Function In Hypertensive Rats Research Articles

Hydrogen sulfide increases excitation-contraction coupling efficiency and modulates LCC and SERCA2a function in hypertensive rats

Hydrogen sulfide increases excitation-contraction coupling efficiency and modulates LCC and SERCA2a function in hypertensive rats

Effects of regulator of G protein signaling 2 (RGS2) overexpression in the paraventricular nucleus on blood pressure in rats with angiotensin II-induced hypertension.

The hypothalamic paraventricular nucleus (PVN) regulates sympathetic activity and blood pressure. The regulator of G protein signaling 2 (RGS2) is a negative G protein regulator, which selectively regulates G⍺q signaling, a potential cause of hypertension. This study aimed to examine angiotensin II (ANG II)-G protein-RGS2 signaling on the central mechanisms of blood pressure control, sympathetic activation, and kidney function. The Sprague Dawley rats were infused with ANG II (200ng/kg/min) via osmotic mini pump to induce hypertension. Adenovirus (AV) vectors encoding RGS2 was transfected into the PVN in vivo. By radio telemetry measurements, we found AV-RGS2 transfection to the PVN significantly attenuated the increase of mean arterial pressure in ANG II infusion rats from days 2-7 of the 2-week experiment (Day 7: ANG II + AV-RGS2 141.3 ± 10.0mmHg vs. ANG II 166.9 ± 9.3mmHg, p < 0.05). AV-RGS2 transfection significantly reduced the serum norepinephrine level and acute volume reflex and increased daily urine volume and sodium excretion in ANG II-infused hypertensive rats. AV-RGS2 transfection significantly reduced G⍺q and PKC protein expressions within the PVN in ANG II infusion rats. In cultured mouse hypothalamic cells, real-time PCR study showed ANG II treatment increased mRNA expression of G⍺q, G⍺s, and RGS2, and AV-RGS2 treatment decreased ANG II-induced mRNA expression of G⍺q and G⍺s. Using confocal imagery, we found that AV-RGS2 attenuated the increase of calcium influx in ANG II-treated cells. Our results suggest that central overexpression of RGS2 in the PVN attenuated the increase of blood pressure and sympathetic outflow, and improves kidney excretory function in hypertensive rats. This may be via the alteration of ANG II-G-protein-RGS2 signaling in the central nervous system.

Quinapril treatment curtails decline of global longitudinal strain and mechanical function in hypertensive rats.

Left ventricular (LV) global longitudinal strain (GLS) has been proposed as an early imaging biomarker of cardiac mechanical dysfunction. To assess the impact of angiotensin-converting enzyme (ACE) inhibitor treatment of hypertensive heart disease on LV GLS and mechanical function. The spontaneously hypertensive rat (SHR) model of hypertensive heart disease (n = 38) was studied. A subset of SHRs received quinapril (TSHR, n = 16) from 3 months (mo). Wistar Kyoto rats (WKY, n = 13) were used as controls. Tagged cardiac MRI was performed using a 4.7 T Varian preclinical scanner. The SHRs had significantly lower LV ejection fraction (EF) than the WKYs at 3 mo (53.0 ± 1.7% vs. 69.6 ± 2.1%, P < 0.05), 14 mo (57.0 ± 2.5% vs. 74.4 ± 2.9%, P < 0.05) and 24 mo (50.1 ± 2.4% vs. 67.0 ± 2.0%, P < 0.01). At 24 mo, ACE inhibitor treatment was associated with significantly greater LV EF in TSHRs compared to untreated SHRs (64.2 ± 3.4% vs. 50.1 ± 2.4%, P < 0.01). Peak GLS magnitude was significantly lower in SHRs hearts compared with WKYs at 14 months (7.5% ± 0.4% vs. 9.9 ± 0.8%, P < 0.05). At 24 months, Peak GLS magnitude was significantly lower in SHRs compared with both WKYs (6.5 ± 0.4% vs. 9.7 ± 1.0%, P < 0.01) and TSHRs (6.5 ± 0.4% vs. 9.6 ± 0.6%, P < 0.05). ACE inhibitor treatment curtails the decline in global longitudinal strain in hypertensive rats, with the treatment group exhibiting significantly greater LV EF and GLS magnitude at 24 mo compared with untreated SHRs.

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.

