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Glial Glutamate Transporters in PVN Suppress Sympathetic Nerve Activity (SNA) and Mean Arterial Pressure (MAP) by Buffering GluN2B‐containing NMDA Receptor Activation
Author(s) -
Bardgett Megan,
Calderon Alfredo,
Toney Glenn
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.987.4
Subject(s) - ifenprodil , nmda receptor , glutamate receptor , chemistry , ionotropic effect , medicine , endocrinology , receptor , excitatory postsynaptic potential
Recent evidence indicates that non‐selective blockade of excitatory amino acid transporters (EAAT) in the hypothalamic PVN increases SNA and MAP by activating local NMDA receptors. The glial expressed EAAT subtype EAAT2 buffers a tonic NMDA current in nearby magnocellular neurons and that EAAT2 buffering is diminished in heart failure. Here we sought to determine the role of EAAT2 in regulating PVN driven levels of renal SNA and MAP. In anesthetized male rats (n=12), bilateral PVN injection (50 nl) of the EAAT2‐selective inhibitor dihydrokainate (DHK, 1.25 pmol) increased renal SNA (DHK: 60±9% vs aCSF: 1±1%) and MAP (DHK: 19±3 mmHg vs aCSF: 0±2 mmHg). Next, ionotropic glutamate receptors (n=3), NMDA receptors (n=6) or GluN2B subunit containing NMDA receptors (n=3) were separately blocked bilaterally in PVN with kynurenic acid (3.6 pmol), AP5 (3 pmol) or ifenprodil (3 pmol), respectively. Whereas resting SNA and MAP were unaltered by KYN, Ifenprodil or AP5, KYN and ifenprodil each attenuated the DHK‐induced increase of renal SNA (DHK: 60±9% vs +KYN: 10±8% or +Ifenprodil: 7±3%) and MAP (DHK: 19±3 mmHg vs +KYN: 2±3 mmHg or +ifenprofil: 5±1 mmHg). Of interest is that AP5 had little effect (renal SNA ‐ DHK: 70±12 % vs +AP5: 55±10 %, MAP ‐ DHK: 23±4 mmHg vs +AP5: 28±3 mmHg). Results indicate that GluN2B containing NMDA receptors, which can be located extrasynaptically and mediate a tonic NMDA current, are mainly responsible for driving sympathetic outflow during PVN inhibition of EAAT2. The inability of AP5 to block responses to DHK is presently unexplained, but could relate to affinity or accessibility differences compared to KYN/Ifenprodil. HL 102310 & 088052 (GMT), HL 07446 (MEB)