Protective effects of the angiotensin II type I (ATI) receptor blockade in low-renin deoxycorticosterone acetate (DOCA)-treated spontaneously hypertensive rats

The present study evaluates the participation of oxidative stress, tissue angiotensin II (Ang II) and endothelin (ET) in the effects of losartan on blood pressure (BP), ventricular hypertrophy and renal injury in spontaneously hypertensive rats (SHRs), and explores how these effects are modified when spontaneous hypertension is transformed in a low-renin model by the administration of deoxycorticosterone acetate (DOCA). The following groups were used: SHR-control, SHR+DOCA, SHR+losartan and SHR+DOCA+losartan. Tail systolic BP was measured once a week. After 9 weeks of treatment, direct BP and metabolic, morphological, biochemical and renal variables were measured. DOCA administration to SHRs produced an increase in BP, ventricular hypertrophy, renal weight, proteinuria, renal histopathological lesions, urinary excretion of isoprostane F2α and ET levels in the renal cortex. Losartan reduced BP, plasma malondialdehyde levels, urinary excretion of isoprostane F2α, renal Ang II and renal and urinary levels of ET in the SHR and DOCA-treated SHR groups. Losartan increased plasma nitrite/nitrate in SHRs, but not in low-renin DOCA-treated SHRs. Losartan reduced ventricular hypertrophy and ventricular Ang II in SHRs, but not in DOCA-treated SHRs. Losartan significantly decreased proteinuria and renal injury in DOCA-treated SHRs. We conclude that (i) the DOCA-induced aggravation of hypertension, ventricular hypertrophy and renal injury in SHRs is accompanied by augmented oxidative stress and increased levels of ET in the renal cortex, which could contribute to their development; and (ii) losartan reduced oxidative stress and renal Ang II and ET in SHRs and DOCA-treated SHRs, which might contribute to its antihypertensive and renoprotective effects, regardless of renin status.

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AT1 receptor‐ independent oxidative stress in angiotensin II (Ang II) infused Male Spontaneously Hypertensive Rats (SHR)

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.605.14 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Kanchan Bhatia ◽

Jennifer C Sullivan

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

Spontaneously Hypertensive Rats ◽

At1 Receptor ◽

Ang Ii ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

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β-Pro7Ang III is a novel highly selective angiotensin II type 2 receptor (AT2R) agonist, which acts as a vasodepressor agent via the AT2R in conscious spontaneously hypertensive rats

Clinical Science ◽

10.1042/cs20150077 ◽

2015 ◽

Vol 129 (6) ◽

pp. 505-513 ◽

Cited By ~ 15

Author(s):

Mark Del Borgo ◽

Yan Wang ◽

Sanja Bosnyak ◽

Morimer Khan ◽

Pia Walters ◽

...

Keyword(s):

Cardiovascular Disease ◽

Angiotensin Ii ◽

Protein Binding ◽

Binding Site ◽

Spontaneously Hypertensive Rats ◽

Protective Effects ◽

Ang Ii ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

We have synthesized a highly selective compound that is able to target a protein-binding site [called angiotensin (Ang) II type 2 receptor, AT2R] in the cardiovascular system. This research tool will enhance our ability to stimulate AT2R to produce protective effects against cardiovascular disease.

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Angiotensin II AT1 Receptor Blockade Abolishes Brain Microvascular Inflammation and Heat Shock Protein Responses in Hypertensive Rats

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600082 ◽

2005 ◽

Vol 25 (7) ◽

pp. 878-886 ◽

Cited By ~ 92

Author(s):

Jin Zhou ◽

Hiromichi Ando ◽

Miroslava Macova ◽

Jingtao Dou ◽

Juan M Saavedra

Keyword(s):

