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Excess dietary salt alters angiotensinergic regulation of neurons in the rostral ventrolateral medulla.

ABSTRACT: Excess dietary salt intake contributes to or exacerbates some forms of hypertension by increasing sympathetic nerve activity (SNA) and arterial blood pressure (ABP) through angiotensin II (Ang II) type 1 receptor activation in the rostral ventrolateral medulla (RVLM). Despite this interaction among dietary salt, Ang II, and the RVLM, no studies have directly examined whether dietary salt by itself alters Ang II-dependent responses and regulation of RVLM neurons, SNA, and ABP. Therefore, the present study directly tested this hypothesis. Male Sprague-Dawley rats were fed normal chow and given access to water or 0.9% NaCl solution for 14 days. Unilateral injection of Ang II (0.6, 6, and 60 pmol) into the RVLM produced a significantly greater increase in renal SNA and mean ABP of rats drinking 0.9% NaCl versus water. However, dietary salt did not alter mRNA levels of RVLM Ang II type 1a receptors or the SNA and ABP responses to stimulation of the dorsolateral funinculus. Additional experiments demonstrate that blockade of RVLM Ang II type 1 receptors significantly reduced renal SNA, splanchnic SNA, and mean ABP of rats drinking 0.9% NaCl but not water. Blockade of iontotropic glutamate receptors had no effect. Altogether, these findings suggest that elevated dietary salt enhances the sympathoexcitatory actions of Ang II in the RVLM via changes in the intrinsic properties of RVLM neurons. Moreover, elevated dietary salt intake differentially affects the tonic activity of the peripheral versus brain RVLM Ang II type 1 receptors to regulate baseline SNA and ABP.

SUBMITTER: Adams JM

PROVIDER: S-EPMC2635570 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Excess dietary salt alters angiotensinergic regulation of neurons in the rostral ventrolateral medulla.

Adams Julye M JM McCarthy John J JJ Stocker Sean D SD

Hypertension (Dallas, Tex. : 1979) 20080908 5

Excess dietary salt intake contributes to or exacerbates some forms of hypertension by increasing sympathetic nerve activity (SNA) and arterial blood pressure (ABP) through angiotensin II (Ang II) type 1 receptor activation in the rostral ventrolateral medulla (RVLM). Despite this interaction among dietary salt, Ang II, and the RVLM, no studies have directly examined whether dietary salt by itself alters Ang II-dependent responses and regulation of RVLM neurons, SNA, and ABP. Therefore, the pres ...[more]

PMID: 18779436

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Project description:Neuroinflammation plays hypertensive roles in the uninjured autonomic nuclei of the central nervous system, while its mechanisms remain unclear. The present study is to investigate the effect of neuroinflammation on autophagy in the neurons of the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of vasomotor tone reside.Stress-induced hypertension (SIH) was induced by electric foot-shock stressors with noise interventions in rats. Systolic blood pressure (SBP) and the power density of the low frequency (LF) component of the SAP spectrum were measured to reflect sympathetic vasomotor activity. Microglia activation and pro-inflammatory cytokines (PICs (IL-1?, TNF-?)) expression in the RVLM were measured by immunoblotting and immunostaining. Autophagy and autophagic vacuoles (AVs) were examined by autophagic marker (LC3 and p62) expression and transmission electron microscopy (TEM) image, respectively. Autophagy flux was evaluated by RFP-GFP-tandem fluorescent LC3 (tf-LC3) vectors transfected into the RVLM. Tissue levels of glutamate, gamma aminobutyric acid (GABA), and plasma levels of norepinephrine (NE) were measured by using high-performance liquid chromatography (HPLC) with electrochemical detection. The effects of the cisterna magna infused minocycline, a microglia activation inhibitor, on the abovementioned parameters were analyzed.SIH rats showed increased SBP, plasma NE accompanied by an increase in LF component of the SBP spectrum. Microglia activation and PICs expression was increased in SIH rats. TEM demonstrated that stress led to the accumulation of AVs in the RVLM of SIH rats. In addition to the Tf-LC3 assay, the concurrent increased level of LC3-II and p62 suggested the impairment of autophagic flux in SIH rats. To the contrary, minocycline facilitated autophagic flux and induced a hypotensive effect with attenuated microglia activation and decreased PICs in the RVLM of SIH rats. Furthermore, SIH rats showed higher levels of glutamate and lower level of GABA in the RVLM, while minocycline attenuated the decrease in GABA and the increase in glutamate of SIH rats.Collectively, we concluded that the neuroinflammation might impair autophagic flux and induced neural excitotoxicity in the RVLM neurons following SIH, which is involved in the development of SIH.

Project description:Current understanding of the contribution of C1 neurons to blood pressure (BP) regulation derives predominantly from experiments performed in anesthetized animals or reduced ex vivo preparations. Here, we use ArchaerhodopsinT3.0 (ArchT) loss-of-function optogenetics to explore BP regulation by C1 neurons in intact, unanesthetized rats. Using a lentivirus that expresses ArchT under the Phox2b-activated promoter PRSx8 (PRSx8-ArchT), ?65% of transduced neurons were C1 (balance retrotrapezoid nucleus, RTN). Other rats received CaMKII-ArchT3.0 AAV2 (CaMKII-ArchT), which transduced C1 neurons and larger numbers of unidentified glutamatergic and GABAergic cells. Under anesthesia, ArchT photoactivation reduced sympathetic nerve activity and BP and silenced/strongly inhibited most (7/12) putative C1 neurons. In unanesthetized PRSx8-ArchT-treated rats breathing room air, bilateral ArchT photoactivation caused a very small BP reduction that was only slightly larger under hypercapnia (6% FiCO2), but was greatly enhanced during hypoxia (10 and 12% FiO2), after sino-aortic denervation, or during isoflurane anesthesia. The degree of hypotension correlated with percentage of ArchT-transduced C1 neurons. ArchT photoactivation produced similar BP changes in CaMKII-ArchT-treated rats. Photoactivation in PRSX8-ArchT rats reduced breathing frequency (FR), whereas FR increased in CaMKII-ArchT rats. We conclude that the BP drop elicited by ArchT activation resulted from C1 neuron inhibition and was unrelated to breathing changes. C1 neurons have low activity under normoxia, but their activation is important to BP stability during hypoxia or anesthesia and contributes greatly to the hypertension caused by baroreceptor deafferentation. Finally, C1 neurons are marginally activated by hypercapnia and the large breathing stimulation caused by this stimulus has very little impact on resting BP.SIGNIFICANCE STATEMENT C1 neurons are glutamatergic/peptidergic/catecholaminergic neurons located in the medulla oblongata, which may operate as a switchboard for differential, behavior-appropriate activation of selected sympathetic efferents. Based largely on experimentation in anesthetized or reduced preparations, a rostrally located subset of C1 neurons may contribute to both BP stabilization and dysregulation (hypertension). Here, we used Archaerhodopsin-based loss-of-function optogenetics to explore the contribution of these neurons to BP in conscious rats. The results suggest that C1 neurons contribute little to resting BP under normoxia or hypercapnia, C1 neuron discharge is restrained continuously by arterial baroreceptors, and C1 neuron activation is critical to stabilize BP under hypoxia or anesthesia. This optogenetic approach could also be useful to explore the role of C1 neurons during specific behaviors or in hypertensive models.

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Excess dietary salt alters angiotensinergic regulation of neurons in the rostral ventrolateral medulla.

Publications

Excess dietary salt alters angiotensinergic regulation of neurons in the rostral ventrolateral medulla.

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