Avocado Oil Prevents Kidney Injury and Normalizes Renal Vasodilation after Adrenergic Stimulation in Hypertensive Rats: Probable Role of Improvement in Mitochondrial Dysfunction and Oxidative Stress.

Hypertension impairs the function of the kidney and its vasculature. Adrenergic activation is involved in these processes by promoting oxidative stress and mitochondrial dysfunction. Thus, the targeting of mitochondrial function and mitochondrial oxidative stress may be an approach to alleviate hypertensive kidney damage. Avocado oil, a source of oleic acid and antioxidants, improves mitochondrial dysfunction, decreases mitochondrial oxidative stress, and enhances vascular function in hypertensive rats. However, whether avocado oil improves the function of renal vasculature during the adrenergic stimulation, and if this is related to improvement in renal damage and enhancement of mitochondrial activity is unknown. Thus, the effects of avocado oil on renal vascular responses to adrenergic stimulation, mitochondrial dysfunction, oxidative stress, and renal damage were compared with prazosin, an antagonist of α1-adrenoceptors, in hypertensive rats induced by L-NAME. Avocado oil or prazosin decreased blood pressure, improved endothelium—dependent renal vasodilation, prevented mitochondrial dysfunction and kidney damage in hypertensive rats. However, avocado oil, but not prazosin, decreased mitochondrial ROS generation and improved the redox state of mitochondrial glutathione. These results suggest that avocado oil and prazosin prevented hypertensive renal damage due to the improvement in mitochondrial function.

Ethanolic extract of Cissus quadrangularis improves vasoreactivity by modulation of eNOS expression and oxidative stress in spontaneously hypertensive rats

ABSTRACT Background Endothelial dysfunction is related to the reduced bioavailability of nitric oxide (NO) and plays a significant role in developing hypertension. The intake of a diet rich in antioxidants decreases the threat of hypertension. Cissus quadrangularis possesses antioxidant, anti-inflammatory, and hypocholesterolemic activities. However, to date, no studies have been performed to explore this plant’s antihypertensive and vasorelaxant activity. Herein, we investigated the chronic effect of C. quadrangularis on blood pressure as well as vascular function in hypertensive rats. Methods Male spontaneously hypertensive rats (SHR) were randomly divided into two groups. Normotensive Wistar rats were taken as the control group. The treatment was done using ethanolic extract of C. quadrangularis (EECQ) at a dose of 200 mg/kg. Results The administration of EECQ for six weeks reduced the systolic blood pressure, mean arterial blood pressure, and heart rate. It also alleviated the cardiac and renal hypertrophy indices. Supplementation of EECQ improved the endothelium-dependent aortic vasodilation induced by acetylcholine. It restored the NO level and endothelial NO synthase expression in the aorta. Subsequently, the extract alleviates the oxidative stress and inflammatory markers in SHR rats. Conclusion Thus, in the present study, the chronic treatment of EECQ to genetically hypertensive rats improved endothelium-dependent relaxation in addition to its antihypertensive effect by eNOS activation and inhibition of ROS production, inflammation.

Effects of carvedilol on myocardial remodeling, oxidative stress, inflammation indexes and endothelial function in hypertensive rats.

Effects of carvedilol on myocardial remodeling, oxidative stress, inflammation indexes and endothelial function in hypertensive rats.

Cardiac, biochemical and histopathological analysis reveals impaired heart function in hypertensive rats with apical periodontitis.