Angiotensin Ii ◽

Heat Shock ◽

Heat Shock Protein ◽

Receptor Antagonist ◽

Spontaneously Hypertensive Rats ◽

Receptor Blockade ◽

Ang Ii ◽

Hypertensive Rats ◽

Cerebral Microvessels ◽

Spontaneously Hypertensive

Endothelial dysfunction and inflammation enhance vulnerability to hypertensive brain damage. To explore the participation of Angiotensin II (Ang II) in the mechanism of vulnerability to cerebral ischemia during hypertension, we examined the expression of inflammatory factors and the heat shock protein (HSP) response in cerebral microvessels from spontaneously hypertensive rats and their normotensive controls, Wistar Kyoto rats. We treated animals with vehicle or the Ang II AT1 receptor antagonist candesartan, 0.3 mg/kg/day, via subcutaneously implanted osmotic minipumps for 4 weeks. Spontaneously hypertensive rats expressed higher Angiotensin II AT1 receptor protein and mRNA than normotensive controls. Candesartan decreased the macrophage infiltration and reversed the enhanced tumor necrosis factor-α and interleukin-1β mRNA and nuclear factor-κB in microvessels in hypertensive rats. The transcription of many HSP family genes, including HSP60, HSP70 and HSP90, and heat shock factor-1 was higher in hypertensive rats and was downregulated by AT1 receptor blockade. Our results suggest a proinflammatory action of Ang II through AT1 receptor stimulation in cerebral microvessels during hypertension, and very potent antiinflammatory effects of the Ang II AT1 receptor antagonist. These compounds might be considered as potential therapeutic agents against ischemic and inflammatory diseases of the brain.

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The Relationship Between Angiotensin II (ANG II) and Oxidative Stress in the Maintenance of Mean Arterial Pressure (MAP) of Spontaneously Hypertensive Rats.

Hypertension ◽

10.1161/hyp.36.suppl_1.686-b ◽

2000 ◽

Vol 36 (suppl_1) ◽

pp. 686-686

Author(s):

Rodney J Bolterman ◽

Clara M Ortiz-Ruiz ◽

Luis A Juncos ◽

Jane F Reckelhoff ◽

Juan C Romero

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Plasma Levels ◽

Spontaneously Hypertensive Rats ◽

Enzyme Inhibitor ◽

Ang Ii ◽

Converting Enzyme ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Converting Enzyme Inhibitor

48 Spontaneously hypertensive rats (SHR) reportedly have inappropriately high levels of Ang II despite normal plasma renin activity (PRA). Because Ang II stimulates oxidative stress, which in turn quenches nitric oxide, it is possible that Ang II-induced increases in oxidative stress contribute to the increase in blood pressure. Indeed, administering either a converting enzyme inhibitor (to decrease Ang II) or Tempol (a potent antioxidant) reduces blood pressure in SHR. We tested whether decreasing Ang II with a converting enzyme inhibitor reduces oxidative stress as well as MAP in SHR. For this, we divided 12 weeks old SHR into two groups (n=5 each). One group was treated with captopril (100 mg/kg/day added to the drinking water) and the other served as our untreated time controls. After 16 days of treatment, the rats were anesthetised and we measured MAP and collected blood samples to determine PRA, and the plasma levels of Ang II and thiobarbituric acid-reactive substances (TBARS). The captopril-treated rats had a lower MAP than the untreated rats (92±4 vs. 160±5 mmHg, respectively) and an increased PRA (42±1 vs. 26±6 ng/ml/h; captopril-treated vs. untreated rats, respectively). The decreased MAP in the captopril-treated SHR was accompanied by reduced plasma levels of Ang II (630±47 vs. 836±205 pg/ml) and TBARS (5.4±1.0 vs. 3.0±0.2 nmol/ml). Despite the significant decrease in Ang II levels in the captopril-treated SHR, they are still 20-fold higher rhan in normotensive Sprague-Dawley rats (34.0±8.8 pg/ml). In summary, captopril-induced decreases of MAP in SHR are accompanied not only by reduced levels of Ang II, but also by reduced oxidative stress. Because antioxidants also lower MAP in SHR, it suggests that oxidative stress induced by Ang II may play a role in the pathogenesis of the increased blood pressure in SHR.

