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

Cardiovasc Res. 2009 Jun 1;82(3):503-12. doi: 10.1093/cvr/cvp073. Epub 2009 Feb 25.


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-kappaB) 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 microg/h), an angiotensin II type 1 receptor (AT1-R) antagonist; pyrrolidine dithiocarbamate (PDTC, 5 microg/h), a NF-kappaB inhibitor; tempol (TEMP, 80 microg/h), a superoxide scavenger; LOS (20 microg/h), and PDTC (5 microg/h); or TEMP (80 microg/h) and PDTC (5 microg/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 IKKbeta, NF-kappaB subunits, AT1-R, superoxide, and gp91phox (a subunit of NADP(H) oxidase) and lower levels of IkappaBalpha 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-kappaB in the PVN and contributes to sympathoexcitation in hypertension. The increased superoxide in the PVN contributes to NF-kappaB activation and neurohumoral excitation in hypertension.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / adverse effects
  • Angiotensin II / antagonists & inhibitors
  • Angiotensin II / metabolism*
  • Angiotensin II Type 1 Receptor Blockers
  • Animals
  • Antioxidants
  • Blood Pressure
  • Cyclic N-Oxides
  • Cytokines / metabolism
  • Hypertension / chemically induced
  • Hypertension / metabolism*
  • Inflammation Mediators / metabolism
  • Male
  • NADPH Oxidases / metabolism
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Oxidative Stress*
  • Paraventricular Hypothalamic Nucleus / metabolism*
  • Proline / analogs & derivatives
  • Rats
  • Rats, Sprague-Dawley
  • Renin-Angiotensin System
  • Spin Labels
  • Superoxides / metabolism
  • Sympathetic Nervous System / drug effects*
  • Thiocarbamates


  • Angiotensin II Type 1 Receptor Blockers
  • Antioxidants
  • Cyclic N-Oxides
  • Cytokines
  • Inflammation Mediators
  • NF-kappa B
  • Spin Labels
  • Thiocarbamates
  • Superoxides
  • Angiotensin II
  • prolinedithiocarbamate
  • Proline
  • NADPH Oxidases
  • tempol