To investigate the association between experimentally induced apical periodontitis (AP) and heart function in hypertensive rats. Forty-eight normotensive Wistar albino and spontaneously hypertensive (SHR) rats were divided into four equal groups: control (C), normotensive with AP (AP), SHR and SHR with AP (SHR+AP). AP was induced on the first right mandibular molars by exposing the pulp chambers to the oral environment for four weeks and confirmed radiographically. Thereafter, the animals were sacrificed by cervical dislocation, whilst hearts were isolated and perfused according to the Langendorff technique gradually increasing coronary perfusion pressures 40-120cmH2 O. The hemimandibles were analysed radiographically (mm2 and pixels) to verify the presence of AP. Biomarkers of cardiac oxidative stress (OS) were determined in coronary venous effluent and cardiac tissue homogenate. Cardiac tissue was analysed histopathologically for signs of heart damage (oedema, fibrosis and necrosis). All data were analysed by Kruskal-Wallis and one-way anova tests (p<.05). The levels of the maximum left ventricular pressure development rate of the SHR+AP group were significantly increased compared to the AP and C groups, and of the SHR group compared with the C group (p<.05). The levels of the minimum left ventricular pressure development rate of the SHR+AP group were significantly decreased compared to the AP, SHR and C groups, and of the SHR group compared to the C group (p<.05). The radiographic AP area was significantly larger in the SHR+AP group than in the AP group (p<.01). The levels of superoxide anion were significantly higher in the SHR+AP group than in the AP, SHR and C groups (p<.05). The activities of superoxide dismutase in cardiac tissue homogenate were significantly lower in the SHR+AP and AP groups compared with the SHR and C groups (p<.05). In rats, AP was associated with impaired cardiodynamics, disturbed cardiac OS, antioxidant defence and cardiac pathologic changes in hypertensive conditions. Hypertension was associated with an increase in the AP radiographic area. Further studies should confirm whether root canal treatment can have a cardioprotective effect and reduce cardiac OS in hypertensive conditions.

Comparative Evaluation of Aloe vera and Diclofenac on Body Weight, Blood Pressure and Renal Function of Hypertensive Rats

Introduction: NSAIDs are known to cause salt and water retention leading to hypertension and renal impairment. Aloe vera gel has been used in medicinal preparations for decades. Limited data is available regarding effect of Aloe vera on renal function. There is a need to search this aspect of Aloe vera, to use it judiciously.&#x0D; Aims &amp; Objectives: To estimate and compare the effects of Aloe vera and diclofenac on systolic blood pressure and renal functions of hypertensive rats.&#x0D; Place and duration of study: This study was conducted at Post Graduate Medical Institute Lahore, Sargodha Medical College, Sargodha and Department of Pharmacy, University of Sargodha for the period of three months.&#x0D; Material &amp; Methods: Male Sprague Dawley rats (n=24) were divided into four groups; Group A (Normal control), Group B (Hypertensive control), Group C (Aloe vera treated) and Group D (Diclofenac treated). Hypertension was induced in groups B, C and D by 20% sucrose diet in 8 weeks. After induction of hypertension, distilled water, dried Aloe vera gel 400 mg/kg and diclofenac 12 mg/kg were given orally to group B, C and D respectively for 2 weeks as a single morning dose. Body weight and systolic blood pressure were measured weekly, while serum creatinine, creatinine clearance and urinary proteins were estimated and compared at 0, 8 and 10 weeks. Data was analyzed using SPSS 23 and p value of ?0.05 was considered significant.&#x0D; Results: Diclofenac decreased body weight of rats non-significantly and increased systolic blood pressure significantly (p&lt; 0.03) whereas Aloe vera increased body weight significantly (p&lt;0.012) and had no significant effect on systolic blood pressure. Diclofenac treated group showed deterioration of renal function as compared to Aloe vera treated group numerically. Conclusion: Aloe vera may be safer anti-inflammatory agent than diclofenac for treatment of chronic inflammatory conditions if the patient also has hypertension or renal disease.

Cratoxylum Formosum extract exhibits antihypertensive effects via suppressing the renin-angiotensin cascade in hypertensive rats

Abstract The effect of Cratoxylum Formosum (CF) extract on blood pressure and changes in vascular structure and function in hypertensive rats was studied. Rats received 40 mg/kg L-NAME and treated with CF extract or captopril or captopril + CF extract (n = 8). CF extract attenuated hypertension, enhancement of nerve-mediated contractile responses, endothelial dysfunction and oxidative stress markers and raised concentrations of nitric oxide metabolites (NOx) in L-NAME treated rats. Aortic hypertrophy associated with increases in serum ACE activity, plasma angiotensin II level, and AT1R/Akt/STAT3 protein expression in hypertensive rats were alleviated by CF extract. In hypertensive rats, captopril + CF extract administration showed greater effects on reducing blood pressure and vascular hypertrophy. Data of this study suggested that an antihypertensive effect of CF extract is linked to its antioxidant effect to enhance NO bioavailability and an inhibitory effect on RAS cascade.

