PP.LB03.02] SIMVASTATIN IMPROVES MICROVASCULAR CEREBRAL BLOOD FLOW AND ATTENUATES ANGIOTENSIN II-INDUCED MICROCIRCULATORY CHANGES IN A HYPERTENSION MODEL

Abstract

Objective: Statins may reduce blood pressure through a direct regulation of RAS and this study was designed to investigate the acute effects of simvastatin (SIM) on cerebral microcirculation and in spontaneously hypertensive rats (SHR), and the possible role of AT2 receptors on statins microvascular effects. Design and method: Male Wistar normotensive rats (WKY) and SHR were divided into 4 groups of 8 animals each: WKY-CTL and SHR-CTL treated with 0.9% saline solution, and WKY+sSIM and SHR+SIM treated with SIM 30 mg/kg/day during 3 days by gavage. We measured systolic blood pressure (SBP) and investigated brain functional capillary density (FCD) using intravital fluorescence videomicroscopy. Microvascular cerebral blood flow (mCBF) before and after local administration (cranial window) of Ang II (1 μM) was investigated using Laser Speckle Contrast Imaging, and the percentage of change on mCBF was calculated. Cerebral AT2 receptor expression was investigated by PCR. Results: SIM administration reduced SBP in SHR (SHR-CTL 203 ± 3 vs.SHR+SIM 172 ± 6 mmHg;p < 0.001). Cerebral FCD was reduced in hypertensive rats compared with normotensive rats (SHR-CTL 337 ± 61 vs. WKY-CTL 421 ± 35 capillaries/mm2; p < 0.05). The administration of SIM during 3 days induced a significant increase in cerebral FCD in hypertensive rats (SHR+SIM 530 ± 31 capillaries/ mm2;p < 0.05). The mCBF was reduced in SHR when compared with normotensive controls (SHR-CTL 185 ± 2 vs. WKY-CTL 231 ± 13 AU; p < 0.05) and SIM treatment was able to increase mCBF (SHR+SIM 208 ± 9 AU; p < 0.05) when compared with non-treated SHR (SHR-CTL). Locally applied, Ang II elicited a reduction in mCBF of hypertensive rats and an increase in normotensive rats (SHR-CTL -13.53 ± 2 % vs.WKY-CTL +13.74 ± 4%; p < 0,001), which was attenuated in hypertensive rats treated with SIM (SHR+SIM -6.7 ± 1%; p < 0,01vs.SHR-CTL). Additionally, AT2 receptor expression was reduced in the brain of SHR compared with WKY (SHR-CTL 0.5 ± 0.2 vs. WKY-CTL 1.5 ± 0.15 AT2R/GAPDH p < 0,05). Treatment of SHR with SIM increased brain expression of AT2 receptor (SHR+SIM 3.1 ± 0.9 AT2R/GAPDH;p < 0,05 vs.SHR-CTL). Conclusions: Acute treatment with SIM reversed cerebral microvascular rarefaction and restored microvascular cerebral blood flow of hypertensive rats. Furthermore, the increase in AT2 receptor expression might be associated with the positive pleiotropic effects of statins on cerebral microcirculation.