Hypertensive Animals Research Articles

Hypertension contributes to exacerbated osteoarthritis pathophysiology in rats in a sex-dependent manner

BackgroundHypertension is a common comorbidity of osteoarthritis (OA) with known autonomic dysregulation; thus, the autonomic nervous system may provide a shared underlying mechanism. The objective of this study was to examine the role of the autonomic nervous system in a preclinical model of OA and hypertension.MethodsExperiments were conducted in spontaneously hypertensive rats and a normotensive control strain, including male and female rats. OA was surgically induced via medial meniscus transection with skin incision used as a sham control (n = 7–8/strain/sex/surgery). Tactile sensitivity, anxiety-related behavior, and serum corticosterone were measured at baseline then bi-weekly across 8 weeks. At weeks 9–10, cardiovascular responses to a chemical vagal nerve agonist were determined to indirectly evaluate vagus nerve function. The joint structure was assessed via grading of histological sections.ResultsIn males, OA resulted in thinner cartilage in both hypertensive (OA vs. non-OA p < 0.001) and normotensive (OA vs. non-OA p < 0.001). Only females with comorbid hypertension and OA displayed thinner cartilage (p = 0.013). Male hypertensive OA animals had increased calcified subchondral bone compared to normotensive OA animals (p = 0.043) while female hypertensive OA animals had increased calcified subchondral bone compared to hypertensive sham animals (p < 0.001). All MCLT+MMT groups developed low-grade synovitis; interestingly, hypertensive OA females had higher synovitis scores than normotensive OA females (p = 0.046). Additionally, hypertension led to larger drops in blood pressure with vagal activation in both OA (hypertensive vs. normotensive p = 0.018) and sham (hypertensive vs. normotensive p < 0.001) male animals. In females, this trend held true only in OA animals (normotensive vs. hypertensive p = 0.005).ConclusionThese data provide preliminary evidence that hypertension influences OA progression and encourages further study into the autonomic nervous system as a possible mechanism.

Microcirculation and Physical Exercise In Hypertension.

Hypertension is associated with important alterations in the morphology of small arteries and arterioles. Vascular-specific manifestations are changes in the structure and function of vascular smooth muscle cells, extracellular matrix, perivascular tissues, and endothelial cells. Arteriole and capillary remodeling and capillary rarefaction have been observed in hypertensive animals and human beings which contribute to increased vascular resistance. An impairment of different angiogenetic factors, such as VEGF (vascular endothelial growth factor), VEGFR-2 (vascular endothelial growth factor receptor-2), TIMP-1 (tissue inhibitor matrix metalloproteinases-1), and TSP-1 (thrombospondin-1), seems to be responsible for the reduction of the microvascular network. Exercise training has been shown to improve vascular structure and function in hypertension not only in the large arteries but also in the peripheral circulation. Exercise training may regress microvascular remodeling and normalize capillary density, leading to capillary growth possibly by increasing proangiogenic stimuli such as VEGF. Exercise enhances endothelium-dependent vascular relaxation through nitric oxide release increase and oxidative stress reduction. Other mechanisms include improved balance between prostacyclin and thromboxane levels, lower circulating levels of endothelin-1, attenuation of infiltration of immune cells into perivascular adipose tissue, and increase of local adiponectin secretion. In addition, exercise training favorably modulates the expression of several microRNAs leading to a positive modification in muscle fiber composition. Identifying the bioactive molecules and biological mechanisms that mediate exercise benefits through pathways that differ from those used by antihypertensive drugs may help to improve our knowledge of hypertension pathophysiology and facilitate the development of new therapeutic strategies.