Quercetin improves vascular endothelial function through promotion of autophagy in hypertensive rats

AimsEndothelial dysfunction is a hallmark of hypertension. Herein, we assessed the effect of quercetin, a common dietary antioxidant, on endothelial function of spontaneously hypertensive rats (SHRs), and investigated the underlying molecular mechanisms. Main methodsThe Wistar-Kyoto (WKY) and SHR rats were administered vehicle (1% w/v methyl cellulose) or quercetin (10 mg/kg body weight) by oral gavage once a day for 6 weeks. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured with a tail-cuff system. Functional of rat mesenteric arterioles was assessed by the temperature-controlled myograph. A dose-response curve was generated by the cumulative addition of acetylcholine (ACh) or sodium nitroprusside (SNP). NO production in the culture medium was assessed by measuring the concentration of nitrite, a stable metabolite of NO, using a modified Griess reagent. Key findingsQuercetin improved endothelial function and decreased blood pressure in SHRs. Endothelial autophagy, an important cellular homeostatic process, was increased in the early phase of treatment, and decreased in the late phase of treatment. Quercetin promoted autophagy in cultured endothelial cells under both normal and oxidative stress conditions. Pharmacological inhibition of autophagy aggravated endothelial dysfunction in quercetin-treated endothelial cells under oxidative stress, and attenuated the antihypertensive and endothelial protective effects of quercetin in SHRs. SignificanceQuercetin protects endothelial function in hypertensive rats through promotion of autophagy. Thus, autophagy could serve as a potential therapeutic target for hypertension.

Enhanced Cardiomyocyte Function in Hypertensive Rats With Diastolic Dysfunction and Human Heart Failure Patients After Acute Treatment With Soluble Guanylyl Cyclase (sGC) Activator.

AimsOur aim was to investigate the effect of nitric oxide (NO)-independent activation of soluble guanylyl cyclase (sGC) on cardiomyocyte function in a hypertensive animal model with diastolic dysfunction and in biopsies from human heart failure with preserved ejection fraction (HFpEF).MethodsDahl salt-sensitive (DSS) rats and control rats were fed a high-salt diet for 10 weeks and then acutely treated in vivo with the sGC activator BAY 58-2667 (cinaciguat) for 30 min. Single skinned cardiomyocyte passive stiffness (Fpassive) was determined in rats and human myocardium biopsies before and after acute treatment. Titin phosphorylation, activation of the NO/sGC/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) cascade, as well as hypertrophic pathways including NO/sGC/cGMP/PKG, PKA, calcium–calmodulin kinase II (CaMKII), extracellular signal-regulated kinase 2 (ERK2), and PKC were assessed. In addition, we explored the contribution of pro-inflammatory cytokines and oxidative stress levels to the modulation of cardiomyocyte function. Immunohistochemistry and electron microscopy were used to assess the translocation of sGC and connexin 43 proteins in the rat model before and after treatment.ResultsHigh cardiomyocyte Fpassive was found in rats and human myocardial biopsies compared to control groups, which was attributed to hypophosphorylation of total titin and to deranged site-specific phosphorylation of elastic titin regions. This was accompanied by lower levels of PKG and PKA activity, along with dysregulation of hypertrophic pathway markers such as CaMKII, PKC, and ERK2. Furthermore, DSS rats and human myocardium biopsies showed higher pro-inflammatory cytokines and oxidative stress compared to controls. DSS animals benefited from treatment with the sGC activator, as Fpassive, titin phosphorylation, PKG and the hypertrophic pathway kinases, pro-inflammatory cytokines, and oxidative stress markers all significantly improved to the level observed in controls. Immunohistochemistry and electron microscopy revealed a translocation of sGC protein toward the intercalated disc and t-tubuli following treatment in both control and DSS samples. This translocation was confirmed by staining for the gap junction protein connexin 43 at the intercalated disk. DSS rats showed a disrupted connexin 43 pattern, and sGC activator was able to partially reduce disruption and increase expression of connexin 43. In human HFpEF biopsies, the high Fpassive, reduced titin phosphorylation, dysregulation of the NO–sGC–cGMP–PKG pathway and PKA activity level, and activity of kinases involved in hypertrophic pathways CaMKII, PKC, and ERK2 were all significantly improved by sGC treatment and accompanied by a reduction in pro-inflammatory cytokines and oxidative stress markers.ConclusionOur data show that sGC activator improves cardiomyocyte function, reduces inflammation and oxidative stress, improves sGC–PKG signaling, and normalizes hypertrophic kinases, indicating that it is a potential treatment option for HFpEF patients and perhaps also for cases with increased hypertrophic signaling.

