Spontaneously Hypertensive Rats Research Articles

Electroacupuncture and manual acupuncture at LR3 and ST36 have attenuating effects on hypertension and subsequent cognitive dysfunction in spontaneously hypertensive rats: A preliminary resting-state functional magnetic resonance imaging study.

Chronic hypertension may have a contributory role toward cognitive impairment. Acupuncture exerts protective effects on cognitive functions while controlling the blood pressure. However, the neural mechanism underlying the dual attenuating effect of acupuncture remains unclear. In this study, we investigated the effects of electroacupuncture (EA) and manual acupuncture (MA) on the functional activity of the brain regions of spontaneously hypertensive rats (SHRs) by through resting-state functional magnetic resonance imaging (rs-fMRI). We also evaluated the differences in these functional activities between the EA and MA groups. We randomly assigned 30 SHRs into the EA, MA, and model (SHR) groups. Wistar Kyoto rats (n = 10) were used as normal control (WKY). The interventions were administered once every alternate day for 12 weeks. The systolic blood pressure of all rats was recorded every 2 weeks until the end of the intervention. After the intervention, rs-fMRI scanning was performed to access the whole brain data of rats randomly selected from each group evenly. The amplitude of low frequency fluctuation (ALFF) analysis, regional homogeneity (ReHo) analysis, and functional connectivity (FC) analysis were also conducted. The Morris water maze (MWM) test was conducted to evaluate the learning and memory of the rats. Hematoxylin-eosin staining and Nissl staining were performed to observe histopathological changes in the key brain regions. We demonstrated that, when compared with the SHR group, the EA and MA groups had significantly lower blood pressure and better performance for behavioral test indices, and that the effect of EA was better than that of MA. ALFF and ReHo analyses revealed enhancement of the neuronal activity of some functionally impaired brain areas in the EA and MA groups. The main callback brain regions included the hypothalamus, entorhinal cortex, brain stem, prelimbic cortex, cingulate cortex, corpus callosum, and cerebellum. The FC analysis demonstrated that EA and MA enhanced the functional connectivity between the seeds and brain regions such as the brain stem, entorhinal cortex, hippocampus, prelimbic cortex, and cerebellum. The pathological test of the entorhinal cortex also verified the protective effect of acupuncture on the neuronal functional activity. Our findings suggested that EA and MA exhibited attenuating effects on hypertension and cognitive dysfunction by enhancing the functional activities in the corresponding brain regions. Moreover, EA activated more callback brain regions and functional connectivity than MA, which may explain why the effect of EA was better than that of MA.

Evaluation of early arterial wall lesions by elastography parameters in spontaneously hypertensive rats

BackgroundArterialsclerosis caused by hypertension can lead to many complications, such as heart attack, stroke and so on. Early diagnosis and treatment of arterialsclerosis can prevent cardiovascular and cerebrovascular diseases and improve the prognosis. The present study aimed to explore the value of ultrasonography in evaluating the early lesion of the local arterial wall in hypertensive rats and identify useful elastography parameters.MethodsA total of 24 spontaneously hypertensive rats (SHR), 10-, 20-, 30-, and 40-weeks-old, were used in this study, with 6 rats in each group. Blood pressure was recorded using the Animal Noninvasive Blood Pressure Measurement System (Kent company, model CODA, USA), and the local elasticity of the abdominal aorta of rats was measured using a ultrasound diagnostic instrument (VINNO, Suzhou city, China). According to the histopathological results, SHR were divided into two groups: the normal arterial elasticity and the early arterial wall lesions. Mann–Whitney U test was used to compare the differences in elastic parameters and influencing factors between the above two groups, and receiver operating characteristic curve (ROC) was used to analyze and judge the value of each elastic parameter in evaluating early arterial lesions.ResultsA total of 22 cases were divided into two groups: 14 in the normal arterial elasticity and 8 in the early arterial wall lesions. The differences in age, blood pressure, pulse wave velocity (PWV), compliance coefficient (CC), distensibility coefficient (DC), and elasticity parameter (EP) between the two groups were compared. The differences in PWV, CC, DC and EP were statistically significant. Subsequently, the ROC curve analysis was performed for the above four evaluation indexes of arterial elasticity; the results were as follows: the area under the curve of PWV, CC, DC, and EP was 0.946, 0.781, 0.946, and 0.911, respectively.ConclusionsEarly arterial wall lesions can be evaluated by ultrasound measurement of local PWV. PWV and DC can accurately evaluate the early arterial wall lesions in SHR, and the combined application of the two can improve the sensitivity and specificity of the approach.

