Local ionotropic glutamate receptor activity is required for the ramp‐like increase of sympathetic activity induced by PVN TNFα

Abstract

Central nervous system actions of pro‐inflammatory cytokines (PIC) play a pivotal role in driving exaggerated sympathetic nerve activity (SNA), a major aggravating factor in cardiovascular and metabolic diseases. We previously reported that delivery of tumor necrosis factor alpha (TNFα), a prototypical early onset PIC, into the hypothalamic paraventricular nucleus (PVN) elicits a progressive, ramp‐like, increase of splanchnic SNA (SSNA) that resembles the response to sympathoexcitatory stimuli such as plasma insulin and leptin. Here we investigated the contribution of local ionotropic glutamate receptors both in triggering and sustaining this SNA response. In anesthetized (α‐chloralose/urethane) male Sprague‐Dawley rats, unilateral PVN injection of vehicle (aCSF) was without affect, but subsequent injection of TNFα (0.6 pmol/50 nl) elicited a significant (P<0.0001) ramp‐like increase of SSNA that averaged +55 ± 5.5% over a period of 60 min. Mean arterial pressure and heart rate were unaffected. Separate PVN pretreatment with the AMPA receptor antagonist NBQX (5.2 nmol/50 nl) and the NMDA antagonist AP5 (24 nmol/50 nl) (n = 5/group) each significantly attenuated (P<0.05) the TNFα elicited SSNA response (55 ± 5.5 % vs. NBQX: 24 ± 5% vs. AP5: 32 ± 6.5%) at the 60 min post‐TNFα time point. PVN pretreatment with a cocktail of NBQX and AP5 abolished the TNFα‐induced SSNA ramp (55 ± 5.5 % vs. 1.3 ± 2.1%; P<0.0001). When delivered separately into the PVN 60 min after TNFα, neither NBQX nor AP5 significantly altered the rate of SSNA ramping over an additional 60 min period. These results indicate that ionotropic glutamate receptor activity in the PVN is required to initiate the progressive increase of SSNA triggered by TNFα, and hint that sympathoexcitatory stimuli such as TNFα that elicit a PVN‐driven ramp‐like SNA response might do so by inducing a long‐term potentiation (LTP)‐like form of glutamatergic synaptic plasticity.Support or Funding InformationCapes (AAM, GRP), NIH HL088052 & AHA 25710176 (GMT)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.