Potential Protective Effects of the Water-Soluble Chinese Propolis on Hypertension Induced by High-Salt Intake.

High‐salt (HS) intake is closely associated with the ignition and progression of hypertension. The mechanisms might be involved in endothelial dysfunction, nitric oxide deficiency, oxidative stress, and proinflammatory cytokines. Propolis is widely used as a natural antioxidant and is a well‐known functional food for its biological activities, which includes anti‐inflammation, antimicrobial, and liver detoxification. In this study, we successfully replicated a HS diet‐induced hypertensive rat model. We found that in the long‐term HS diet group, the myocardial function of the rats was altered and led to a significant decrease (around 49%) in heart function. However, doses of Chinese water‐soluble propolis (WSP) were found directly proportional (11%, 60%, 91%, respectively) to the myocardial function improvement in hypertensive rats. The results from the blood circulation test and hematoxylin‐eosin stains showed that propolis had protective effects on myocardial functions and blood vessels in hypertensive rats. Also, based on the results of western blot and polymerase chain reaction, WSP effectively regulated Nox2 and Nox4 levels and was responsible for a decrease in reactive oxygen species synthesis. Our findings demonstrate that Chinese WSP has a significant effect on the blood pressure of hypertensive rats and their cardiovascular functions that improved significantly. The improvement in the cardiovascular functions might be related to the process of anti‐oxidation, anti‐inflammation, and the improvements of the endothelial function in hypertensive rats.

Calcitriol ameliorated autonomic dysfunction and hypertension by down-regulating inflammation and oxidative stress in the paraventricular nucleus of SHR

The hypothalamic paraventricular nucleus (PVN) plays crucial roles in central cardiovascular regulation. Increasing evidence in humans and rodents shows that vitamin D intake is important for achieving optimal cardiovascular function. The purpose of this study was to investigate whether calcitriol, an active form of vitamin D, improves autonomic and cardiovascular function in hypertensive rats and whether PVN oxidative stress and inflammation are involved in these beneficial effects. Male spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were treated with either calcitriol (40 ng/day) or vehicle (0.11 μL/h) through chronic PVN infusion for 4 weeks. Blood pressure and heart rate were recorded continuously by radiotelemetry. PVN tissue, heart and plasma were collected for molecular and histological analysis. Compared to WKY rats, SHR exhibited increased systolic blood pressure, sympathetic drive, and cardiac hypertrophy and remodeling. These were associated with higher mRNA and protein expression levels of high mobility box 1 (HMGB1), receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), proinflammatory cytokines, NADPH oxidase subunit in the PVN. In addition, increased norepinephrine in plasma, elevated reactive oxygen species levels and activation of microglia in the PVN were also observed in SHR. Chronic calcitriol treatment ameliorated these changes but not in WKY rats. Our results demonstrate that chronic infusion of calcitriol in the PVN ameliorates hypertensive responses, sympathoexcitation and retains cardiovascular function in SHR. Reduced inflammation and oxidative stress within the PVN are involved in these calcitriol-induced effects.

Dietary Supplementation with Silicon-Enriched Spirulina Improves Arterial Remodeling and Function in Hypertensive Rats.

Vascular aging is characterized by increase in arterial stiffness and remodeling of the arterial wall with a loss of elastic properties. Silicon is an essential trace element highly present in arteries. It is involved in the constitution and stabilization of elastin fibers. The nutritional supply and bioavailability of silicon are often inadequate. Spirulina (Sp), micro algae have recognized nutritional properties and are able to incorporate minerals in a bioavailable form. We evaluated the effects of nutritional supplementation with silicon-enriched spirulina (SpSi) on arterial system structure and function in hypertension. Experiments were performed on hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats supplemented with SpSi or Sp over a period of three months. Arterial pressure, vascular function and morphometric parameters of thoracic aorta were analyzed. SpSi supplementation lowered arterial pressure in SHR and minimized morphometric alterations induced by hypertension. Aortic wall thickness and elastic fibers fragmentation were partially reversed. Collagen and elastin levels were increased in association with extracellular matrix degradation decrease. Vascular reactivity was improved with better contractile and vasorelaxant responses to various agonists. No changes were observed in SHR supplemented with Sp. The beneficial effects of SpSi supplementation evidenced here, may be attributable to Si enrichment and offer interesting opportunities to prevent cardiovascular risks.