S-27-6: ADAPTIVE IMMUNITY REGULATES RENAL SALT-RETENTION AND BLOOD PRESSURE

Hypertension is a major public health problem, which contributes to a plethora of other cardiovascular diseases. A long-time postulate is that a defect in the kidney plays a key role in the development of hypertension. Years of intense research have confirmed that distal nephron plays important role in excessive salt retention, which contributes to the pathogenesis of hypertension. Yet the precise identity of this kidney defect and the downstream signaling mechanisms that impair sodium handling remain unclear. In the past decade, T cells, in particular CD8+ T cells (CD8Ts), have garnered attention as an important contributor to hypertension. T cells infiltrate into the kidneys of hypertensive animals, possibly driven by elevated perfusion pressure. Subsequently elevation of blood pressure and salt content stimulate T cell-activation and cytokine production. We recently reported a new mechanism by which renal infiltrated CD8Ts contribute to salt retention and hypertension: CD8Ts upregulate the sodium-chloride cotransporter (NCC) in the renal distal tubules, resulting in excessive salt retention via direct interactions between CD8Ts and renal distal convoluted tubule cells (DCTs) (Image in enclosed figure). This finding raises the exciting prospect that kidney-accumulation of CD8Ts and their interactions with DCTs represent one kidney defect in the pathogenesis of salt-sensitive hypertension. Although blocking NCC using thiazide temporarily lowered blood pressure in hypertensive animals, it failed to diminish T cell-homing to the kidneys, and hypertension returned after withdrawal of thiazide. Thus, in order to design effective therapeutics for salt-sensitive hypertension which interrupt the initial stimuli that trigger renal sodium retention, it is critical for us to define mechanisms of T cell-homing to the kidney and identify the key molecules mediating the CD8T-DCT interaction. Here, we further identified critical molecular players and demonstrated their roles in augmenting the CD8T-DCT interaction leading to salt-sensitive hypertension. We found that activated CD8Ts exhibit enhanced interaction with DCTs via IFNγ-induced upregulation of MHC-I and PDL1 in DCTs, thereby stimulating higher expression of NCC in DCTs to cause excessive salt retention and progressive elevation of blood pressure. Eliminating IFNγ or renal tubule-specific knockdown of PDL1 prevented T cell homing into the kidney, thereby attenuating hypertension in two different mouse models. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets.

Egg white protein hydrolysate decreased blood pressure via the competing endogenous RNA regulatory networks in female spontaneously hypertensive rats.

Despite numerous studies having reported the effects and mechanisms of antihypertensive peptides including peptides derived from egg white proteins, the role of peptides in a female hypertensive animal model is unknown. On the other hand, the role of epigenetic modulation by peptide treatment has rarely been investigated. This study sought to investigate the effect of egg white protein hydrolysate (EWH) in female spontaneously hypertensive rats (SHRs) as well as to explore the underlying mechanisms from the perspectives of the transcriptome and the profiles of non-coding RNAs. Young (12-14-week-old) female SHRs were orally administered 250 mg per kg body weight (low-dose) or 1000 mg per kg body weight (high-dose) EWH daily for 10 weeks. The blood pressure of the rats was monitored weekly. The mRNA and non-coding RNAs (miRNA, lncRNA, and circRNA) in the aorta were profiled by the high-throughput RNA-seq technique. Differentially expressed (DE) RNAs in the aorta were identified for the construction of the competing endogenous RNA (ceRNA) networks and key molecules were validated by qRT-PCR. The treatment of the high-dose EWH showed a significant effect on reducing blood pressure in female SHRs. Bioinformatic analyses revealed 813, 90, 347 and 869 DE-mRNAs, DE-miRNAs, DE-lncRNAs and DE-circRNAs, respectively. The CNTN5-LncRNA-XR_001835895.1-miR-384-5p was identified as the central network which was validated in the aorta and circulation of female SHRs. The results from this study demonstrated that the treatment with EWH reduced blood pressure via regulating the ceRNA networks in female SHRs, which provided novel insights into the mechanisms of food protein-derived antihypertensive peptides.

MiR-145 Alleviates Smooth Muscle Cell Phenotype Transition via ADAM17-Mediated ACE2 Shedding.

It has been shown that miR-145 is involved in the differentiation of vascular smooth muscle cells (VSMCs) and may regulate vascular remodeling. However, the molecular mechanisms behind these pathological processes in hypertension are not fully elucidated. The present study was to examine whether miR-145 modulates phenotypic transformation of VSMCs under normal state and synthetic state and to explore the possible role of ADAM17-mediated ACE2 shedding and ACE2-Ang-(1-7)-Mas receptor axis. Wistar rats were fed with high-sucrose/high-fat diet for 30 weeks to establish a metabolic hypertension animal model. VSMCs were cultured and treated with Ang II with or without miR-145 mimics or miR-145 inhibitor. Results showed the expression of contractile markers α-SMA and SM22α, miR-145, ACE2, and Mas receptor reduced in the thoracic aorta of metabolic hypertensive rats (MHRs), while that of synthetic marker OPN increased as compared to the control group. In in vitro study, miR-145 inhibitor inhibited the expression of α-SMA, SM22α, ACE2, Mas receptor, and the Ang-(1-7) excretion and induced the expression of synthetic markers OPN, EREG, and MMP2. However, miR-145 mimic produced opposite effects on the VSMCs. In addition, in the synthetic VSMC induced by Ang II, miR-145 inhibitor partially reversed the induced expression of OPN, EREG, and MMP2 by Ang II, while further decreasing the expression of α-SMA and SM22α and ACE2-Ang-(1-7)-Mas receptor. Cotreatment with ADAM17 siRNA partially reversed the inducible effect of miR-145 inhibitor on the EREG and MMP2, induced Ang-(1-7) excretion, and upregulated ACE2 and Mas receptor expression. In conclusion, miR-145 alleviates phenotype transition from contractile to synthetic type via ADAM17-mediated ACE2 shedding in VSMCs and retains the activation of ACE2-Ang-(1-7)-Mas axis, which may benefit the vascular structural remodeling in the metabolic hypertension.