Activation of the Vascular Smooth Muscle GLP-1/NCX1 Pathway Regulates Cytoplasmic Ca2+ Homeostasis and Improves Blood Pressure Variability in Hypertension

Background: Hypertension is the most common cardiovascular disease, and its main harmful effect is chronic damage to target organs. In some patients with well-controlled blood pressure, target organ damage still occurs. GLP-1 agonists have significant cardiovascular benefits, but their antihypertensive effect is limited. The cardiovascular protective effect of GLP-1 is worth studying. Methods: The ambulatory blood pressure of spontaneously hypertensive rats (SHRs) was detected by ambulatory blood pressure monitoring, and the characteristics of blood pressure and the effect of subcutaneous intervention with a GLP-1R agonist on blood pressure were observed. To explore the mechanism of the cardiovascular benefit of GLP-1R agonists in SHRs, we evaluated the effects of GLP-1R agonists on vasomotor function and calcium homeostasis in vascular smooth muscle cells (VSMCs) in vitro. Results: Although the blood pressure of SHRs was significantly higher than that of WKY rats, the blood pressure variability of SHRs was also significantly higher than that of the control group. The GLP-1R agonist significantly reduced blood pressure variability in SHRs, but the antihypertensive effect was not obvious. GLP-1R agonists can significantly improve the cytoplasmic calcium overload of VSMCs in SHRs by upregulating the expression of NCX1, improving the systolic and diastolic functions of arterioles, and reducing blood pressure variability. Conclusions: Taken together, these results provide evidence that GLP-1R agonists improved VSMC cytoplasmic Ca2+ homeostasis through upregulated NCX1 expression in SHRs, which plays a key role in blood pressure stability and broad cardiovascular benefits.

Recent Advances in In Vitro and In Vivo Studies of Antioxidant, ACE-Inhibitory and Anti-Inflammatory Peptides from Legume Protein Hydrolysates.

Consumption of legumes has been shown to enhance health and lower the risk of cardiovascular disease and specific types of cancer. ACE inhibitors, antioxidants, and synthetic anti-inflammatories are widely used today; however, they have several undesirable side effects. Thus, researchers have focused on finding ACE inhibitors, antioxidant, and anti-inflammatory peptides from natural sources, such as legumes. Recently, in vitro and in vivo research has shown the bioactive peptides generated from legume protein hydrolysates, such as antioxidant, anti-hypertensive, anticancer, anti-proliferative, anti-inflammatory, etc., in the context of different disease mitigation. Therefore, this review aims to describe the recent advances in in vitro and in vivo studies of antioxidant, anti-hypertensive and anti-inflammatory peptides isolated from legume-derived protein hydrolysates. The results indicated that antioxidant legumes peptides are characterized by short-chain sequence amino acids and possess anti-hypertensive properties by reducing systolic blood pressure (SBP) in spontaneously hypertensive rats (SHR).

Novel regenerative drug, SPG302 promotes functional recovery of diaphragm muscle activity after cervical spinal cord injury.

Spinal cord hemisection at C2 (C2 SH), sparing the dorsal column is widely used to investigate the effects of reduced phrenic motor neuron (PhMN) activation on diaphragm muscle (DIAm) function, with reduced DIAm activity on the injured side during eupnoea. Following C2 SH, recovery of DIAm EMG activity may occur spontaneously over subsequent days/weeks. Various strategies have been effective at improving the incidence and magnitude of DIAm recovery during eupnoea, but little is known about the effects of C2 SH on transdiaphragmatic pressure (Pdi ) during other ventilatory and non-ventilatory behaviours. We employ SPG302, a novel type of pegylated benzothiazole derivative, to assess whether enhancing synaptogenesis (i.e., enhancing spared local connections) will improve the incidence and the magnitude of recovery of DIAm EMG activity and Pdi function 14 days post-C2 SH. In anaesthetised Sprague-Dawley rats, DIAm EMG and Pdi were assessed during eupnoea, hypoxia/hypercapnia and airway occlusion prior to surgery (C2 SH or sham), immediately post-surgery and at 14 days post-surgery. In C2 SH rats, 14 days of DMSO (vehicle) or SPG302 treatments (i.p. injection) occurred. At the terminal experiment, maximum Pdi was evoked by bilateral phrenic nerve stimulation. We show that significant EMG and Pdi deficits are apparent in C2 SH compared with sham rats immediately after surgery. In C2 SH rats treated with SPG302, recovery of eupneic, hypoxia/hypercapnia and occlusion DIAm EMG was enhanced compared with vehicle rats after 14 days. Treatment with SPG302 also ameliorated Pdi deficits following C2 SH. In summary, SPG302 is an exciting new therapy to explore for use in spinal cord injuries. KEY POINTS: Despite advances in our understanding of the effects of cervical hemisection (C2 SH) on diaphragm muscle (DIAm) EMG activity, very little is understood about the impact of C2 SH on the gamut of ventilatory and non-ventilatory transdiaphragmatic pressures (Pdi ). Recovery of DIAm activity following C2 SH is improved using a variety of approaches, but very few pharmaceuticals have been shown to be effective. One way of improving DIAm recovery is to enhance the amount of latent local spared connections onto phrenic motor neurons. A novel pegylated benzothiazole derivative enhances synaptogenesis in a variety of neurodegenerative conditions. Here, using a novel therapeutic SPG302, we show that 14 days of treatment with SPG302 ameliorated DIAm EMG and Pdi deficits compared with vehicle controls. Our results show that SPG302 is a compound with very promising potential for use in improving functional outcomes post-spinal cord injury.

