Article

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: 1.88). 10/2012; 30(6). DOI: 10.3892/ijmm.2012.1153
Source: PubMed

ABSTRACT Aims To compare the effectiveness of transient prehypertensive treatment with losartan versus amlodipine in spontaneously hypertensive rats (SHR) on long-term blood pressure and cardiac protection Main methods SHR were prehypertensively (weeks 4–10 of age) treated with losartan (SHR-Los: 20 mg/kg/day), amlodipine (SHR-Aml: 10 mg/kg/day) or saline (n=24 each group). Rats were followed up until week 46. Systolic blood pressure (SBP) was measured by tail-cuff method. Cardiac parameters including Left ventricular (LV) mass index (LVMI), collagen volume fraction (CVF) and LV function were assessed by histomorphometry and echocardiography. Plasma and myocardium angiotensin II (Ang II) and aldosterone (Aldo) were measured by radioimmunoassay. Cardiac angiotensin II type 1 and type 2 receptor (AT1R and AT2R) protein were determined by immunoblotting and brain natriuretic peptide (BNP) mRNA was semi-quantified by reverse transcription-PCR (RT-PCR).
Key findings The SBP in SHR-Los was reduced until age 46 weeks, but returned to untreated SHR levels in SHR-Aml from 30 weeks onwards. Compared to untreated SHR, the LVMI and CVF in SHR-Los were markedly decreased until week 46, and the LV ejection fraction (LVEF) (SHR-Los vs SHR: 83.1±2.3% vs 79.5±1.9%, p<0.05) and cardiac BNP mRNA expression were improved, whereas comparable LVMI and elevated CVF were found in SHR-Aml, and the LVEF fell significantly below that of untreated SHR at week 46 (SHR-Aml vs SHR: 74.4±4.3% vs 79.5±1.9%, p<0.05), with cardiac BNP mRNA expression increasing slightly. Compared to untreated SHR, the plasma and myocardium Ang II and Aldo levels in SHR-Los at week 46 were remarkably decreased (plasma Ang II: 302±32 vs 458±32 pg/ml; plasma Aldo: 172±20 vs 252±41 pg/ml; cardiac Ang II: 126±11 vs 199±14 pg/100 mg; cardiac Aldo: 497±43 vs 766±46 pg/100 mg, all p<0.05), and the cardiac AT1R protein was down-regulated and AT2R protein was up-regulated, no significant difference of these indices was found between SHR-Aml and untreated SHR. Significance Prehypertensive treatment with losartan was more effective than amlodipine on delaying long-term blood pressure rise and meliorating cardiac structure and function, which might be related to permanent attenuation of circulating and local renin-angiotensin (R-A) systems.

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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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