A peptide fraction from hardened common beans (Phaseolus vulgaris) induces endothelium-dependent antihypertensive and renal effects in rats

Beans reached the research spotlight as a source of bioactive compounds capable of modulating different functions. Recently, we reported antioxidant and oxidonitrergic effect of a low molecular weight peptide fraction (<3 kDa) from hardened bean (Phaseolus vulgaris) in vitro and ex vivo, which necessitate further in vivo assessments. This work aimed to evaluate the hypotensive effect and the involved physiological mechanisms of the hardened common bean peptide (Phaseolus vulgaris) in normotensive (Wistar) and hypertensive (SHR) animals. Bean flour was combined with a solution containing acetonitrile, water and formic acid (25: 24: 1). Protein extract (PV3) was fractioned (3 kDa membrane). We assessed PV3 effects on renal function and hemodynamics of wistar (WT–normotensive) and spontaneously hypertensive rats (SHR) and measured systemic arterial pressure and flow in aortic and renal beds. The potential endothelial and oxidonitrergic involvements were tested in isolated renal artery rings. As results, we found that PV3: I) decreased food consumption in SHR, increased water intake and urinary volume in WT, increased glomerular filtration rate in WT and SHR, caused natriuresis in SHR; II) caused NO- and endothelium-dependent vasorelaxation in renal artery rings; III) reduced arterial pressure and resistance in aortic and renal vascular beds; IV) caused antihypertensive effects in a dose-dependent manner. Current findings support PV3 as a source of bioactive peptides and raise the potential of composing nutraceutical formulations to treat renal and cardiovascular diseases.

Renal lysophospholipase A1 contributes to Enterococcus faecalis-induced hypertension by enhancing sodium reabsorption.

Our recent study has found that gut bacteria Enterococcus faecalis contributes to hypertension and upregulates lysophospholipase A1 (LYPLA1) in the renal medulla of rats. This work aimed to investigate the role of LYPLA1 in the development of E.faecalis-induced hypertension. Compared to control, E.faecalis treatment increased blood pressure (BP), serum angiotensin II, sodium reabsorption, and expression of αENaC and LYPLA1 in the renal medulla of mice, and these effects were attenuated by knockdown of LYPLA1. Moreover, the intrarenal lypla1 overexpression increased sodium reabsorption and BP. Further studies showed that LYPLA1 promoted the accumulation of renal glycerophosphocholine (GPC), which directly elevated the expression of αENaC and sodium reabsorption. In addition, enriched abundance of LYPLA1 in the renal medulla and urine was also observed in other hypertensive animals. Overall, our results demonstrate that LYPLA1 contributes to E.faecalis-induced hypertension by accumulating GPC and activating ENaC in the renal medulla.

Development of a new intraocular hypertension and glaucoma animal model with gold nanoparticles

AbstractPurpose: The aim of this study was to develop a new rabbit model of glaucoma produced by GNPs with characteristics like human chronic glaucoma and to evaluate different inflammation and oxidative stress biomarkers related with glaucoma in tears, aqueous humour and retina samples, to characterize the model.Methods: Fifteen rabbits were used to the animal model development, n = 7 for model group, n = 4 for control group and n = 4 for Positive control group. The ocular hypertension model was developed by making multiple intracameral injections of 100 μl of PBS + GNPs(70 nM) in model group, only PBS (10 nM) in the control group and 100 μl of 20% Chondroitin Sulfate in the Positive control group. Increasing intraocular pression (IOP) protocol was developed during a period of 4 weeks by series of two weekly injections, followed by one‐week injection for the model group, to increase the volume of the anterior chamber. IOP was measured by Tonometer for 5 hours postoperatively and daily until the enucleation. Corneal thickness was evaluated by OCT. For biomarkers evaluation, nine rabbits were included, n = 3 for the three group. Tear collection was performed, weekly, using Schirmer test. Following the animal model design, 100 μl of aqueous humour was extracted, weekly, before the intracameral injection for the three groups. After Sacrifice, retina samples were collected. Level of Osteopontin were measured by HPLC, and Level of MMP‐9, TNF‐alpha, TGF‐beta, IL‐8 were measured by Elisa and compared between the groups.Results: The IOP was increased in the study group from 12.7 ± 1.8 mmHg at the baseline to 21.24 ± 5 mmHg after 6 weeks experiments for the model group and to 22.37 ± 4 mmHg for the positive control group, being the trend statistically significant (p &lt; 0.05). The increasing was constant, being around 3 mmHg each week. However, no differences were found in control group for any measurement, keeping in similar values during all experiment. The corneal thickness was increased in the model group (650 ± 300 mm) and positive control group (620 ± 200 mm) comparing to control group (350 ± 50 mm). Therefore, IOP was adjusted, considering the corneal thickness. Regarding biomarkers evaluation, it was found a significant increasing of IL‐8 and MMP‐9 and a decrease of Osteopontin, in tears, after 6 weeks experiments in Model group comparing to Control group. Also, a significant increase of IL‐8 and Osteopontin, in the aqueous humour and in the retina after sacrifice, was found in model group comparing to control group. For TGF‐beta and TNF‐alpha, the difference of the concentration of biomarkers was not significant between the groups.Conclusion: Osteopontin's increase in retina of the model group, comparing to control group, can be a good alternative to convert the ocular hypertension model to Glaucoma model. This model seems to be a great option to study potential biomarkers of glaucoma. New long‐term studies to analyse the effect of GNPs in the ganglion cells density are needed to validate the glaucoma model.