Pharmacological Characterization of Aprocitentan, a Dual Endothelin Receptor Antagonist, Alone and in Combination with Blockers of the Renin Angiotensin System, in Two Models of Experimental Hypertension.

The endothelin (ET) system has emerged as a novel target for hypertension treatment where a medical need persists despite availability of several pharmacological classes, including renin angiotensin system (RAS) blockers. ET receptor antagonism has demonstrated efficacy in preclinical models of hypertension, especially under low-renin conditions and in hypertensive patients. We investigated the pharmacology of aprocitentan (N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-sulfamide), a potent dual ETA/ETB receptor antagonist, on blood pressure (BP) in two models of experimental hypertension: deoxycorticosterone acetate (DOCA)-salt rats (low-renin model) and spontaneously hypertensive rats [(SHR), normal renin model]. We also compared the effect of its combination with RAS blockers (valsartan and enalapril) with that of the combination of the mineraloreceptor antagonist spironolactone with the same RAS blockers on BP and renal function in hypertensive rats. Aprocitentan was more potent and efficacious in lowering BP in conscious DOCA-salt rats than in SHRs. In DOCA-salt rats, single oral doses of aprocitentan induced a dose-dependent and long-lasting BP decrease and 4-week administration of aprocitentan dose dependently decreased BP (statistically significant) and renal vascular resistance, and reduced left ventricle hypertrophy (nonsignificant). Aprocitentan was synergistic with valsartan and enalapril in decreasing BP in DOCA-salt rats and SHRs while spironolactone demonstrated additive effects with these RAS blockers. In hypertensive rats under sodium restriction and enalapril, addition of aprocitentan further decreased BP without causing renal impairment, in contrast to spironolactone. In conclusion, ETA/ETB receptor antagonism represents a promising therapeutic approach to hypertension, especially with low-renin characteristics, and could be used in combination with RAS blockers, without increasing the risk of renal impairment.

Inhibition of endothelial nitric oxide synthase reverses the effect of exercise on improving cognitive function in hypertensive rats.

Hypertension-induced endothelial dysfunction is associated with β-amyloid (Aβ) deposition, a typical pathology of Alzheimer's disease (AD). Endothelial nitric oxide synthase (eNOS) phosphorylation, impaired by phosphatidylinositol 3-kinase (PI3K)/protein kinase-B(Akt) pathway abnormalities in hypertensive rats, has a critical role in endothelial function. However, it is unknown whether eNOS participates in the hypertension-induced pathology of AD. In this study, we investigated the role of eNOS in Aβ deposition and cognitive function in stroke-prone spontaneously hypertensive (SHRSP) rats. Physical exercise was used as a promoter, and Nω-nitro L-arginine methyl ester (L-NAME) was used as an inhibitor of eNOS to determine the effects of eNOS on SHRSP rats. Compared with Wistar Kyoto (WKY) rats, the hypertensive challenge caused cognitive impairment, decreased eNOS levels and increased amyloid precursor protein (APP), β-secretase, and Aβ levels in the cortex and hippocampus. Sixteen weeks of exercise lowered blood pressure (BP), promoted eNOS expression, ameliorated Alzheimer's pathology, and improved cognitive function in 29-week-old SHRSP rats. Furthermore, daily treatment with L-NAME reversed the beneficial effects of exercise on SHRSP rats. Exercise also decreased the protein levels of insulin-like growth factor-1 (IGF-1), PI3K, and phospho-Akt (p-Akt, ser473). In addition, long-term exercise increased the expression levels of IGF-1, PI3K, and p-Akt (ser473) in the brains of SHRSP rats. In conclusion, eNOS downregulation contributed to hypertension-induced Alzheimer pathology and cognitive impairment. Long-term exercise initiated in rats at a young age promoted eNOS expression and attenuated vascular-related Alzheimer's pathology via the IGF-1/PI3K/p-Akt pathway in SHRSP rats.