Clostridium butyricum Prevents Dysbiosis and the Rise in Blood Pressure in Spontaneously Hypertensive Rats

Hypertension is accompanied by dysbiosis and a decrease in the relative abundance of short-chain fatty acid (SCFA)-producing bacteria. However, there is no report to examine the role of C. butyricum in blood pressure regulation. We hypothesized that a decrease in the relative abundance of SCFA-producing bacteria in the gut was the cause of spontaneously hypertensive rats (SHR)-induced hypertension. C. butyricum and captopril were used to treat adult SHR for six weeks. C. butyricum modulated SHR-induced dysbiosis and significantly reduced systolic blood pressure (SBP) in SHR (p < 0.01). A 16S rRNA analysis determined changes in the relative abundance of the mainly SCFA-producing bacteria Akkermansia muciniphila, Lactobacillus amylovorus, and Agthobacter rectalis, which increased significantly. Total SCFAs, and particularly butyrate concentrations, in the SHR cecum and plasma were reduced (p < 0.05), while C. butyricum prevented this effect. Likewise, we supplemented SHR with butyrate for six weeks. We analyzed the flora composition, cecum SCFA concentration, and inflammatory response. The results showed that butyrate prevented SHR-induced hypertension and inflammation, and the decline of cecum SCFA concentrations (p < 0.05). This research revealed that increasing cecum butyrate concentrations by probiotics, or direct butyrate supplementation, prevented the adverse effects of SHR on intestinal flora, vascular, and blood pressure.

The sustainable antihypertensive and target organ damage protective effect of transcranial focused ultrasound stimulation in spontaneously hypertensive rats.

In this study, we aimed to investigate the sustainable antihypertensive effects and protection against target organ damage caused by low-intensity focused ultrasound (LIFU) stimulation and the underlying mechanism in spontaneously hypertensive rats (SHRs) model. SHRs were treated with ultrasound stimulation of the ventrolateral periaqueductal gray (VlPAG) for 20 min every day for 2 months. Systolic blood pressure (SBP) was compared among normotensive Wistar-Kyoto rats, SHR control group, SHR Sham group, and SHR LIFU stimulation group. Cardiac ultrasound imaging and hematoxylin-eosin and Masson staining of the heart and kidney were performed to assess target organ damage. The c-fos immunofluorescence analysis and plasma levels of angiotensin II, aldosterone, hydrocortisone, and endothelin-1 were measured to investigate the neurohumoral and organ systems involved. We found that SBP was reduced from 172 ± 4.2 mmHg to 141 ± 2.1 mmHg after 1 month of LIFU stimulation, P < 0.01. The next month of treatment can maintain the rat's blood pressure at 146 ± 4.2 mmHg at the end of the experiment. LIFU stimulation reverses left ventricular hypertrophy and improves heart and kidney function. Furthermore, LIFU stimulation enhanced the neural activity from the VLPAG to the caudal ventrolateral medulla and reduced the plasma levels of ANGII and Aldo. We concluded that LIFU stimulation has a sustainable antihypertensive effect and protects against target organ damage by activating antihypertensive neural pathways from VLPAG to the caudal ventrolateral medulla and further inhibiting the renin-angiotensin system (RAS) activity, thereby supporting a novel and noninvasive alternative therapy to treat hypertension.

Effect of long-term antihypertensive treatment on cerebrovascular structure and function in hypertensive rats

Midlife hypertension is an important risk factor for cognitive impairment and dementia, including Alzheimer’s disease. We investigated the effects of long-term treatment with two classes of antihypertensive drugs to determine whether diverging mechanisms of blood pressure lowering impact the brain differently. Spontaneously hypertensive rats (SHR) were either left untreated or treated with a calcium channel blocker (amlodipine) or beta blocker (atenolol) until one year of age. The normotensive Wistar Kyoto rat (WKY) was used as a reference group. Both drugs lowered blood pressure equally, while only atenolol decreased heart rate. Cerebrovascular resistance was increased in SHR, which was prevented by amlodipine but not atenolol. SHR showed a larger carotid artery diameter with impaired pulsatility, which was prevented by atenolol. Cerebral arteries demonstrated inward remodelling, stiffening and endothelial dysfunction in SHR. Both treatments similarly improved these parameters. MRI revealed that SHR have smaller brains with enlarged ventricles. In addition, neurofilament light levels were increased in cerebrospinal fluid of SHR. However, neither treatment affected these parameters. In conclusion, amlodipine and atenolol both lower blood pressure, but elicit a different hemodynamic profile. Both medications improve cerebral artery structure and function, but neither drug prevented indices of brain damage in this model of hypertension.