Identification of Pulmonary Hypertension Animal Models Using a New Evolutionary Machine Learning Framework Based on Blood Routine Indicators.

Pulmonary Hypertension (PH) is a global health problem that affects about 1% of the global population. Animal models of PH play a vital role in unraveling the pathophysiological mechanisms of the disease. The present study proposes a Kernel Extreme Learning Machine (KELM) model based on an improved Whale Optimization Algorithm (WOA) for predicting PH mouse models. The experimental results showed that the selected blood indicators, including Haemoglobin (HGB), Hematocrit (HCT), Mean, Platelet Volume (MPV), Platelet distribution width (PDW), and Platelet-Large Cell Ratio (P-LCR), were essential for identifying PH mouse models using the feature selection method proposed in this paper. Remarkably, the method achieved 100.0% accuracy and 100.0% specificity in classification, demonstrating that our method has great potential to be used for evaluating and identifying mouse PH models.

Features of the planimetric organization of the endocrine part of the pancreas in hypertensive rats of the SHR line

Analysis of the endocrine structure of the pancreas and assessment of its degree of heterogeneity is key to assessing such important physiological parameters as islet endocrinocyte mass in healthy people or functional reserve of β-cells in patients with type 1 and type 2 diabetes. The aim of the study is to perform a comparative planimetric analysis of pancreatic islets of normotensive Wistar rats and hypertensive SHR rats, using the method of double immunofluorescent staining of endocrinocytes. Materials and methods. The study was performed on the pancreas of SHR and Wistar rats. Insulin and glucagon in the islets of the pancreas were determined by immunofluorescence. The immunofluorescence reaction was studied with an AxioImager-M2 fluorescent microscope. Results. Planimetric analysis showed the presence of pancreatic islets of all types in the pancreatic tissue of SHR and Wistar rats. The number of single endocrinocytes in SHR hypertensive animals was 2.3 times higher (P &lt; 0.001), and the number of giant islets was 34.2 % higher (P &lt; 0.001), than in normotensive Wistar rats. The presence of regions in some endocrinocytes, that show immunoreactivity to both hormones at once – insulin and glucagon. Such areas were present in islets of all types of both rat lines, however, the total rates in hypertensive rats of the SHR line were 21.8 % lower (P &lt; 0.001), than in normotensive rats of the Wistar line. Conclusions. Planimetric analysis showed, that the pancreatic islets in normotensive Wistar rats and hypertensive SHR rats occupy 1.4 % of the cross-sectional area of the pancreas. In hypertensive rats the SHR line in the gland by 16.9 % larger total area of the material immunoreactive to insulin. In contrast to Wistar rats, the number of single α-endocrinocytes in the pancreas of hypertensive SHR rats was significantly increased.

Prophylactic Treatment with Hydrogen Sulphide Can Prevent Renal Ischemia-Reperfusion Injury in L-NAME Induced Hypertensive Rats with Cisplatin-Induced Acute Renal Failure.

