Abstract 417: Central PPAR-γ Activation Attenuates Angiotensin II-Induced Hypertension by Inhibiting Brain Inflammation and Renin-Angiotensin System Activity in Rats.

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Upregulation of inflammation and renin-angiotensin system (RAS) activity in the brain contributes to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. Peroxisome proliferator-activated receptor (PPAR)-γ, a nuclear transcription factor, is expressed in key brain areas involved in drinking, vasopressin release and cardiovascular regulation, including the paraventricular nucleus of hypothalamus (PVN). We recently reported that activation of brain PPAR-γ reduced inflammation and RAS activity in the PVN and ameliorated the peripheral manifestations of heart failure. Here we hypothesized that activation of central PPAR-γ might have beneficial effects on angiotensin II (ANG II)-induced hypertension. Spague-Dawley rats received a continuous 2 week subcutaneous infusion of ANG II (120 ng/kg/min), combined with intracerebroventricular infusion of vehicle (VEH) or the PPAR-γ agonist pioglitazone (3 nmoL/h). At 2 weeks, blood pressure (BP) had significantly (*P<0.05) increased (131±3* vs 98±3 mmHg) and the BP response to ganglionic blockade (70±4* vs 43±3 mmHg) was greater in conscious VEH-treated ANG II rats compared with normal (control) rats. Water intake (34±2* vs 25±2 mL) and plasma vasopressin following 4 hours of water restriction (20.79±2.62* vs 10.62±1.27 pg/mL) were increased. PPAR-γ mRNA in the PVN was unchanged in VEH-treated ANG II rats, compared with control rats, but PPAR-γ DNA binding activity (0.05±0.01* vs 0.09±0.01 OD 450nm ) was reduced and mRNA for interleukin-1β (2.76±0.22* vs 1.09±0.21 fold change), tumor necrosis factor-α (1.58±0.09* vs 1.04±0.12 fold change) and ANG II type-1 receptor (1.71±0.15* vs 1.03±0.10 fold change) was augmented. All of these findings were ameliorated (by 24-36%*) in ANG II rats treated with pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA binding activity in the PVN (by 73-77%*). The results suggest that activating brain PPAR-γ to reduce central inflammation and RAS activity, thereby suppressing fluid intake, vasopressin release and sympathetic drive, may be a novel approach to the treatment of ANG II-dependent hypertension.