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Central blockade of the AT1 receptor attenuates pressor effects via reduction of glutamate release and downregulation of NMDA/AMPA receptors in the rostral ventrolateral medulla of rats with stress-induced hypertension

Hypertension Research volume 42, pages 1142–1151 (2019)Cite this article

Abstract

Glutamatergic activity in the rostral ventrolateral medulla (RVLM), which is an important brain area where angiotensin II (Ang II) elicits its pressor effects, contributes to the onset of hypertension. The present study aimed to explore the effect of central Ang II type 1 receptor (AT1R) blockade on glutamatergic actions in the RVLM of stress-induced hypertensive rats (SIHR). The stress-induced hypertension (SIH) model was established by electric foot shocks combined with noises. Normotensive Sprague–Dawley rats (control) and SIHR were intracerebroventricularly infused with the AT1R antagonist candesartan or artificial cerebrospinal fluid for 14 days. Mean arterial pressure (MAP), heart rate (HR), plasma norepinephrine (NE), glutamate, and the expression of N-methyl-d-aspartic acid (NMDA) receptor subunit NR1, and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in the RVLM increased in the SIH group. These increases were blunted by candesartan. Bilateral microinjection of the ionotropic glutamate receptor antagonist kynurenic acid, the NMDA receptor antagonist d-2-amino-5-phosphonopentanoate, or the AMPA/kainate receptors antagonist 6-cyano-7-nitroquinoxaline-2,3-dione into the RVLM caused a depressor response in the SIH group, but not in other groups. NR1 and AMPA receptors expressed in the glutamatergic neurons of the RVLM, and glutamate levels, increased in the intermediolateral column of the spinal cord of SIHR. Central Ang II elicits release of glutamate, which binds to the enhanced ionotropic NMDA and AMPA receptors via AT1R, resulting in activation of glutamatergic neurons in the RVLM, increasing sympathetic excitation in SIHR.

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Acknowledgements

This work was supported by the Chinese National Natural Science Fund (31371155).

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  1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Xuan Zhou, Hongyu Yang, Xiaoshan Song, Jijiang Wang, Linlin Shen & Jin Wang

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  1. Xuan Zhou
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Zhou, X., Yang, H., Song, X. et al. Central blockade of the AT1 receptor attenuates pressor effects via reduction of glutamate release and downregulation of NMDA/AMPA receptors in the rostral ventrolateral medulla of rats with stress-induced hypertension. Hypertens Res 42, 1142–1151 (2019). https://doi.org/10.1038/s41440-019-0242-6

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  • DOI: https://doi.org/10.1038/s41440-019-0242-6

Keywords:

  • Angiotensin II type 1 receptor
  • NMDA/AMPA receptor
  • Glutamatergic neurons
  • Rostral ventrolateral medulla
  • Stress-induced hypertension

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