(Background and Objectives): Renal ischemia perfusion injury is one of the major issues in kidney transplant. The aim of the study was to investigate the hypothesis that prophylactic treatment-with a hydrogen sulphide donor to an acute renal failure case of hypertensive rats-can minimize the ischemia reperfusion injury of the kidney which is beneficial for kidney transplant. To check this hypothesis, the present study was designed to investigate the effect of chronic administration of a hydrogen sulphide (H2S) donor and sodium hydrosulfide (NaHS) on nuclear factor kappa B (NF-kB) and inter cellular adhesion molecule-1 (ICAM-1) concentration in non-renal failure (NRF) and acute renal failure (ARF) rats in the ischemia-reperfusion injury (IRI) model of the kidney in both normotensive WKY and hypertensive rats (L-nitro arginine methyl ester (L-NAME-induced); (Materials and Methods): A total number of 48 Sprague-Dawley rats were recruited into eight groups each consisting of six animals. Each of these eight groups was used to measure systemic and renal parameters, H2S, antioxidant parameters in plasma, plasma concentration of NF-kB and ICAM-1 and renal cortical blood pressure. ARF was induced by single intraperitoneal (i.p.) cisplatin injection (5 mg/kg). Hypertension was induced by oral administration of L-NAME in drinking water for four weeks at 40 mg/kg/day. NaHS was administered (i.p) at 56 µmol/kg for five weeks while dL-propargylglycine (PAG), a H2S generation inhibitor, was administered as a single intra-peritoneal injection (50 mg/kg). An acute surgical experiment was performed for the induction of renal ischemia for 30 min by renal artery clamping followed by reperfusion for three hours; (Results): Chronic administration of NaHS attenuated the severity of ARF in both normotensive and hypertensive animals (L-NAME) along with lowering the blood pressure in hypertensive groups. NaHS improved the oxidative stress parameters such as total superoxide dismutase (T-SOD), glutathione (GSH) and reduced the malondialdehyde (MDA) concentration along with reduction of NF-kB and ICAM-1 following renal IRI; Conclusions: These findings demonstrate that H2S not only reduced the severity of cisplatin induced ARF but also reduced the severity of renal IRI by upregulating antioxidants along with decreased concentrations of NF-kB and ICAM-1 in normotensive and L-NAME induced hypertensive rats.

Abstract 10254: Renal CD11c + F4/80 - Dendritic Cells, but Not Renal CD11c + F4/80 + Macrophages, Transfer the Hypertension From Angiotensin II-mice

Introduction: Immune system participates in Angiotensin II (AngII)-hypertension (HTN). Previously, it was shown that dendritic cells (DCs)-CD11c + are required for HTN development. However, new CD11c + cell subpopulations, presenting macrophages (Mφ) characteristics (F4/80 + ), have been described. Since renal DCs and Mφ share several markers, their participation in AngII-HTN remains under discussion. Our objective was to analyze whether renal DCs-CD11c + F4/80 - or/and CD11c + F4/80 + (Mφ) modify their phenotype in the AngII-HTN, and to determine if they promote HTN by transferring this phenotype to normotensive animals. Methods: Male C57BI/6 mice (8-10 weeks-old, n=6) were infused with AngII (490 ng/kg/min) by 14-days. We measured systolic blood pressure (SBP), and renal DCs-CD11c + F4/80 - and Mφ-CD11c + F4/80 + infiltrations were evaluated by flow cytometry. In addition, these cells were isolated at 14-days and transferred to normotensive mice (n=4-5) for SBP measurements. Finally, renal Mφ-CD11c + F4/80 + from HTN mice were stimulated in vitro with AngII (100nM-24h) to analyze the mRNAs abundance of Nox2 , Sgk1 , ENaC and AT 1 R , by qRT-PCR. Results: AngII increased SBP (AngII 134.7±6.9 vs. Vehicle (Vh) 114.5±7.8mmHg; p&lt;0.001) and promoted the infiltration of DCs-CD11c + F4/80 - (AngII=45.6±11.9% vs. Vh=31.7±6.7%; p&lt;0.05) and Mφ-CD11c + F4/80 + (AngII=66.1±8.4% vs. Vh=55.6±5.1%; p&lt;0.05) in renal medulla. No statistical differences we observed in the renal cortex. Interestingly, the adoptive transfer of renal Mφ-CD11c + F4/80 + (1x10 6 -cells) from AngII animals to healthy recipient mice did not transfer HTN after 24h (baseline=106.8.0±2.3 vs. 112.4±4.5mmHg; ns), compared to DCs-CD11c + F4/80 - (baseline=110.0±8.3 vs. 132.0±14.3mmHg; p&lt;0.05). Finally, renal Mφ-CD11c + -F4/80 + purified from HTN animals and re-stimulated in vitro with AngII did not show changes in the mRNA levels evaluated (p&gt;0.05). Conclusions: The AngII-HTN promotes a differentiated infiltration of DCs-CD11c + F4/80 - and Mφ-CD11c + F4/80 + in renal medulla. However, only renal DCs, and not renal Mφ, acquire the ability to transfer HTN, suggesting that renal CD11c + cell subpopulations may have a differential role in AngII-HTN.Supported by Fondecyt-ANID #1201251 and #3201016

Resolvin D2 Attenuates Cardiovascular Damage in Angiotensin II-Induced Hypertension.

