Activity of Hypothalamic Paraventricular Nucleus (PVN) Neurons Controls Sympathetic Nerve Activity (SNA) and Respiration in Angiotensin II (AngII)‐Salt Hypertensive Rats: No Role for Local NMDA Receptors (NMDAR)

We recently reported that mean arterial pressure (MAP) is maintained in water-deprived rats by an irregular tonic component of vasomotor sympathetic nerve activity (SNA) that is driven by neuronal activity in the hypothalamic paraventricular nucleus (PVN). To establish whether generation of tonic SNA requires time-dependent (i.e., hours or days of dehydration) neuroadaptive responses or can be abruptly generated by even acute circuit activation, forebrain sympathoexcitatory osmosensory inputs to PVN were stimulated by infusion (0.1 ml/min, 10 min) of hypertonic saline (HTS; 1.5 M NaCl) through an internal carotid artery (ICA). Whereas isotonic saline (ITS; 0.15 M NaCl) had no effect ( n = 5), HTS increased ( P < 0.001; n = 6) splanchnic SNA (sSNA), phrenic nerve activity (PNA), and MAP. Bilateral PVN injections of muscimol ( n = 6) prevented HTS-evoked increases of integrated sSNA and PNA ( P < 0.001) and attenuated the accompanying pressor response ( P < 0.01). Blockade of PVN NMDA receptors with d-(2 R)-amino-5-phosphonovaleric acid (AP5; n = 6) had similar effects. Analysis of respiratory rhythmic bursting of sSNA revealed that ICA HTS increased mean voltage ( P < 0.001) without affecting the amplitude of inspiratory or expiratory bursts. Analysis of cardiac rhythmic sSNA likewise revealed that ICA HTS increased mean voltage. Cardiac rhythmic sSNA oscillation amplitude was also increased, which is consistent with activation of arterial baroreceptor during the accompanying pressor response. Increased mean sSNA voltage by HTS was blocked by prior PVN inhibition (muscimol) and blockade of PVN NMDA receptors (AP5). We conclude that even acute glutamatergic activation of PVN (i.e., by hypertonicity) is sufficient to selectively increase a tonic component of vasomotor SNA.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00322.2021 ◽

2021 ◽

Author(s):

Aline A. Mourao ◽

Caroline G. Shimoura ◽

Mary Ann Andrade ◽

Tamara T. Truong ◽

Gustavo R. Pedrino ◽

...

Keyword(s):

Nmda Receptors ◽

Glutamate Receptors ◽

Paraventricular Nucleus ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Hypothalamic Paraventricular Nucleus ◽

Ionotropic Glutamate Receptors ◽

Sprague Dawley ◽

Nerve Activity ◽

Necrosis Factor Alpha

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.

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