Abstract
Background and purpose: Fimasartan is a novel angiotensin receptor blocker (ninth), and its safety and efficacy have been established as an antihypertensive drug. Anti-apoptotic or anti-inflammatory effects of angiotensin receptor blockers were reported. However, few studies have elaborated on the effects of long-term treatment with low-dose ARB on cerebral ischemia independent of blood pressure lowering. Methods: Noninvasive blood pressure monitoring was performed in Sprague-Dawley rats which 0.5 mg/kg of fimasartan or phosphate-buffered saline (PBS) were administered for 4 weeks. Fimasartan (0.5, 1 or 3 mg/kg) was administered intraorally for 4 weeks, and we induced ischemia-reperfusion injury in rats. Infarct volume and the number of TUNEL-positive apoptotic cells were measured at 7 days. Functional outcomes were evaluated by modified limb placing test. To identify the anti-inflammatory effect of fimasartan, the number of inflammatory cells (OX6-positive cells) was measured. To identify mediators, phospho-STAT3 and IkB proteins were measured via Western blot analyses at 48 hours. Results: Blood pressures were decreased after administration of 1 mg/kg or 3 mg/kg of fimasartan for 4 weeks, but were not decreased in 0.5 mg/kg group. All doses of fimasartan decrease infarct volumes, and low-dose fimasartan (0.5 mg/kg) maximally reduced infarct volume up to 70% of those of the control group ( p < 0.05). Quantitative analysis showed that the number of TUNEL-positive cells was remarkably decreased in the low-dose fimasartan group (622 ± 57 cell/mm 3 vs. 235 ± 48 cells/mm 3 ; p < 0.05). Low-dose fimasartan improved functional outcomes at 14 days (74% recovery in fimasartan group vs. 43% in control group; p < 0.05). The low-dose fimasartan group exhibited a lower number of OX6-positive cells (fimsartan group: 157 ± 17 cells/mm 3 ; control: 86 ± 11 cell/mm 3 ; p < 0.05). The IkB degradation as a marker of NF-kB activation, was delayed, and phospho-STAT3 was decreased in the low-dose fimasartan group ( p < 0.05). Conclusion: We demonstrate that long-term treatment with fimasartan improves neurological outcome in transient focal ischemia in rats. This protective effect of fimasartan is independent blood pressure lowering.
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