Paeonol improves renal and vascular angiotensin II type 1 receptor function via inhibiting oxidative stress in spontaneously hypertensive rats

ABSTRACT Background Oxidative stress has been shown to play a critical role in the pathogenesis of hypertension. Paeonol, a major phenolic component extracted from Moutan Cortex, exerts a beneficial effect in preventing cardiovascular disease via reducing oxidative stress. The present study investigated the protective mechanism of paeonol against high blood pressure in spontaneous hypertension rats (SHRs). Methods Wistar-Kyoto (WKY) rats and SHRs received vehicle or peaonol in the drinking water for 5 weeks. Blood pressure was measured by tail-cuff plethysmography and oxidative stress in kidney and vascular tissue was examined by enzyme-linked immunosorbed assay. The functions of angiotensin II type 1 receptors (AT1R) in the kidney and mesenteric artery were measured by natriuresis and vasoconstrictor response, respectively. Results Compared with vehicle-treated WKY rats, vehicle-treated SHRs exhibited higher blood pressure, increased oxidative stress, accompanied by exaggerated diuretic and natriuretic responses to candesartan (AT1 receptor antagonist) and vasoconstrictor responses to angiotensin II (Ang II). Moreover, SHRs had higher ACE and AT1R in the kidney and mesenteric artery, and higher Ang II and lower renin levels. Interestingly, paeonol treatment reduced the candesartan-induced increase in diuresis and natriuresis and vasoconstrictor responses to Ang II, and lowered blood pressure in SHRs, accompanied by reducing AT1R protein expression in the kidney and mesenteric artery of SHR, and Ang II levels in plasma and increasing renin levels in renal cortex. In addition, these changes were associated with reducing oxidative stress. Conclusions The present study suggests that paeonol improves renal and vascular AT1R functions by inhibition of oxidative stress, thus lowering blood pressure in SHRs.

Integrated network pharmacology and molecular docking analyses of the mechanisms underlying the antihypertensive effects of lotusine

Hypertension is a modifiable cardiovascular risk factor and cause of death worldwide. Lotusine, an alkaloid extracted from a plant used in traditional Chinese Medicine, has shown anti-hypertensive effects. However, its therapeutic efficacy requires further investigation. We adopted integrated network pharmacology and molecular docking approaches with the aim of investigating lotusine's antihypertensive effects and mechanisms of action in rat models. After identifying the optimal intravenous dosage, we observed the effects of lotusine administration on two-kidney, one-clip (2K1C) rats and spontaneously hypertensive rats (SHRs). Based on network pharmacology and molecular docking analyses, we measured renal sympathetic nerve activity (RSNA) to evaluate lotusine's effect. Finally, an abdominal aortic coarctation (AAC) model was established to evaluate lotusine's long-term effects. The network pharmacology analysis identified 21 intersection targets; of these, 17 were also implicated by the neuroactive live receiver interaction. Further integrated analysis showed high lotusine affinity for the cholinergic receptor nicotinic alpha 2 subunit, adrenoceptor beta 2, and adrenoceptor alpha 1B. Blood pressure of the 2K1C rats and SHRs decreased after treatment with 2.0 and 4.0 mg/kg of lotusine (P < 0.001 versus saline control). We also observed RSNA decreases consistent with the network pharmacology and molecular docking analysis results. Results from the AAC rat model indicated that myocardial hypertrophy was decreased with lotusine administration, demonstrated by echocardiography and hematoxylin and eosin and Masson staining. This study provides insights into the antihypertensive effects and underlying mechanisms of lotusine; lotusine may exert long-term protective effects against myocardial hypertrophy caused by elevated blood pressure.

Effect of electroacupuncture on transforming growth factor-β1 and renal tubular epithelial mesenchymal transformation in renal tissue of spontaneously hypertensive rats

