Corticotropin-releasing hormone (CRH) is a
neuropeptide regulating neuroendocrine and autonomic function. CRH
mRNA and
protein levels in the hypothalamic paraventricular nucleus (PVN) are increased in
primary hypertension. However, the role of CRH in elevated sympathetic outflow in
primary hypertension remains unclear. CRHR1
proteins were distributed in retrogradely labeled PVN presympathetic neurons with an increased level in the PVN tissue in adult spontaneously hypertensive rats (SHRs) compared with age-matched male Wistar-Kyoto (WKY) rats. CRH induced a more significant increase in the firing rate of PVN-rostral ventrolateral medulla (RVLM) neurons and sympathoexcitatory response in SHRs than in WKY rats, an effect that was blocked by preapplication of
NMDA receptors (NMDARs) antagonist AP5 and PSD-95 inhibitor,
Tat-N-dimer. Blocking CRHRs with
astressin or CRHR1 with
NBI35965 significantly decreased the firing rate of PVN-RVLM output neurons and reduced arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) in SHRs but not in WKY, whereas blocking CRHR2 with
antisauvagine-30 did not. Furthermore, Immunocytochemistry staining revealed that CRHR1 colocalized with NMDARs in PVN presympathetic neurons. Blocking CRHRs significantly decreased the
NMDA currents in labeled PVN neurons. PSD-95-bound CRHR1 and PSD-95-bound GluN2A in the PVN were increased in SHRs. These data suggested that the upregulation of CRHR1 in the PVN is critically involved in the hyperactivity of PVN presympathetic neurons and elevated sympathetic outflow in
primary hypertension.SIGNIFICANCE STATEMENT Our study found that
corticotropin-releasing hormone receptor (CRHR)1
protein levels were increased in the paraventricular nucleus (PVN), and CRHR1 interacts with
NMDA receptors (NMDARs) through
postsynaptic density protein (PSD)-95 in the PVN neurons in
primary hypertension. The increased CRHR1 and CRHR1-NMDAR-PSD-95 complex in the PVN contribute to the hyperactivity of the PVN presympathetic neurons and elevated sympathetic vasomotor tone in
hypertension in SHRs. Thus, the antagonism of CRHR1 decreases sympathetic outflow and blood pressure in
hypertension. These findings determine a novel role of CRHR1 in elevated sympathetic vasomotor tone in
hypertension, which is useful for developing novel
therapeutics targeting CRHR1 to treat elevated sympathetic outflow in
primary hypertension. The CRHR1 receptor antagonists, which are used to treat health consequences resulting from chronic stress, are candidates to treat
primary hypertension.