title: Long-term prehypertension treatment with losartan effectively prevents brain damage and stroke in stroke-prone spontaneously hypertensive rats.
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.
authors: Department of Cardiology, The First Affiliated Hospital of Xiamen University, Fuzhou, Fujian, P.R. China.
authors: De-Hua
authors: DH
authors: He
authors: Department of Cardiology, The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, P.R. China.
authors: Liang-Min
authors: LM
authors: Zhang
authors: Department of Cardiology, Affiliated Hospital of Putian College, Fuzhou, Fujian, P.R. China.
authors: Li-Ming
authors: LM
authors: Lin
authors: Department of Cardiology, The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, P.R. China.
authors: Ruo-Bing
authors: RB
authors: Ning
authors: Fujian Institute of Hypertension, Fuzhou, Fujian, P.R. China.
authors: Hua-Jun
authors: HJ
authors: Wang
authors: Fujian Institute of Hypertension, Fuzhou, Fujian, P.R. China.
authors: Chang-Sheng
authors: CS
authors: Xu
authors: Department of Cardiology, The First Clinical Medical College of Fujian Medical University, Fuzhou, Fujian, P.R. China.
authors: Jin-Xiu
authors: JX
authors: Lin
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D017311:Amlodipine / Q000494:pharmacology; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006973:Hypertension / Q000150:complications / Q000517:prevention & control; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D058246:Prehypertension / Q000188:drug therapy*; D051381:Rats; D011918:Rats, Inbred SHR; D012084:Renin-Angiotensin System / Q000187:drug effects; D020521:Stroke / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
chemical_list: D008562:Membrane Glycoproteins; D000804:Angiotensin II; D017311:Amlodipine; D000450:Aldosterone; D013482:Superoxide Dismutase; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D019808:Losartan