The effects of single and combined application of ramipril and losartan on renal structure and function in hypertensive rats

ABSTRACTThe objective of the present study was to investigate the effects of single and combined administration of ramipril and losartan on renal structure and function in spontaneously hypertensive rats (SHRs). Thirty-two 9-week-old SHRs and eight Wistar-Kyoto (WKY) rats were randomly divided into five groups: the WKY control group, the SHR control group, the SHR-ramipril group, the SHR-losartan group, and the SHR-combined mediation group. The rat body weight, SBP, heart rate, and urinary albumin excretion rate (UAER) were measured. (1) The SBP was reduced to the normal level in all groups of rats except for the SHR control group. Combined administration of ramipril and losartan can be reduced to the normal level earlier than single (P < 0.01). (2) The SHR-ramipril group and the SHR-losartan group still experienced a higher UAER than that in the WKY control group (P < 0.01). (3) The renal mass/BW ratio was decreased in the SHR-ramipril group, SHR-losartan group, and SHR-combined medication group compared to that in the SHR control group (P < 0.01). (4) Compared with the SHR control group, the SHR-ramipril group, the SHR-losartan group, and the SHR-combined medication group had a lower percentage of the IOD of glomerular collagen relative to the glomerular area (P < 0.01). (5) The reduction in tubulointerstitial injury score was more significant in the SHR-combined medication group than in the SHR-ramipril group and the SHR-losartan group (P < 0.01). The combination of ramipril and losartan is superior to either single drug in reducing the UAER, resisting glomerular collagen deposition, and protecting renal tubular structure.

Simultaneous Imaging of Cerebrovascular Structure and Function in Hypertensive Rats Using Synchrotron Radiation Angiography.

Hypertension has a profound influence on the structure and function of blood vessels. Cerebral vessels undergo both structural and functional changes in hypertensive animals. However, dynamic changes of cerebrovasculature and the factors involved in this process are largely unknown. In this study, we explored the dynamic changes of vascular structure in hypertensive rats using novel synchrotron radiation angiography. Twenty-four spontaneously hypertensive rats (SHR) and 24 Sprague–Dawley (SD) rats underwent synchrotron radiation (SR) angiography. Each group had 8 animals. We studied the cerebral vascular changes in SHR over a time period of 3–12-month and performed quantitative analysis. No vascular morphology differences between SHR and SD rats were observed in the early stage of hypertension. The number of twisted blood vessels in the front brain significantly increased at the 9- and 12-month observation time-points in the SHR compared to the SD rats (p < 0.01). The vessel density of the cortex and the striatum in SHR was consistently higher than that in SD rats at time points of 3-, 9-, and 12-month (p < 0.001). Vascular elasticity decreased both in SHR and SD rats with aging. There were statistically significant differences in the relative vascular elasticity of extracranial/intracranial internal carotid artery, middle cerebral artery, posterior cerebral artery and anterior cerebral artery between SHR and SD rats at 12-month (p < 0.01). We concluded that the dynamic vascular alterations detected by SR angiography provided novel imaging data for the study of hypertension in vivo. The longer the course of hypertension was, the more obvious the vascular differences between the SHR and the SD rats became.

Tert-butylhydroquinone promotes angiogenesis and improves heart functions in rats after myocardial infarction

ABSTRACTBackground: Hypertension is an increased risk of heart failure and acute myocardial infarction (MI). Tert-butylhydroquinone (tBHQ), as an antioxidant, shows multiple cardioprotective actions including the reduction in blood pressure. The aim of this study was to investigate whether and how tBHQ improves heart functions in rats. Methods: The MI model was established in WKY and spontaneously hypertensive rats (SHRs) by ligation of left anterior descending coronary artery. Akt phosphorylation was examined by western blot in human umbilical vein endothelial cells (HUVECs) or in rats. Angiogenesis was assessed by immunohistochemistry and immunofluorescence. Heart function was determined by echocardiography. Results: tBHQ increased Akt phosphorylation, promoted cell proliferations and migrations in HUVECs, which were abolished by Akt inhibitor wortmannin. In SHRs following MI, administration of tBHQ significantly increased Akt phosphorylation, promoted angiogenesis, reduced infarct size, and improved heart functions after 14 postoperative days. Importantly, these in vivo effects of tBHQ were ablated by wortmannin in SHRs. Conclusion: tBHQ via Akt activation promotes ischemia-induced angiogenesis and improves heart functions in hypertensive rats. In perspectives, the application of tBHQ should be considered in patients with ischemic diseases such as MI and stroke.