Resolution of inflammation is orchestrated by specialized proresolving lipid mediators (SPMs), and this would be impaired in some cardiovascular diseases. Among SPMs, resolvins (Rv) have beneficial effects in cardiovascular pathologies, but little is known about their effect on cardiovascular damage in hypertension. Aorta, small mesenteric arteries, heart, and peritoneal macrophages were taken from C57BL/6J mice, infused or not with angiotensin II (AngII; 1.44 mg/kg/day, 14 days) in presence or absence of resolvin D2 (RvD2) (100 ng/mice, every second day) starting 1 day before or 7 days after AngII infusion. Enzymes and receptors involved in SPMs biosynthesis and signaling were increased in aorta or heart from AngII-infused mice. We also observed a differential regulation of SPMs in heart from these mice. Preventive treatment with RvD2 partially avoided AngII-induced hypertension and protected the heart and large and small vessels against functional and structural alterations induced by AngII. RvD2 increased the availability of vasoprotective factors, modified SPMs profile, decreased cardiovascular fibrosis, and increased the infiltration of pro-resolving macrophages. When administered in hypertensive animals with established cardiovascular damage, RvD2 partially improved cardiovascular function and structure, decreased fibrosis, reduced the infiltration of neutrophils, and shifted macrophage phenotype toward a pro-resolving phenotype. There is a disbalance between proinflammatory and resolution mediators in hypertension. RvD2 protects cardiovascular function and structure when administered before and after the development of hypertension by modulating vascular factors, fibrosis and inflammation. Activating resolution mechanisms by treatment with RvD2 may represent a novel therapeutic strategy for the treatment of hypertensive cardiovascular disease.

Taxifolin Reduces Blood Pressure in Elderly Hypertensive Male Wistar Rats.

Male Wistar rats aged 10 months were assigned to groups according to the initial level of systolic BP: hypertensive (systolic BP >115 mm Hg) and normotensive (systolic BP <115 mm Hg). The animals were injected intraperitoneally with 100 μg/kg taxifolin daily for 7 days. Systolic BP and HR were measured on the next day after single taxifolin administration and on the next day after 7-day injection course. In the group of hypertensive animals, systolic BP markedly decreased on the next day after the first injection; this decrease became even more pronounced (to the level of normotensive animals) at the end of the taxifolin course. In the group of normotensive animals, systolic BP remained unchanged. Hence, we demonstrate the possibility of course administration of taxifolin for BP normalization in hypertensive patients.

Vascular Collagen Type-IV in Hypertension and Cerebral Small Vessel Disease.

Cerebral small vessel disease (SVD) is common in older people and causes lacunar stroke and vascular cognitive impairment. Risk factors include old age, hypertension and variants in the genes COL4A1/COL4A2 encoding collagen alpha-1(IV) and alpha-2(IV), here termed collagen-IV, which are core components of the basement membrane. We tested the hypothesis that increased vascular collagen-IV associates with clinical hypertension and with SVD in older persons and with chronic hypertension in young and aged primates and genetically hypertensive rats. We quantified vascular collagen-IV immunolabeling in small arteries in a cohort of older persons with minimal Alzheimer pathology (N=52; 21F/31M, age 82.8±6.95 years). We also studied archive tissue from young (age range 6.2-8.3 years) and older (17.0-22.7 years) primates (M mulatta) and compared chronically hypertensive animals (18 months aortic stenosis) with normotensives. We also compared genetically hypertensive and normotensive rats (aged 10-12 months). Collagen-IV immunolabeling in cerebral small arteries of older persons was negatively associated with radiological SVD severity (ρ: -0.427, P=0.005) but was not related to history of hypertension. General linear models confirmed the negative association of lower collagen-IV with radiological SVD (P<0.017), including age as a covariate and either clinical hypertension (P<0.030) or neuropathological SVD diagnosis (P<0.022) as fixed factors. Reduced vascular collagen-IV was accompanied by accumulation of fibrillar collagens (types I and III) as indicated by immunogold electron microscopy. In young and aged primates, brain collagen-IV was elevated in older normotensive relative to young normotensive animals (P=0.029) but was not associated with hypertension. Genetically hypertensive rats did not differ from normotensive rats in terms of arterial collagen-IV. Our cross-species data provide novel insight into sporadic SVD pathogenesis, supporting insufficient (rather than excessive) arterial collagen-IV in SVD, accompanied by matrix remodeling with elevated fibrillar collagen deposition. They also indicate that hypertension, a major risk factor for SVD, does not act by causing accumulation of brain vascular collagen-IV.

