Transient prehypertensive treatment in spontaneously hypertensive rats: A comparison of losartan and amlodipine regarding long-term blood pressure, cardiac and renal protection
The First Clinical Medical College of Fujian Medical University, Fuzhou 350005, P.R. China.International Journal of Molecular Medicine (Impact Factor: 2.09). 10/2012; 30(6). DOI: 10.3892/ijmm.2012.1153
The aim of this study was to compare the effectiveness of transient prehypertensive treatment with losartan compared with amlodipine in spontaneously hypertensive rats (SHRs) on long-term blood pressure (BP), cardiac and renal protection. SHRs were prehypertensively treated with losartan, amlodipine or saline. Rats were followed up until 46 weeks of age. The left ventricular (LV) geometry and function were assessed by echocardiography. Angiotensin II (Ang II) and aldosterone (Aldo) were measured by radioimmunoassay. Ang II type 1 (AT1R) and type 2 (AT2R) receptor protein expression was determined by western blotting. The systolic blood pressure (SBP) in losartan-treated SHRs (SHR-Los) was persistently reduced until 46 weeks of age, but returned to untreated SHR levels in amlodipine-treated SHRs (SHR-Aml) from 30 weeks onwards. Compared to untreated SHRs, the albuminuria excretion in SHR-Los at week 46 was markedly decreased, the plasma, myocardium and renal tissue Ang II and Aldo levels in SHR-Los at week 46 were markedly decreased; AT1R and TGF-β1 protein expression was downregulated and AT2R protein was upregulated. Compared to untreated SHRs, the left ventricular mass index (LVMI) and collagen volume fraction (CVF) in SHR-Los were markedly decreased until week 46, and the left ventricular ejection fraction (LVEF) and cardiac brain natriuretic peptide mRNA expression were improved, whereas similar LVMI and elevated CVF were observed in SHR-Aml, and the LVEF decreased significantly below that of untreated SHRs at week 46, with cardiac BNP mRNA expression increasing slightly. Prehypertensive treatment with losartan was more effective than amlodipine on delaying long-term BP increase and ameliorating cardiac, renal structure and function, which may be related to the permanent attenuation of the circulating and local renin-angiotensin systems.
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ABSTRACT: To investigate the effects of losartan and amlodipine on cell apoptosis in the cerebral cortex of stroke-prone spontaneously hypertensive rats (SHRSP) from the onset of prehypertension or hypertension. SHRSP were randomly divided into five experimental groups that were administered losartan, amlodipine (n=8 in each group; 4 weeks old or 10 weeks old), or vehicle, respectively. Wistar-Kyoto rats were used as control animals. Systolic blood pressure was measured using the tail-cuff method every 2 weeks. At 20 weeks of age, apoptosis was analyzed by TdT-mediated dUTP-biotin nick end labeling, and the level of angiotensin II was measured by radioimmunoassay. Protein expressions of gp91, superoxide dismutase, and angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors in the cerebral cortex were detected by western blot. Losartan and amlodipine effectively delayed the progression of systolic blood pressure elevation, especially from the onset of prehypertension, and they had no obvious effects on the level of angiotensin II. In addition, treatment with losartan or amlodipine significantly decreased cell apoptosis, downregulated the protein expression of gp91, and upregulated the protein expression of superoxide dismutase. The protein expressions of AT1R and AT2R were decreased by the administration of both drugs. No difference was found in the expression of AT1R among the drug treatment groups, whereas the expression of AT2R was increased in rats with increased blood pressure. Amlodipine, especially from the onset of prehypertension, was more effective than losartan in reducing apoptosis in the cerebral cortex in SHRSP. This may be related to the antioxidative stress properties of amlodipine.
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ABSTRACT: Prehypertension has been associated with adverse cerebrovascular events and brain damage. The aims of this study were to investigate ⅰ) whether short‑ and long-term treatments with losartan or amlodipine for prehypertension were able to prevent blood pressure (BP)-linked brain damage, and ⅱ) whether there is a difference in the effectiveness of treatment with losartan and amlodipine in protecting BP-linked brain damage. In the present study, prehypertensive treatment with losartan and amlodipine (6 and 16 weeks treatment with each drug) was performed on 4-week‑old stroke-prone spontaneously hypertensive rats (SHRSP). The results showed that long-term (16 weeks) treatment with losartan is the most effective in lowering systolic blood pressure in the long term (up to 40 weeks follow-up). Additionally, compared with the amlodipine treatment groups, the short‑ and long-term losartan treatments protected SHRSP from stroke and improved their brains structurally and functionally more effectively, with the long-term treatment having more benefits. Mechanistically, the short‑ and long-term treatments with losartan reduced the activity of the local renin-angiotensin-aldosterone system (RAAS) in a time-dependent manner and more effectively than their respective counterpart amlodipine treatment group mainly by decreasing AT1R levels and increasing AT2R levels in the cerebral cortex. By contrast, the amlodipine treatment groups inhibited brain cell apoptosis more effectively as compared with the losartan treatment groups mainly through the suppression of local oxidative stress. Taken together, the results suggest that long-term losartan treatment for prehypertension effectively protects SHRSP from stroke-induced brain damage, and this protection is associated with reduced local RAAS activity than with brain cell apoptosis. Thus, the AT1R receptor blocker losartan is a good candidate drug that may be used in the clinic for long-term treatment on prehypertensive populations in order to prevent BP-linked brain damage.
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ABSTRACT: Background: The purpose of this study was to evaluate the effects of prehypertensive losartan and amlodipine administration on left ventricular (LV) remodeling and function in spontaneously hypertensive rats-stroke prone (SHRSP). Methods: Spontaneously hypertensive rats-stroke prone were prehypertensively administered losartan, amlodipine, or vehicle. Wistar-Kyoto ratswere used as a control. Blood pressure of the ratswas determined by tail-cuffmethod, and LV structure and function were measured by echocardiography and LV cannulation. Collagen volume fraction was analyzed by picrosirius red staining. Protein expressions of brain natriuretic peptide (BNP) and angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors were determined by use of the Western blotting method. Results: Although both drugs downregulated BNP protein expression, the LV remodeling and function were more improved with losartan than with amlodipine treatment. Losartan upregulated AT1R and downregulated AT2R protein expression. Conclusions: Both drugs inhibited LV remodeling and improved LV function in prehypertensively treated SHRSP. Losartan provided better continued heart protection, potentially due to its persistent inhibition of AT1R and activation of AT2R in the myocardium.