (OR 6.737, 95% CI 1.530 - 29.662).

Conclusions:
ACE inhibitor-induced cough, CCB-related peripheral edema and statin-induced myalgia are common in older hypertensive adults. SNRI antidepressants and GERD are independently associated with ACE inhibitor-induced cough, while angiotensin-receptor antagonists are predictive of CCB-related peripheral edema. GERD is also associated with statin myalgia.
HUMAN AMNION EPITHELIAL CELLS REDUCE BLOOD PRESSURE AND PREVENT AORTIC INFLAMMATION AND COLLAGEN EXPRESSION DURING EXPERIMENTAL HYPERTENSION
Authors: Dinh Quynh Nhu , De Silva Cecilia , Diep Henry , Zhang Shenpeng R , Arce Liz J Barreto , Lim Rebecca , Drummond Grant R , Sobey Christopher G , Silva T. Michael De 
Published: April 2021

Objective:
Vascular inflammation and fibrosis are hallmarks of hypertension and contribute to the development of cardiovascular disease. Current treatments for hypertension may reduce blood pressure but do not target the associated pathological changes and end-organ damage. Cell therapy has great therapeutic potential for many conditions as, unlike single pharmacological agents, cells can deliver multiple mediators which could more effectively target complex disease mechanisms. Human amnion epithelial cells (hAECs) have many properties (eg. anti-inflammatory, anti-fibrotic, regenerative and immunologically inert) that make them attractive candidates for a cell-based therapy for vascular pathology. This study aimed to test the potential of hAECs to treat vascular pathology in angiotensin II-induced hypertension.

Design and method:
Male C57Bl6 mice (8–12 weeks) were administered vehicle (saline; n = 35) or angiotensin II (0.7 mg/kg/d, n = 37) for 14 d via a subcutaneous osmotic minipump. After minipump implantation, a subset of mice were injected with 10^6 of hAECs intravenously. Systolic blood pressure was measured using tail-cuff; inflammation was assessed using flow cytometry and markers of fibrosis using quantitative PCR.

Results:
Angiotensin II infusion increased systolic blood pressure and promoted accumulation of aortic leukocytes, specifically macrophages and monocytes, which were elevated by ∼3-fold compared to vehicle-infused mice (n = 9–11, P < 0.05). Angiotensin II also increased aortic mRNA expression of collagen type 1 alpha 1 (Col1a1) by ∼4-fold and collagen type 5 alpha 1 (Col5a1) by ∼7-fold compared to vehicle (n = 6–8, P < 0.05). Co-administration of hAECs limited the development of hypertension by angiotensin II (185 ± 5 mmHg vs 165 ± 4 mmHg; n = 9–11, P < 0.05), as well as the aortic infiltration of macrophages and monocytes (n = 9–11, P < 0.05) and expression of Col1a1 and Col5a1 (n = 6–8, P < 0.05).

Conclusions:
Intravenous administration of hAECs blunted angiotensin II-induced hypertension, aortic inflammation and collagen expression in male mice. This study suggests that hAECs or their cellular products could be explored as treatments for vascular pathology during hypertension.
LOSS OF ADD1 METHYLATION ADDS ON BLOOD PRESSURE IN YOUNG ADULTS
Authors: Omar Wan Fatein Nabei Wan , Talib Norlelawati A. , Rahman Jamalludin Ab. , Shah Azarisman Shah Mohd , Abdullah Aszrin 
Published: April 2021

Objective:
To investigate the association between alpha-Adducin (ADD1) methylation and blood pressure in young adults with essential hypertension.

Design and method:
A total of 160 subjects (80 normotensive and 80 incident hypertensive) aged between 18 to 45 years from Kuantan, Pahang were included in a cross-sectional study by purposive sampling. They were assessed for ADD1 methylation in peripheral blood using MethyLight assay. Anthropometric measurements and biochemical parameters were also examined.

Results:
ADD1 methylation was inversely correlated with systolic (p = 0.006, r = –0.240), diastolic (p = 0.001, r = –0.281) and mean arterial pressures (p = 0.002, r = –0.270). Hypertensive subjects had significantly higher ADD1 methylation than normotensive control (p = 0.005). After adjusting for other relevant covariates (age, body mass index, HbA1c, high-sensitivity C-reactive protein and low density lipoprotein cholesterol), ADD1 methylation remained a significant predictor for hypertension in young adults (p = 0.020)

Conclusions:
ADD1 methylation is a significant predictor of hypertension in young adults. ADD1 methylation could serve as a future preventive and therapeutic target for hypertension and related cardiovascular disease.