Glucocorticoid receptors regulate hypothalamic CRH neuron activity in primary hypertension

Abstract

The hypothalamic-pituitary-adrenal axis is important in maintaining homeostasis in response to physical and psychological stressors. The corticotropin-releasing hormone (CRH) is a neuropeptide synthesized by CRH neurons in brain regions including paraventricular nucleus (PVN) of the hypothalamus. The glucocorticoids synthesized and released in adrenal gland act on hypothalamic CRH-expressing neurons inhibit the CRH production and maintain the level of glucocorticoids. The glucocorticoid receptor (GR) is critical for this negative feedback to regulate CRH synthesis and release. Hypertension is associated with high stress response and CRH mRNA levels. The number of CRH-expression neurons are significantly increased in PVN of the hypothalamus in primary hypertension patients. this study determined if the HPA axis negative feedback is altered and contribute to maintaining hypertension. We measured mRNA expression levels of GRs and MR in PVN tissue obtained from adult Wistar-Kyoto normotensive rats (WKYs) and spontaneously hypertensive rats (SHRs) and found that the GR mRNA expression level was significantly lower in SHRs that in WKY rats, while the MR gene expression did not differ between WKY rats and SHRs. Furthermore, we found that acute perfusion of dexamethasone (DEX), a synthetic glucocorticoid, significantly decreased frequency of spontaneous excitatory postsynaptic synaptic currents (EPSCs) in identified PVN-CRH expressing neurons in brain slices prepared from WKY and SHRs. DEX caused a greater reduction of frequency of EPSCs in SHRs was than in WKY rats. Acute perfusion of DEX significantly increased the firing rate of PVN-CRH neurons in WKY rats but did not change the firing rate in SHRs. In addition, incubation of brain slices with DEX for 1 hr significantly inhibited the firing activity of PVN-CRH neurons in WKY rats but did not change the firing activity of PVN CRH neurons in SHRs. These data suggested that the glucocorticoid excites PVN-CRH neurons in acute phase while inhibits these neurons in chronic phase in normotensive rat. In hypertension, downregulated GR may be responsible for impaired the HPA axis feedback and contribute to hypertension. HL139523, HL142133, and HL159157. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.