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Group III metabotropic glutamate receptors regulate hypothalamic presympathetic neurons through opposing presynaptic and postsynaptic actions in hypertension.
- Source :
-
Neuropharmacology [Neuropharmacology] 2020 Sep 01; Vol. 174, pp. 108159. Date of Electronic Publication: 2020 May 23. - Publication Year :
- 2020
-
Abstract
- The hypothalamic paraventricular nucleus (PVN) plays a major role in generating increased sympathetic output in hypertension. Although group III metabotropic glutamate receptors (mGluRs) are expressed in the hypothalamus, little is known about their contribution to regulating PVN presympathetic neurons in hypertension. Here we show that activating group III mGluRs with L-2-amino-4-phosphonobutyric acid (L-AP4) consistently inhibited the firing activity of spinally projecting PVN neurons in normotensive rats. However, in spontaneously hypertensive rats (SHRs), L-AP4 inhibited 45% of PVN neurons but excited 37%. L-AP4 significantly reduced glutamatergic and GABAergic input to PVN neurons in both groups. Blocking postsynaptic G protein signaling eliminated the excitatory but not the inhibitory effect of L-AP4 on PVN neurons in SHRs. Remarkably, prior activation of group I mGluRs converted the L-AP4 effect from inhibitory to excitatory in PVN neurons, and L-AP4 consistently inhibited PVN neurons when mGluR5 was blocked in SHRs. Furthermore, the expression level of mGluR4 and mGluR6 in the PVN was significantly higher in SHRs than in normotensive rats. Microinjection of L-AP4 into the PVN decreased blood pressure and lumbar sympathetic nerve discharges in normotensive rats and SHRs. Additionally, blocking group I mGluRs in the PVN potentiated L-AP4's sympathoinhibitory effect in SHRs. Therefore, activation of presynaptic group III mGluRs inhibits the excitability of PVN presympathetic neurons to attenuate sympathetic vasomotor activity. Through crosstalk with mGluR5, postsynaptic group III mGluR stimulation paradoxically excites PVN presympathetic neurons in SHRs. Concurrently blocking mGluR5 and activating group III mGluRs in the PVN can effectively reduce sympathetic outflow in hypertension.<br />Competing Interests: Declaration of competing interest The authors declare no conflict of interest with the contents of this article.<br /> (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Dose-Response Relationship, Drug
Excitatory Postsynaptic Potentials drug effects
Hypertension physiopathology
Male
Microinjections methods
Neurons drug effects
Organ Culture Techniques
Paraventricular Hypothalamic Nucleus drug effects
Presynaptic Terminals drug effects
Propionates administration & dosage
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Receptors, Metabotropic Glutamate agonists
Excitatory Postsynaptic Potentials physiology
Hypertension metabolism
Neurons metabolism
Paraventricular Hypothalamic Nucleus metabolism
Presynaptic Terminals metabolism
Receptors, Metabotropic Glutamate metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 174
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 32454125
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2020.108159