Abstract 171: Glycogen Synthase Kinase-3 beta Inhibition in the PVN Attenuate Hypertensive Response: Role of inflammation

Emerging evidence indicate that the balance between proinflammatory cytokines (PIC) and anti-inflammatory cytokines (AIC) is an important determinant in the outcomes of cardiovascular disease. Recent evidence suggests that GSK3β has unique immunomodulatory properties to regulate both the PIC and AIC arms of the immune system. Therefore we hypothesized that chronic ANGII infusion causes phosphorylation of GSK3β in PVN neurons and alters the balance between PIC and AIC and contributes to increased sympathetic activity and high blood pressure. To test our hypothesis we used a GSK3 inhibitor given bilaterally into the PVN which inhibits the phosphorylation of GSK3β in the PVN. Rats were implanted with radiotelemetry probes and bilateral PVN cannulae and allowed to recover. Subsequently rats were implanted with osmotic minipumps for the continuous infusion of ANGII or its vehicle; simultaneously rats were also infused with GSK3β inhibitor at a dose of 100ng/kg/min given into the PVN or vehicle, for 28 days. ANGII infusion resulted in a significant increase in blood pressure by day 7(136±3.6) which remained elevated throughout the study (154±4.1; DAY 28 values) and this was accompanied by a significant increase in norepinephrine and PIC in the circulation and PVN. In contrast, treatment with the GSK3 inhibitor+ ANGII resulted in a significant decrease in blood pressure (123±1.8; day 28 values), plasma NE and PIC in the circulation and PVN neurons. These findings suggest there is a continuous, PVN-specific phosphorylation GSK3β after ANGII infusion and this modulates PIC and AIC in the PVN and contribute to high circulating levels of NE and blood pressure response.