[PP.12.01] SYMPATHETIC INHIBITION IMPROVES INFLAMMATION AND ENDOTHELIAL DYSFUNCTION IN BRAIN MICROCIRCULATION OF RATS WITH METABOLIC SYNDROME

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Abstract

Objective:

We aimed to investigate the effects of a chronic oral treatment using centrally-acting sympatho-inhibitory drugs, clonidine (CLO) or a selective I1 imidazoline agonist LNP599 (LNP) on the brain microcirculation of rats under long-term high-fat diet (HFD).

Design and method:

Male Wistar rats were maintained under normal diet (CON, n = 10) or high-fat diet (HFD, n = 30) during 20 weeks. Thereafter, the HFD group received oral CLO (0.1 mg/kg), LNP (20 mg/kg) or vehicle. Systolic blood pressure (SBP) was evaluated by photo-plethysmography during the long-term treatment, cerebral microcirculation flow was evaluated by Laser Speckle contrast Imaging and the brain functional capillary density, endothelial function and endothelial-leukocyte interactions were evaluated by intravital microscopy. Brain oxidative stress was evaluated by gene expressions of endothelial NOS (e-NOS) and NADPH oxidase using the reverse transcriptase-polymerase chain reaction (RT-PCR) technique in brain samples of HFD animals compared to CON group. All experimental procedures were conducted in accordance with the internationally accepted principles for the Care and Use of Laboratory Animals and were approved by the Oswaldo Cruz Foundation Animal Welfare Committee (CEUA license #LW31/11) compared to CON group.

Results:

HFD group presented a decreased blood perfusion in the brain (163 ± 25, arbitrary perfusion units, APU) compared to CON group (239 ± 14 APU). Chronic sympathetic inhibition increased cerebral blood flow (CLO:211 ± 33APU and LNP:226 ± 22APU vs HFD group; p < 0.05) and the vasodilation response to Ach. CLO and LNP treatment reversed the brain capillary rarefaction (326 ± 51 and 378 ± 8 vs HFD:117 ± 11 capillaries/mm2) and decreased 3 fold the cerebral rolling leukocytes observed in pial venules. Decreases in gene expressions of NADPH oxidase and increases of eNOS in the brain of HFD treated groups suggest a reduction in oxidative stress and improvement of endothelial function induced by sympathetic inhibition.

Conclusions:

These results suggest that the modulation of sympathetic activity results in an improvement of brain perfusion, capillary rarefaction and microvascular endothelial dysfunction and oxidative stress in a diet-induced rat model of metabolic syndrome.

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