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Electroacupuncture Improved Chronic Cerebral Hypoperfusion-Induced Anxiety-Like Behavior and Memory Impairments in Spontaneously Hypertensive Rats by Downregulating the ACE/Ang II/AT1R Axis and Upregulating the ACE2/Ang-(1-7)/MasR Axis

Neural Plasticity ◽

10.1155/2020/9076042 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Peipei Feng ◽

Zemin Wu ◽

Hao Liu ◽

Yafang Shen ◽

Xu Yao ◽

...

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Spontaneously Hypertensive Rats ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Ang Ii ◽

Converting Enzyme ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Memory Impairments

Electroacupuncture (EA) can effectively alleviate anxiety disorders and memory impairments caused by various neurodegenerative diseases; however, the molecular mechanisms underlying its neuroprotective effects are unclear. Previous studies have shown that the renin-angiotensin system (RAS) comprises of two axes with mutual antagonism: the classical angiotensin converting enzyme/angiotensin II/angiotensin II type 1 receptor (ACE/Ang II/AT1R) axis and the protective angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor (ACE2/Ang-(1-7)/MasR) axis. In this study, we observed that chronic cerebral hypoperfusion (CCH) mediated anxiety-like behavior and memory impairments in spontaneously hypertensive rats (SHR) via upregulation of the hippocampal classical axis (ACE/Ang II/AT1R) and the partial hippocampal protective axis (ACE2/Ang-(1-7)). However, Ang II levels were much higher than those of Ang-(1–7), indicating that the ACE/Ang II/AT1R axis plays a dominant role in the comorbidity of CCH and hypertension. Moreover, candesartan cilexetil (Canc) and perindopril (Peril) were used as positive control drugs. We found that EA, Canc, and Peril attenuated CCH-induced anxiety-like behavior and memory impairments in SHR, potentially via downregulation of the hippocampal classical axis (ACE/Ang II/AT1R) and upregulation of the whole hippocampal protective axis (ACE2/Ang-(1-7)/MasR). These results suggest that EA therapy for CCH with hypertension may be mediated by two hippocampal RAS axes.

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Candesartan prevents L-NAME-induced cardio-renal injury in spontaneously hypertensive rats beyond hypotensive effects

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/14703203010020011501 ◽

2001 ◽

Vol 2 (1_suppl) ◽

pp. S84-S90 ◽

Cited By ~ 6

Author(s):

Daniel Casellas ◽

Abderraouf Herizi ◽

Annie Artuso ◽

Albert Mimran ◽

Bernard Jover

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Renal Injury ◽

Spontaneously Hypertensive Rats ◽

Candesartan Cilexetil ◽

Vascular Lesions ◽

Heart Weight ◽

Hypertensive Rats ◽

Renal Protection ◽

Spontaneously Hypertensive

Our goal was to assess the cardiovascular and renal protection afforded by angiotensin II type 1-receptor blockade against NG-nitro-L-arginine methyl ester (L-NAME)-exacerbated hypertension in young spontaneously hypertensive rats (SHR), in comparison with the antihypertensive drug, hydralazine. Male SHR were assigned to four groups (n=8 per group): no treatment (controls); L-NAME-treated group (20 mg/kg/day, 10 days, orally); co-treatment with L-NAME and hydralazine (15 mg/kg/day, by gavage); co-treatment with L-NAME and candesartan cilexetil (10 mg/kg/day, by gavage), i.e. at a dose that inhibited acute pressor responses to 5—20 ng angiotensin II. One animal died in the L-NAME group, and tail-cuff systolic blood pressure (SBP) increased significantly compared with controls to 201±5 mmHg. Albumin excretion increased 235-fold in L-NAME-treated rats. Heart weight index averaged 3.5±0.1 and 3.8±0.1 mg/g body weight (p<0.05) in control and L-NAME rats, respectively, indicating moderate cardiac hypertrophy induced by L-NAME. Preglomerular vascular lesions affected 63±6% of interlobular arteries and 10±2% of afferent arterioles (vs. 8±3 and 0.8±0.4% in controls, respectively). Hydralazine and candesartan cilexetil treatment similarly reduced SBP to 153±7, and 165±6 mmHg, respectively. However, candesartan provided more protection, in terms of no significant change in albuminuria (vs. 25-fold increase with hydralazine), regression of cardiac hypertrophy, frequency of vascular lesions and histological indices of renal injury maintained within control values. In conclusion, candesartan cilexetil prevented L-NAME-exacerbated hypertension and associated cardio-renal injury in young SHR, the beneficial effects exceeding those of hydralazine.

