Brain nuclear factor-kappa B activation contributes to neurohumoral excitation in angiotensin II-induced hypertension.

Aims Angiotensin II (ANG II)-induced inflammatory and oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether nuclear factor-kappa B (NF-κB) activation in the hypothalamic paraventricular nucleus (PVN) increases oxidative stress and contributes to the ANG II-induced hypertensive response. Methods and results Rats were infused intravenously with ANG II (10 ng/kg per min) or saline for 4 weeks. These rats received either vehicle or losartan (LOS, 20 µg/h), an angiotensin II type 1 receptor (AT1-R) antagonist; pyrrolidine dithiocarbamate (PDTC, 5 µg/h), a NF-κB inhibitor; tempol (TEMP, 80 µg/h), a superoxide scavenger; LOS (20 µg/h), and PDTC (5 µg/h); or TEMP (80 µg/h) and PDTC (5 µg/h), given intracerebroventricularly (ICV) via osmotic minipump. ANG II infusion resulted in increased mean arterial pressure, renal sympathetic nerve activity, plasma proinflammatory cytokines (PIC), norepinephrine, and aldosterone. These rats also had higher levels of Fra-LI (an indicator of chronic neuronal activation), PIC, phosphorylated IKKβ, NF-κB subunits, AT1-R, superoxide, and gp91phox (a subunit of NADP(H) oxidase) and lower levels of IκBα in the PVN than control animals. ICV treatment with LOS, PDTC, or TEMP attenuated these changes, and combined treatment with ICV LOS and PDTC, or ICV TEMP and PDTC prevented these ANG II-induced hypertensive responses. Conclusion These findings suggest that an ANG II-induced increase in the brain renin–angiotensin system activates NF-κB in the PVN and contributes to sympathoexcitation in hypertension. The increased superoxide in the PVN contributes to NF-κB activation and neurohumoral excitation in hypertension.