To observe the effects of electroacupuncture (EA) on renal fibrosis, the expression of transforming growth factor-β1 (TGF-β1) and epithelial mesenchymal transition (EMT) marker proteins in renal tissue of spontaneously hypertensive rats (SHR), so as to explore the underlying mechanism on EA alleviating hypertensive renal impairment. Twenty-four male SHR were randomly divided into model group, losartan group and EA group, with 8 rats in each group, and eight male Wistar-Kyoto rats were taken as the normal group. Rats in the losartan group received gavage of losartan potassium solution (3 mg/mL, 30 mg·kg-1·d-1),once every other day for 12 weeks. Rats in the EA group received EA stimulation at bilateral "Shenshu" (BL23) and "Geshu" (BL17) (2 Hz/15 Hz, 1.0 mA), 15 min each time, once every other day for 12 weeks. The systolic blood pressure of caudal artery was measured before, and 4, 8 and 12 weeks after the intervention. The 24-hour urinary protein was measured before, and 6 and 12 weeks after the intervention. Histopathological changes of the left renal tissue were observed under light mircoscope after H.E. stain. Extracellular matrix (ECM) in renal tissues was observed after periodate Schiff staining. Basement membrane and collagen fibers were observed after Masson staining with collagen volume fraction (CVF) evaluated. The expression of TGF-β1 mRNA in the right renal was detected by real-time fluorescence quantitative PCR. The expression of TGF-β1 and EMT marker E-cadherin, α-SMA and fibronectin (FN) proteins in the left renal tissue was measured by immunohistochemistry. In the model group, irregular arrangement of nephrocytes, renal tubule atrophy, lumen stenosis, ECM hyperplasia and deposition, scar and sclerosis were observed, which were relatively milder in the EA and losartan groups. Compared with the normal group, tubulointerstitium CVF, systolic blood pressure of caudal artery before, and at 4, 8 and 12 weeks after the intervention, 24-hour urinary protein before, and at 6 and 12 weeks after the intervention, the expression of TGF-β1 mRNA, area of TGF-β1, α-SMA and FN positive staining in renal tissues were significantly increased (P<0.01), while the area of E-cadherin positive staining was significantly decreased (P<0.01) in the model group. Compared with the model group, tubulointerstitium CVF, systolic blood pressure of caudal artery at 4, 8 and 12 weeks after the intervention, 24-hour urinary protein at 6 and 12 weeks after the intervention, the expression of TGF-β1 mRNA, area of TGF-β1, α-SMA and FN positive staining in renal tissues were significantly decreased (P<0.01，P<0.05), while area of E-cadherin positive staining was significantly increased (P<0.01) in the losartan and EA groups. Compared with the losartan group, the area of E-cadherin was conside-rately increased (P<0.01), while the area of α-SMA protein decreased (P<0.01) in the EA group. EA could effectively alleviate hypertension and renal interstitial fibrosis in SHR, the mechanism of which may be related to its function in reducing the expression of TGF-β1 and inhibiting EMT in renal tissue.

5-Aminolevulinic acid hydrochloride enhances bupivacaine-induced hypotension in spontaneously hypertensive rats

PurposeOral administration of 5-aminolevulinic acid hydrochloride (5-ALA-HCl) has been reported to enhance the hypotensive effects associated with anesthetics, especially in elderly hypertensive patients treated with antihypertensive agents. The present study aimed to clarify the effects of antihypertensive-agent- and anesthesia-induced hypotension by 5-ALA-HCl in spontaneously hypertensive rats (SHRs). MethodsWe measured blood pressure (BP) of SHRs and normotensive Wistar Kyoto (WKY) rats treated with amlodipine or candesartan before and after administration of 5-ALA-HCl. We also investigated the change in BP following intravenous infusion of propofol and intrathecal injection of bupivacaine in relation to 5-ALA-HCl administration. FindingsOral administration of 5-ALA-HCl significantly reduced BP in SHRs and WKY rats with amlodipine and candesartan. Infusion of propofol significantly reduced BP in SHRs treated with 5-ALA-HCl. Intrathecal injection of bupivacaine significantly declined SBP and DBP in both SHRs and WKY rats treated with 5-ALA-HCl. The bupivacaine-induced decline in SBP was significantly larger in SHRs compared with WKY rats. ConclusionThese findings suggest that 5-ALA-HCl does not affect the antihypertensive agents-induced hypotensive effect, but enhances the bupivacaine-induced hypotensive effect, especially in SHRs, indicating that 5-ALA may contribute to anesthesia-induced hypotension via suppression of sympathetic nerve activity in patients with hypertension.

Trained hypertensive rats exhibit decreased transcellular vesicle trafficking, increased tight junctions' density, restored blood-brain barrier permeability and normalized autonomic control of the circulation.