Swimming Exercise Alleviates Endothelial Mitochondrial Fragmentation via Inhibiting Dynamin-Related Protein-1 to Improve Vascular Function in Hypertension.

Regular exercise has been recommended clinically for all individuals to protect against hypertension but the underlying mechanisms are not fully elucidated. We recently found a significant mitochondrial fragmentation in the vascular endothelium of hypertensive human subjects. In this study, we investigated whether exercise could restore endothelial mitochondrial dynamics and thus improve vascular function in hypertension. Vascular endothelial mitochondrial morphological alterations were examined in patients with hypertension and hypertensive animal models. Furthermore, swimming exercise-induced endothelial mitochondrial dynamics and vascular function changes were investigated in spontaneously hypertensive rats (SHRs). Mitochondrial fragmentation with an elevated mitochondrial fission mediator Drp1 (dynamin-related protein-1) was observed in the mesenteric artery endothelium from hypertensive patients. A similar mitochondrial fragmentation with increased Drp1 expression were exhibited in the aortic endothelium of angiotensin II-induced hypertensive mice and SHRs. Interestingly, swimming exercise significantly reduced vascular Drp1 expression and alleviated endothelial mitochondrial fragmentation, thus improving blood pressure in SHRs. In cultured endothelial cells, angiotensin II exposure induced Drp1 upregulation, mitochondrial fragmentation and dysfunction, and reduced nitric oxide production, which was blunted by Drp1 genetic reduction or its inhibitor Mdivi-1. Mdivi-1 administration also ameliorated endothelial mitochondrial fragmentation, vascular dysfunction and blood pressure elevation in SHRs while swimming exercise plus Mdivi-1 treatment provided no additional benefits, suggesting that Drp1 inhibition may partially contribute to swimming exercise-conferred anti-hypertensive effects. These findings suggest that swimming exercise alleviates endothelial mitochondrial fragmentation via inhibiting Drp1, which may contribute to exercise-induced improvement of vascular function and blood pressure in hypertension.

Exploring the Anti-Hypertensive Potential of Lemongrass-A Comprehensive Review.

Simple SummaryLemongrass is an herb used in folk medicine for the treatment of hypertension, although its pharmacological potential has not yet been thoroughly studied. This paper provides the first comprehensive review on the anti-hypertensive potential of lemongrass, from in vitro to clinical studies. Even though the composition of lemongrass is dependent on its geographical origin, citral constitutes its major compound. Both citral and lemongrass display vasorelaxant activity ex vivo, promoting the secretion of endothelial vasodilators and the blockage of calcium channels in the vascular smooth muscle. Additionally, citral also displays a negative chronotrope effect. In animal models and in human subjects, lemongrass significantly decreases blood pressure, probably due to the combination of the above-mentioned effects together with diuretic activity. Future preclinical studies are necessary to identify other anti-hypertensive compounds/pathways, as well as to better characterize the safety profile of lemongrass.Lemongrass (Cymbopogon citratus (DC) Stapf) is a herb commonly used in folk medicine for many purposes. However, its anti-hypertensive potential has not yet been thoroughly studied. This paper reviews the anti-hypertensive effects of both lemongrass and its main compound citral in in vitro, ex vivo, preclinical and clinical studies. Lemongrass essential oil contains terpenes and their derivatives, whereas extracts contain different classes of polyphenols. Both citral and lemongrass display vasorelaxant activity ex vivo, acting by the promotion of endothelial nitric oxide/prostanoids secretion together with the blockage of calcium channels in the vascular smooth muscle. Citral also displays a negative chronotrope effect, probably due to a centrally mediated enhancement of parasympathetic activity. In both healthy and hypertensive animals, the acute administration of lemongrass results in a decrease in blood pressure, sometimes accompanied by a compensatory increase in heart rate. Similarly, in healthy and hypertensive human subjects, the consumption of lemongrass tea decreases blood pressure. Additionally, a weak/moderate diuretic activity has also been reported in animals and humans, although the mechanisms of action remain elusive. Future preclinical studies are necessary to identify other compounds with anti-hypertensive activity and additional pharmacological pathways. Although well tolerated, the safety profile of lemongrass should be better characterized.

