Renal responses to increases in renal sympathetic nerve activity induced by brainstem stimulation in rabbits

Malpas, Simon C.; Head, Geoffrey A.; Anderson, Warwick P.

doi:10.1016/0165-1838(96)00060-4

Cited by 14 publications

(1 citation statement)

References 42 publications

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“…Typical tracings of the RSNA, MAP, and HR responses to the administration of NMDA (200 pmol) into the PVN in the four groups of rats (Sham, Sham+ HIF-1α siRNA, CHF, CHF+ HIF-1α siRNA) are shown in Figure 6A. Basal (calculated as the absolute value or as the percent of maximum change) 28, 29 was significantly higher in CHF rats compared to the Sham rats (Figure 6B). Silencing of HIF-1α significantly reduced baseline RSNA in rats with CHF suggesting that there is a tonic effect of elevated levels of HIF-1α to increased sympathetic tone in rats with CHF.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia-Inducible Factor-1α Mediates Increased Sympathoexcitation via Glutamatergic N-Methyl- d -Aspartate Receptors in the Paraventricular Nucleus of Rats With Chronic Heart Failure

Sharma

Cunningham

Zheng

et al. 2016

Circ: Heart Failure

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Background Increased sympathetic outflow is a major contributor to the progression of chronic heart failure (CHF). Potentiation of glutamatergic tone has been causally related to the sympathoexcitation in CHF. Specifically, an increase in the N-methyl-D-aspartate-type1 receptor (NMDA-NR1) expression within the paraventricular nucleus (PVN) is critically linked to the increased sympathoexcitation during CHF. However, the molecular mechanism(s) for the up-regulation of NMDA-NR1 remains unexplored. We hypothesized that hypoxia via HIF-1α might contribute to the augmentation of the NMDA-NR1 mediated sympathoexcitatory responses from the PVN in CHF. Methods and Results Immunohistochemistry staining, mRNA, and protein for hypoxia-inducible-factor 1α (HIF-1α) were up-regulated within the PVN of left coronary artery ligated CHF rats. In neuronal cell line (NG108-15) in vitro, hypoxia caused a significant increase in mRNA as well as protein for HIF-1α (2-fold) with the concomitant increase in NMDA-NR1 mRNA, protein levels, as well as glutamate-induced Ca+ influx. ChIP assay identified HIF-1α binding to NMDA-NR1 promoter during hypoxia. Silencing of HIF-1α in NG108 cells leads to a significant decrease in expression of NMDA-NR1 suggesting that expression of HIF-1α is necessary for the upregulation of NMDA-NR1. Consistent with these observations, HIF-1α silencing within the PVN abrogated the increased basal sympathetic tone as well as sympathoexcitatory responses to microinjection of NMDA in the PVN of rats with CHF. Conclusions These results uncover a critical role for HIF-1 in the up-regulation of NMDA-NR1 to mediate sympathoexcitation in CHF. We conclude that subtle hypoxia within the PVN may act as a metabolic cue to modulate sympathoexcitation during CHF.

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Section: Resultsmentioning

confidence: 99%