Introduction: Chronic hypertension is accompanied by either blood-brain barrier (BBB) leakage and autonomic dysfunction. There is no consensus on the mechanism determining increased BBB permeability within autonomic areas. While some reports suggested tight junction's breakdown, others indicated the involvement of transcytosis rather than paracellular transport changes. Interestingly, exercise training was able to restore both BBB permeability and autonomic control of the circulation. We sought now to clarify the mechanism(s) governing hypertension- and exercise-induced BBB permeability. Methods: Spontaneously hypertensive rats (SHR) and normotensive controls submitted to 4-week aerobic training (T) or sedentary protocol (S) were chronically cannulated for baseline hemodynamic and autonomic recordings and evaluation of BBB permeability. Brains were harvested for measurement of BBB function (FITC-10kDa leakage), ultrastructural analysis of BBB constituents (transmission electron microscopy) and caveolin-1 expression (immunofluorescence). Results: In SHR-S the increased pressure, augmented sympathetic vasomotor activity, higher sympathetic and lower parasympathetic modulation of the heart and the reduced baroreflex sensitivity were accompanied by robust FITC-10kDa leakage, large increase in transcytotic vesicles number/capillary, but no change in tight junctions' density within the paraventricular nucleus of the hypothalamus, the nucleus of the solitary tract and the rostral ventrolateral medulla. SHR-T exhibited restored BBB permeability and normalized vesicles counting/capillary simultaneously with a normal autonomic modulation of heart and vessels, resting bradycardia and partial pressure reduction. Caveolin-1 expression ratified the counting of transcellular, not other cytoplasmatic vesicles. Additionally, T caused in both groups significant increases in tight junctions' extension/capillary border. Discussion: Data indicate that transcytosis, not the paracellular transport, is the primary mechanism underlying both hypertension- and exercise-induced BBB permeability changes within autonomic areas. The reduced BBB permeability contributes to normalize the autonomic control of the circulation, which suppresses pressure variability and reduces the occurrence of end-organ damage in the trained SHR. Data also disclose that hypertension does not change but exercise training strengthens the resistance of the paracellular pathway in both strains.

High-Intensity Interval Training Minimizes the Deleterious Effects of Arterial Hypertension on the Urinary Bladder of Spontaneously Hypertensive Rats.

Arterial hypertension promotes urological complications by modifying the functional capacity of the urinary bladder. On the other hand, physical exercise has been suggested as a nonpharmacological tool to improve blood pressure regulation. High-intensity interval training (HIIT) can effectively increase peak oxygen consumption, body composition, physical fitness, and health-related characteristics of adults; however, its action on the urinary bladder is little discussed. In the present study, we verified the effect of HIIT on the modulation of the redox state, morphology, and inflammatory and apoptotic processes of the urinary bladder of hypertensive rats. Spontaneously hypertensive rats (SHR) were divided into two groups: SHR sedentary and SHR submitted to HIIT. Arterial hypertension promoted an increase in the plasma redox state, modified the volume of the urinary bladder, and increased collagen deposition in detrusor muscle. It was also possible to identify, in the sedentary SHR group, an increase in inflammatory markers such as IL-6 and TNF-α in the urinary bladder, as well as a reduction in BAX expression. However, in the HIIT group, reduced blood pressure levels were observed, together with an improvement in morphology, such as a decrease in collagen deposition. HIIT also regulated the proinflammatory response, promoting increases in IL-10 and BAX expressions and in the number of plasma antioxidant enzymes. The present work highlights the intracellular pathways involved with the oxidative and inflammatory capacity of the urinary bladder and the potential effect of HIIT on the regulation of the urothelium and detrusor muscle of hypertensive rats.

Inducible co-stimulatory molecules participate in mesenteric vascular endothelial-mesenchymal transition and sclerosis of mesenteric vessels in spontaneously hypertensive rats

To investigate the correlation of inducible co-stimulatory molecules (ICOS) with mesenteric vascular endothelial- mesenchymal transition (EndMT) and sclerosis in spontaneously hypertensive rats (SHR). Twenty 4-week-old WKY rats and 20 SHRs of the same strain were both randomly divided into 4 groups for observation at 4, 6, 10 and 30 weeks of age. ICOS expression frequency in rat spleen CD4+T cells was analyzed using flow cytometry, and the expressions of ICOS, VE-cad, α-SMA and Col3 mRNA in rat mesentery were detected by RT-PCR. The distributions of ICOS, IL-17A and TGF-β in rat mesentery were detected by immunohistochemistry. The levels of IL-17A and TGF-β in rat plasma were measured using ELISA. The morphological changes of rat mesenteric vessels were observed with Masson staining. Spearman or Pearson correlation analyses were used to evaluate the correlation between ICOS expression and the expressions of the markers of vascular EndMT and sclerosis. Compared with the control WKY rats, the SHRs began to show significantly increased systolic blood pressure and ICOS expression frequency on CD4+T cells at 6 weeks of age (P < 0.05). In the SHRs, the mRNA and protein expressions of ICOS, α-SMA, Col3, IL-17A and TGF-β in the mesentery were significantly higher than those in control group (P < 0.05), while the mRNA and protein expressions of VE-cad started to reduce significantly at 10 weeks of age (P < 0.05). The plasma levels of IL-17A and TGF-β were significantly increased in SHRs since 6 weeks of age (P < 0.05) with progressive worsening of mesenteric vascular sclerosis (P < 0.05). ICOS mRNA and protein expression levels in the mesenteric tissues of SHRs began to show positive correlations with α-SMA and Col3 expression levels and the severity of vascular sclerosis at 6 weeks of age (P < 0.05) and a negative correlation with VE-cad expression level at 10 weeks (P < 0.05). ICOS play an important pathogenic role in EndMT and sclerosis of mesenteric vessels in essential hypertension by mediating related immune responses.