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Nebivolol reduces cardiac angiotensin II, associated oxidative stress and fibrosis but not arterial pressure in salt-loaded spontaneously hypertensive rats

Journal of Hypertension ◽

10.1097/hjh.0b013e328356766f ◽

2013 ◽

pp. 1 ◽

Cited By ~ 6

Author(s):

Jasmina Varagic ◽

Sarfaraz Ahmad ◽

Jessica L. Voncannon ◽

Norihito Moniwa ◽

Stephen W. Simington ◽

...

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

Arterial Pressure ◽

Spontaneously Hypertensive Rats ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

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The HuoXue DiTan Recipe Attenuates Left Ventricular Hypertrophy in Spontaneously Hypertensive Rats by Increasing Autophagy Through the PTEN/PI3K/AKT/mTOR Pathway

10.21203/rs.3.rs-1047223/v1 ◽

2021 ◽

Author(s):

YAO Jiamei ◽

ZHANG Cui ◽

YANG Yushu ◽

YANG Haiyan ◽

ZHANG Dan ◽

...

Keyword(s):

Oxidative Stress ◽

Left Ventricular Hypertrophy ◽

Spontaneously Hypertensive Rats ◽

Ventricular Hypertrophy ◽

Myocardial Hypertrophy ◽

Left Ventricular ◽

Mtor Pathway ◽

Mtor Signaling Pathway ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

Abstract Background Hypertension-induced left ventricular hypertrophy (LVH) is associated with a reduction in autophagy, which can be inhibited by disruption of the PTEN/PI3K/AKT/mTOR pathway. The HuoXue DiTan recipe (HDR) is a commonly used prescription that has shown therapeutic effects on hypertension and its complications. However, its mechanisms are still unclear. In the present study, we hypothesized that HDR can regulate the PTEN/PI3K/AKT/mTOR signaling pathway and thereby reverse LVH by increasing autophagy in spontaneously hypertensive rats. Methods Twelve-week-old male spontaneously hypertensive (SH) rats and age-matched normotensive-control Wistar-Kyoto (WKY) rats were divided into four groups. After 12 weeks of treatment, echocardiographic measurements were made on the left ventricle, blood samples were collected for oxidative stress analysis, left ventricle tissue was processed for hematoxylin and eosin, Masson's trichrome, and immunohistochemical/ immunofluorescence staining, and TUNEL, RT-qPCR and Western blot analyses were performed. Results Compared with age-matched WKY rats, SH rats at 16 weeks of age exhibited significantly greater myocardial hypertrophy and remodeling with abnormal heart function. There was a reduction in autophagy and increase in apoptosis, resulting in an imbalance of oxidative stress manifested as left ventricular hypertrophy and impaired cardiac function. These effects may be related to a decrease in PTEN expression, which leads to activation of the PI3K/AKT/mTOR signaling pathway, resulting in abnormal expression of autophagy- and apoptosis-related proteins. After 12 weeks of HDR administration, blood pressure and ventricular hypertrophy were reduced, MDA and SOD levels and NADPH oxidase activity were better regulated, and gene expression of myocardial hypertrophy markers (ANP and β-MHC) was inhibited. HDR can promote autophagy and inhibit apoptosis, which may be related to regulation of autophagy- and apoptosis-related genes and proteins. HDR can also induce autophagy by enhancing expression of PTEN and inhibiting activation of the PI3K/AKT/mTOR signal pathway. Importantly, we demonstrated that VO-Ohpic, an inhibitor of PTEN, could suppress the effect of HDR on LVH in spontaneously hypertensive rats. Conclusion In conclusion, these results provide evidence for an important role of HDR in inhibition of left ventricular hypertrophy in spontaneously hypertensive rats, and indicate that it may act by improving autophagy through the PTEN/PI3K/AKT /mTOR pathway.

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