Angiotensin II slow-pressor hypertension enhances NMDA currents and NOX2-dependent superoxide production in hypothalamic paraventricular neurons. Academic Article uri icon

Overview

abstract

  • Adaptive changes in glutamatergic signaling within the hypothalamic paraventricular nucleus (PVN) may play a role in the neurohumoral dysfunction underlying the hypertension induced by "slow-pressor" ANG II infusion. We hypothesized that these adaptive changes alter production of gp91phox NADPH oxidase (NOX)-derived reactive oxygen species (ROS) or nitric oxide (NO), resulting in enhanced glutamatergic signaling in the PVN. Electron microscopic immunolabeling showed colocalization of NOX2 and N-methyl-D-aspartate receptor (NMDAR) NR1 subunits in PVN dendrites, an effect enhanced (+48%, P < 0.05 vs. saline) in mice receiving ANG II (600 ng·kg⁻¹·min⁻¹ sc). Isolated PVN cells or spinally projecting PVN neurons from ANG II-infused mice had increased levels of ROS at baseline (+40 ± 5% and +57.6 ± 7.7%, P < 0.01 vs. saline) and after NMDA (+24 ± 7% and +17 ± 5.5%, P < 0.01 and P < 0.05 vs. saline). In contrast, ANG II infusion suppressed NO production in PVN cells at baseline (-29.1 ± 5.2%, P < 0.05 vs. saline) and after NMDA (-18.9 ± 2%, P < 0.01 vs. saline), an effect counteracted by NOX inhibition. In whole cell recording of unlabeled and spinally labeled PVN neurons in slices, NMDA induced a larger inward current in ANG II than in saline groups (+79 ± 24% and +82.9 ± 6.6%, P < 0.01 vs. saline), which was reversed by the ROS scavenger MnTBAP and the NO donor S-nitroso-N-acetylpenicillamine (P > 0.05 vs. control). These findings suggest that slow-pressor ANG II increases the association of NR1 with NOX2 in dendrites of PVN neurons, resulting in enhanced NOX-derived ROS and reduced NO during glutamatergic activity. The resulting enhancement of NMDAR activity may contribute to the neurohumoral dysfunction underlying the development of slow-pressor ANG II hypertension.

publication date

  • April 10, 2013

Research

keywords

  • Angiotensin II
  • Hypertension
  • Membrane Glycoproteins
  • N-Methylaspartate
  • NADPH Oxidases
  • Paraventricular Hypothalamic Nucleus
  • Superoxides

Identity

PubMed Central ID

  • PMC3680791

Scopus Document Identifier

  • 84879144136

Digital Object Identifier (DOI)

  • 10.1152/ajpregu.00367.2012

PubMed ID

  • 23576605

Additional Document Info

volume

  • 304

issue

  • 12