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Angiotensin II (ANG II) slow pressor hypertension enhances NMDA receptor (NMDAR)‐mediated currents and Nox2‐ dependent superoxide (O2‐) production in spinally‐projecting (SP) neurons of hypothalamic paraventricular nucleus (PVN)
Author(s) -
Wang Gang,
Davisson Robin L,
Pickel Virginia M,
Iadecola Costantino
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.695.5
Subject(s) - medicine , endocrinology , nmda receptor , chemistry , angiotensin ii , nadph oxidase , neurotransmission , nitric oxide , saline , receptor , biology , oxidative stress
Adaptive changes in glutamate (GLU) neurotransmission in the PVN play a role in the increased sympathetic output driving the elevation in blood pressure induced by slow pressor ANG II infusion. We hypothesized that these adaptions alter neuronal production of nitric oxide (NO) and NADPH oxidase (Nox2)‐ derived O 2 − , resulting in enhanced GLU neurotransmission in SP pre‐sympathetic PVN neurons. Electron microscopic immunolabeling showed a marked increase in the association between Nox2 and the NMDAR NR1 subunits in PVN dendrites of 14 days ANG II‐infused mice (600 ng/kg/min, P<0.01 vs. saline). NMDAR‐mediated O 2 − production was enhanced in isolated SP PVN neurons of ANG II‐infused mice (P<0.01 vs. saline), an effect blocked by Nox2 inhibitor gp91ds‐tat. NMDAR‐mediated NO production was suppressed in PVN neurons of ANG II infused mice (P<0.01 vs. saline), an effect opposed by gp91ds‐tat. In patch‐clamp recording of SP PVN neurons, NMDAR mediated a larger inward current in ANG II‐infused mice (P<0.01 vs. saline), an effect inhibited by gp91ds‐tat or an NO donor. These findings suggest that slow pressor doses of ANG II increase the association of NR1 with Nox2 in SP PVN neurons, resulting in enhanced production of Nox2‐derived O 2 − during GLU synaptic activity. The resulting depletion of NO and enhancement of NMDA currents may contribute to the increased sympathetic outflow underlying slow pressor ANG II hypertension. (Supported by NIH HL096571)