Intermittent heat exposure induces thoracic aorta injury in spontaneously hypertensive rats by activating the AMPK/mTOR/ULK1 pathway

To investigate the effects of different manners of heat exposure on thoracic aorta injury in spontaneously hypertensive rats (SHRs) and explore the underlying mechanism. Normal 6 to 7-week-old male SHRs were randomized into control group (cage at room temperature), intermittent heat exposure group (SHR-8 group, exposed to 32 ℃ for 8 h daily for 7 days) and SHR-24 group (with continuous exposure to 32 ℃ for 7 days). After the treatments, the pathologies of the thoracic aorta of the rats were observed with HE staining, and the expressions of Beclin1, LC3B and p62 were detected with Western blotting and immunofluorescence assay; TUNEL staining was used to observe cell apoptosis in the thoracic aorta, and the expressions of caspase-3, Bax, and Bcl-2 were detected using Western blotting. The effects of intraperitoneal injections of 3-MA (an autophagy agonist), rapamycin (an autophagy inhibitor) or compound C 30 min before intermittent heat exposure on the expressions of proteins associated with autophagy, apoptosis and the AMPK/mTOR/ULK1 pathway in the aorta were examined with immunohistochemistry. In SHR-8 group, the rats showed incomplete aortic intima with disordered cell distribution and significantly increased expressions of Beclin1, LC3II/LC3I and Bax, lowered expressions of p62 and Bcl-2, and increased apoptotic cells in the thoracic aorta (P < 0.05). Pretreatment with 3-MA obviously inhibited the expressions of autophagy- and apoptosis-related proteins, whereas rapamycin promoted their expressions. Compared with the control group, the rats in SHR-8 group had significantly down-regulated p-mTOR and up-regulated p-AMPK and p-ULK1 expression of in the aorta; Treatment with compound C obviously lowered the expressions of p-AMPK and p-ULK1 and those of LC3B and Beclin1 as well. In SHRs, intermittent heat exposure causes significant pathologies and promotes autophagy and apoptosis in the thoracic aorta possibly by activating the AMPK/mTOR/ULK1 pathway.

Effects of Propofol Combined with Sufentanil Target-Controlled Intravenous Anesthesia on Expression of Bax, Bcl-2, and Caspase-3 Genes in Spontaneous Hypertensive Rats with Cerebral Hemorrhage: a Prospective Case-Controlled Study.

It is a well-known fact that general anesthesia leads to cerebral hemorrhage in patients with spontaneous hypertension apart of the fact that the hypertension is under control. The literature is already flooded with this debate, and still, there appears a lag regarding the effects of high blood pressure on pathological changes in the brain after cerebral hemorrhage. They are still not well recognized. Furthermore, it is the stage of anesthesia resuscitation which is known to have adverse effects on the body during cerebral hemorrhage. Owing to the lag of knowledge in the above said facts, the objectives of this study were to evaluate the effects of propofol combined with sufentanil on the expression of Bax, BCL-2, and caspase-3 genes in spontaneously hypertensive rats suffering with cerebral hemorrhage. The initial sample consisted of 54 male Wrister rats. All were of the age of 7 to 8months with a weight of 500 ± 100 gm. All the rats were evaluated by the investigators before enrolment. A total of 0.5mg/kg ketamine followed by a 10mg/kg intravenous injection of propofol was introduced to each included rat. It was followed by a total of 1 μG/kg/h of sufentanil which was administered to rats who had cerebral hemorrhage (n = 27). The rest 27 normal rats were not administered with sufentanil. Hemodynamic parameters, biochemistry, western blot assay, and immunohistochemical staining were performed. The results were statistically analyzed. Heart rate (p < 0.0001) was higher for rats who had a cerebral hemorrhage. The cytokine levels of rats who had cerebral hemorrhage were higher than those of normal rats (p < 0.01 for all). Bacl-2 (p < 0.01), bax (p < 0.01), and caspase-3 (p < 0.01) expressions were reported to be disturbed in rats who had cerebral hemorrhage. Urine volume was reduced in rats who had cerebral hemorrhage (p < 0.01). It was concluded that in spontaneously hypertensive rats with cerebral hemorrhage, propofol combined with sufentanil target-controlled intravenous anesthesia increased hemodynamic parameters and cytokine levels. Furthermore, cerebral hemorrhage disturbs the expression of bacl-2, Bax, and caspase-3 expressions.

