Angiotensin II (AngII) “slow‐pressor” hypertension enhances p47 membrane translocation and glutamate receptor‐induced production of reactive oxygen species (ROS) in hypothalamic paraventricular nucleus (PVN) neurons

Abstract

Administration of low-dose AngII produces a delayed blood pressure (BP) elevation through mechanisms involving the subfornical organ (SFO), a circumventricular region with glutamatergic projections to the PVN. We tested the hypothesis that activation of glutamate receptors and NADPH oxidase (NOX)-generated ROS in the PVN plays a role in the developing hypertension. To this end, we examined the membrane trafficking of the p47 NOX subunit in the PVN in vivo, and ROS production in dissociated PVN neurons of mice receiving AngII (600 ng/kg/min; s.c.) for 2 weeks. AngII elevated BP (+44 mmHg at day 14; p<0.05 vs. saline; n=5/group), an effect coupled with increased plasmalemmal-associated (+42.2±8.3%; p<0.05) and decreased cytosolic (−20.2±7.1%; p<0.01) p47 immunogold labeling in postsynaptic dendrites of PVN neurons. Application of NMDA (100μM) to dissociated PVN neurons increased ROS more in AngII-infused mice (+40.2±7.4%; n=21) than in controls (+13.1±3.7%; n=15; p<0.01 from AngII). NMDA was not effective in mice lacking the NOX2 subunit of NOX (p>0.05; n=10). We conclude that sustained AngII administration modifies the assembly state of NOX in PVN neurons and enhances the coupling between glutamatergic signaling and NOX activity in these neurons. The resulting ROS increase is likely to contribute to the sympathetic hyperactivity and humoral dysregulation driving the hypertension. Supported by HL96571