Open AccessDownregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats
Author(s) -
Zhou JingJing,
Ma HuiJie,
Shao Jianying,
Wei Yan,
Zhang Xiangjian,
Zhang Yi,
Li DePei
Publication year - 2019
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.118.011434
Subject(s) - medicine , endocrinology , orexin a , blood pressure , hypothalamus , downregulation and upregulation , receptor , rna , rostral ventrolateral medulla , orexin , neuropeptide , heart rate , chemistry , gene , biochemistry
Background Orexin and its receptors are critical regulating sympathetic vasomotor tone under physiological and pathophysiological conditions. Orexin receptor 1 ( OXR 1) is upregulated in the paraventricular nucleus ( PVN ) in the hypothalamus and contributes to increased sympathetic outflow in obese Zucker rats ( OZR s). We hypothesized that silencing OXR 1 expression in the PVN decreases heightened blood pressure and elevated sympathetic outflow in OZR s. Methods and Results An adeno‐associated virus ( AAV ) vector containing a short hairpin RNA (sh RNA ) targeting rat OXR 1 was designed to silence OXR 1 expression in the PVN . The AAV ‐ OXR 1‐sh RNA or scrambled sh RNA was injected into the PVN in OZR s. The arterial blood pressure in free‐moving OZR s was continuously monitored by using a telemetry approach. The firing activity of spinally projecting PVN neurons in rat brain slices was recorded 3 to 4 weeks after injection of viral vectors. The free‐moving OZR s treated with AAV ‐ OXR 1‐sh RNA had markedly lower OXR 1 expression and lower mean arterial blood pressure, heart rate, and ratio of low‐ to high‐frequency components of heart rate variability compared with OZR s treated with scrambled sh RNA . Furthermore, AAV ‐ OXR 1‐sh RNA treatment markedly reduced renal sympathetic nerve activity and attenuated sympathoexcitatory response induced by microinjection of orexin A into the PVN . In addition, treatment with AAV ‐ OXR 1‐sh RNA substantially decreased the basal firing activity of spinally projecting PVN neurons in OZR s and attenuated the excitatory effect of orexin A on the firing activity of these neurons. Conclusions These data suggest that chronic downregulation of OXR 1 expression in the PVN reduces sympathetic vasomotor tone in obesity‐related hypertension.