title: Angiotensin II slow-pressor hypertension enhances NMDA currents and NOX2-dependent superoxide production in hypothalamic paraventricular neurons.
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.
authors.affiliation: Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065, USA. gaw2001@med.cornell.edu
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Christal G
authors.initials: CG
authors.lastname: Coleman
authors.forename: June
authors.initials: J
authors.lastname: Chan
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Faraco
authors.forename: Jose
authors.initials: J
authors.lastname: Marques-Lopes
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Milner
authors.forename: Mallikarjuna R
authors.initials: MR
authors.lastname: Guruju
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davisson
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Pickel
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D023421:Models, Animal; D016202:N-Methylaspartate / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013481:Superoxides / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D013481:Superoxides; D000804:Angiotensin II; D009569:Nitric Oxide; D016202:N-Methylaspartate; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D002118:Calcium
keywords: NADPH oxidase; NMDA receptors; electron microscopy; nitric oxide; patch clamp; reactive oxygen species