Local ionotropic glutamate receptors are required to trigger and sustain ramping of sympathetic nerve activity by hypothalamic paraventricular nucleus TNFα

Aline A. Mourão, Caroline G. Shimoura, Mary Ann Andrade, Tamara T. Truong, Gustavo R. Pedrino, Glenn M. Toney

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Tumor necrosis factor-A (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. When compared with that of vehicle (n = 5), prior blockade of PVN AMPA or NMDA receptors in anesthetized (urethane/a-chloralose) adult male Sprague Dawley rats dose-dependently (ED50: 2,3-dioxo-6-nitro-1,2,3,4-Tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), 2.48 nmol; D-(-)-2-Amino-5-phosphonopentanoic acid (APV), 12.33 nmol), but incompletely (Emax: NBQX, 64%; APV, 41%), attenuated TNFa-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 TNFa 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 TNFa increased local TNFa immunofluorescence after 120, but not 60 min. Findings indicate that AMPA and NMDA receptors each contribute to SSNA ramping to PVN TNFa, 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 TNFa involves progressive local glutamatergic excitation that recruits downstream neurons capable of maintaining heightened SSNA, but incapable of sustaining SSNA ramping. NEW & NOTEWORTHY The proinflammatory cytokine TNFα contributes to heightened SNA in cardiovascular disease models, but mechanisms remain obscure. Here, we demonstrate that TNFα injection into the hypothalamic PVN triggers SNA ramping by mechanisms dependent on local ionotropic glutamate receptor availability, but largely independent of TNFα autoinduction. Continued SNA ramping depends on ionotropic glutamate receptor and neuronal activity in PVN, indicating that strengthening and/or increased efficacy of glutamatergic transmission is necessary for acute sympathoexcitation by PVN TNFα.

Original languageEnglish (US)
Pages (from-to)H580-H591
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number3
StatePublished - Sep 2021


  • Glutamatergic transmission
  • Hypertension
  • Proinflammatory cytokine
  • Stress
  • Synaptic plasticity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology


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