Local Ionotropic Glutamate Receptors are Required to Trigger and Sustain Ramping of Sympathetic Nerve Activity by Hypothalamic Paraventricular Nucleus TNFα.

Tumor necrosis factor alpha (TNFa) in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA) in cardiovascular disease models, but mechanisms are incompletely understood. As previously reported, bilateral PVN TNFa (0.6 pmol, 50 nL) induced acute ramping of splanchnic SNA (SSNA) that averaged +64 ± 7% after 60 min and +109 ± 17% after 120 min (P<0.0001, n=10). Given that TNFa can rapidly strengthen glutamatergic transmission, we hypothesized that progressive activation of ionotropic glutamate receptors is critically involved. Compared to vehicle (n=5), prior blockade of PVN AMPA or NMDA receptors in anesthetized (urethane/α-chloralose) adult male Sprague-Dawley rats dose-dependently (ED50: NBQX, 2.48 nmol; APV, 12.33 nmol), but incompletely (Emax: NBQX, 64%; APV, 41%) attenuated TNFα-induced SSNA ramping (n=5/dose). By contrast, combined receptor blockade prevented ramping (1.3 ± 2.1%, P<0.0001, n=5). Whereas separate blockade of PVN AMPA or NMDA receptors (n=5/group) had little effect on continued SSNA ramping when performed 60 min after TNFα injection, combined blockade (n=5) or PVN inhibition with the GABA-A receptor agonist muscimol (n=5) effectively stalled, without reversing, the SSNA ramp. Notably, PVN TNFα increased local TNFα immunofluorescence after 120, but not 60 min. Findings indicate that AMPA and NMDA receptors each contribute to SSNA ramping to PVN TNFα, and that their collective availability and ongoing activity are required to initiate and sustain the ramping response. We conclude that acute sympathetic activation by PVN TNFα involves progressive local glutamatergic excitation that recruits downstream neurons capable of maintaining heightened SSNA, but incapable of sustaining SSNA ramping.