Soluble epoxide hydrolase inhibitor, t-AUCB, improves salivary gland function by ameliorating endothelial injury

AimsInhibitor of soluble epoxide hydrolase (t-AUCB) has been used in the experimental therapy of hypertension. This study aimed to investigate whether the secretion of submandibular glands (SMGs) altered in renal hypertensive rats, and to explore whether t-AUCB could improve the salivary secretion. Main methods2-kidney 1-clip Sprague-Dawley rats were used as renal hypertensive animals. t-AUCB treatment was given for 1 week after 8 weeks modeling. Blood pressure, blood perfusion and the secretion of SMGs, and endothelium-dependent relaxation of external maxillary artery were measured to investigate the effects of t-AUCB on the vascular tone and the secretion of SMGs in renal hypertensive rats. SMGs were collected for histological evaluation and the internal arteries were dissected for primary endothelial cells culture. Key findingsThe blood perfusion and flow rate of SMGs in the renal hypertensive rats were significantly lower than those in the controls. Endothelium-dependent relaxation of the external maxillary artery and AMPK/Akt/eNOS signaling was impaired in hypertensive rats. The glandular morphology and the concentration of salivary ions did not change obviously. t-AUCB treatment ameliorated the secretion of SMGs, the blood perfusion, and the dysfunction of endothelium-dependent relaxation of the external maxillary artery by activating the AMPK/Akt/eNOS pathway in hypertensive rats. Significancet-AUCB increases the blood perfusion through ameliorating dysfunction of endothelium-dependent relaxation of SMGs arteries and thus improves the hyposecretion of SMGs in hypertensive rats.

Targeting the blood–brain barrier disruption in hypertension by ALK5/TGF-Β type I receptor inhibitor SB-431542 and dynamin inhibitor dynasore

IntroductionIn this study, we aimed to target two molecules, transforming growth factor-beta (TGF-β) and dynamin to explore their roles in blood–brain barrier (BBB) disruption in hypertension. MethodsFor this purpose, angiotensin (ANG) II-induced hypertensive mice were treated with SB-431542, an inhibitor of the ALK5/TGF-β type I receptor, and dynasore, an inhibitor of dynamin. Albumin-Alexa fluor 594 was used to assess BBB permeability. The alterations in the expression of claudin-5, caveolin (Cav)-1, glucose transporter (Glut)-1, and SMAD4 in the cerebral cortex and the hippocampus were evaluated by quantification of immunofluorescence staining intensity. ResultsANG II infusion increased BBB permeability to albumin-Alexa fluor 594 which was reduced by SB-431542 (P < 0.01), but not by dynasore. In hypertensive animals treated with dynasore, claudin-5 immunofluorescence intensity increased in the cerebral cortex and hippocampus while it decreased in the cerebral cortex of SB-431542 treated hypertensive mice (P < 0.01). Both dynasore and SB-431542 prevented the increased Cav-1 immunofluorescence intensity in the cerebral cortex and hippocampus of hypertensive animals (P < 0.01). SB-431542 and dynasore decreased Glut-1 immunofluorescence intensity in the cerebral cortex and hippocampus of mice receiving ANG II (P < 0.01). SB-431542 increased SMAD4 immunofluorescence intensity in the cerebral cortex of hypertensive animals, while in the hippocampus a significant decrease was noted by both SB-431542 and dynasore (P < 0.01). ConclusionOur data suggest that inhibition of the TGFβ type I receptor prevents BBB disruption under hypertensive conditions. These results emphasize the therapeutic potential of targeting TGFβ signaling as a novel treatment modality to protect the brain of hypertensive patients.

Antihypertensive activity and acute toxicity of turmeric (Curcuma longa L.) in L-NAME-induced hypertension animals

Hypertension is one of the significant risk factors for cardiovascular disease and can lead to complications. Uncontrolled hypertension can lead to vascular endothelial dysfunction and other complications of cardiovascular disease. This study aimed to determine the effect of turmeric rhizome (Curcuma longa L.) in extracts and the fractions on a hypertensive rat’s model induced by L-NAME 40 mg/kg for three weeks and an acute toxicity study of the extract. Antihypertensive research was performed on male Wistar rats utilizing non-invasive procedures. Turmeric extract at doses of 50, 100, and 200 mg/kg and its fraction of n-hexane, acetyl acetate, and ethanol at a dose of 25 mg/kg, respectively, were given daily per oral for three weeks to 2.5 mg/kg captopril. The systolic and diastolic blood pressure were measured at 0, 21, and 42 days after treatment and was calculated as mean arterial blood pressure (MAP). Acute toxicity testing refers to the OECD 420 Fixed-Dose method with several dosage levels, consists of 300, 2000, and 5000 mg/kg. The turmeric extract at doses of 50, 100, and 200 mg/kg and its fraction of n-hexane, acetyl acetate, and ethanol significantly reduced mean arterial blood pressure (p&lt;0.05) compared to the control group. Acute administration of turmeric extracts up to a dose of 5000 mg/kg in test animals did not show any death. Turmeric and its components are considered to possess antihypertensive actions. Antihypertensive activity increased in a dose-dependent manner. Turmeric extract is categorized as being almost entirely non-toxic.