Urinary excretion of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine is positively related to nitric oxide level in tissues of normotensive and hypertensive rats

Nitric oxide (NO) is one of the gaseous transmitters which play a very important role in the regulation of the circulatory system. Decreased NO availability is associated with hypertension, cardiovascular and kidney diseases. Endogenous NO is generated enzymatically by nitric oxide synthase (NOS) depending on the availability of the substrate, cofactors, or presence/absence of inhibitors, such as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). The objective of this study was to evaluate the potential relationship between NO level in rat tissues (heart and kidneys) and the concentrations of endogenous metabolites related to NO in plasma and urine. The experiment was carried out with 16- and 60-week-old male Wistar Kyoto (WKY) and age-matched male Spontaneously Hypertensive Rats (SHR). NO level in tissue homogenates was determined by the colorimetric method. RT-qPCR was used to verify the expression of the eNOS (endothelial NOS) gene. Plasma and urine concentrations of arginine, ornithine, citrulline, and dimethylarginines were examined by the UPLC-MS/MS method. 16-week-old WKY rats had the highest tissue NO and plasma citrulline levels. Furthermore, 16-week-old WKY rats showed higher urinary excretion of ADMA/SDMA compared to other experimental groups, however, plasma concentrations of arginine, ADMA, and SDMA were comparable between the groups. In conclusion, our research shows that hypertension and aging decrease tissue NO levels and are associated with reduced urinary excretion of NOS inhibitors, i.e., ADMA and SDMA.

The Differences of Mechanisms in Antihypertensive and Anti-Obesity Effects of Eucommia Leaf Extract between Rodents and Humans

In the 1970s, Eucommia leaf tea, known as Tochu-cha in Japanese, was developed from roasted Eucommia leaves in Japan and is considered as a healthy tea. The antihypertensive, diuretic, anti-stress, insulin resistance improving, and anti-obesity effects of Eucommia leaf extract have been reported. However, the identification and properties of the active components as well as the underlying mechanism of action are largely unknown. In this review, we summarize studies involving the oral administration of geniposidic acid, a major iridoid component of Eucommia leaf extract which increases plasma atrial natriuretic peptide (ANP) on the atria of spontaneously hypertensive rats (SHR) by activating the glucagon-like peptide-1 receptor (GLP-1R). To achieve the antihypertensive effects of the Eucommia leaf extract through ANP secretion in humans, combining a potent cyclic adenosine monophosphate phosphodiesterase (cAMP-PDE) inhibitor, such as pinoresinol di-β-d-glucoside, with geniposidic acid may be necessary. Changes in the gut microbiota are an important aspect involved in the efficacy of asperuloside, another component of the Eucommia leaf extract, which improves obesity and related sequelae, such as insulin resistance and glucose intolerance. There are species differences of mechanisms associated with the antihypertensive and anti-obesity effects between rodents and humans, and not all animal test results are consistent with that of human studies. This review is focused on the mechanisms in antihypertensive and anti-obesity effects of the Eucommia leaf extract and summarizes the differences of mechanisms in their effects on rodents and humans based on our studies and those of others.

Chronic high‑salt intake induces cardiomyocyte autophagic vacuolization during left ventricular maladaptive remodeling in spontaneously hypertensive rats.

The role of autophagy in high-salt (HS) intake associated hypertensive left ventricular (LV) remodeling remains unclear. The present study investigated the LV autophagic change and its association with the hypertensive LV remodeling induced by chronic HS intake in spontaneously hypertensive rats (SHR). Wistar Kyoto (WKY) rats and SHR were fed low-salt (LS; 0.5% NaCl) and HS (8.0% NaCl) diets and were subjected to invasive LV hemodynamic analysis after 8, 12 and 16 weeks of dietary intervention. Reverse transcription-quantitative PCR and western blot analysis were performed to investigate the expression of autophagy-associated key components. The LV morphologic staining was performed at the end of the study. The rat H9c2 ventricular myoblast cell-associated experiments were performed to explore the mechanism of HS induced autophagic change. A global autophagy-associated key component, as well as increased cardiomyocyte autophagic vacuolization, was observed after 12 weeks of HS intake. During this period, the heart from HS-diet-fed SHR exhibited a transition from compensated LV hypertrophy to decompensation, as shown by progressive impairment of LV function and interstitial fibrosis. Myocardial extracellular [Na+] and the expression of tonicity-responsive enhancer binding protein (TonEBP) was significantly increased in HS-fed rats, indicating myocardial interstitial hypertonicity by chronic HS intake. The global autophagic change and overt deterioration of LV function were not observed in LS-fed SHR and HS-fed WKY rats. The study of rat H9c2 cardiomyocytes demonstrated a cytosolic [Na+] elevation-mediated, reactive oxygen species-dependent the autophagic change occurred when exposed to an increased extracellular [Na+]. The present findings demonstrated that a myocardial autophagic change participates in the maladaptive LV remodeling induced by chronic HS intake in SHR, which provides a possible target for future intervention studies on HS-induced hypertensive LV remodeling.