| First Author | Wang G | Year | 2013 |
| Journal | Am J Physiol Regul Integr Comp Physiol | Volume | 304 |
| Issue | 12 | Pages | R1096-106 |
| PubMed ID | 23576605 | Mgi Jnum | J:197903 |
| Mgi Id | MGI:5494882 | Doi | 10.1152/ajpregu.00367.2012 |
| Citation | Wang G, et al. (2013) Angiotensin II slow-pressor hypertension enhances NMDA currents and NOX2-dependent superoxide production in hypothalamic paraventricular neurons. Am J Physiol Regul Integr Comp Physiol 304(12):R1096-106 |
| abstractText | 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. |
