Dataset Information

Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats.

ABSTRACT: 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.

SUBMITTER: Zhou JJ

PROVIDER: S-EPMC6662376 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats.

Zhou Jing-Jing JJ Ma Hui-Jie HJ Shao Jianying J Wei Yan Y Zhang Xiangjian X Zhang Yi Y Li De-Pei DP

Journal of the American Heart Association 20190619 13

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 ...[more]

PMID: 31213116

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Project description:Aims: Long-term salt diet induces the oxidative stress in the paraventricular nucleus (PVN) and increases the blood pressure. Extracellular superoxide dismutase (Ec-SOD) is a unique antioxidant enzyme that exists in extracellular space and plays an essential role in scavenging excessive reactive oxygen species (ROS). However, the underlying mechanism of Ec-SOD in the PVN remains unclear. Methods: Sprague-Dawley rats (150-200 g) were fed either a high salt diet (8% NaCl, HS) or normal salt diet (0.9% NaCl, NS) for 6 weeks. Each group of rats was administered with bilateral PVN microinjection of AAV-Ec-SOD (Ec-SOD overexpression) or AAV-Ctrl for the next 6 weeks. Results: High salt intake not only increased mean arterial blood pressure (MAP) and the plasma noradrenaline (NE) but also elevated the NAD(P)H oxidase activity, the NAD(P)H oxidase components (NOX2 and NOX4) expression, and ROS production in the PVN. Meanwhile, the NOD-like receptor protein 3 (NLRP3)-dependent inflammatory proteins (ASC, pro-cas-1, IL-β, CXCR, CCL2) expression and the tyrosine hydroxylase (TH) expression in the PVN with high salt diet were higher, but the GSH level, Ec-SOD activity, GAD67 expression, and GABA level were lower than the NS group. Bilateral PVN microinjection of AAV-Ec-SOD decreased MAP and the plasma NE, reduced NAD(P)H oxidase activity, the NOX2 and NOX4 expression, and ROS production, attenuated NLRP3-dependent inflammatory expression and TH, but increased GSH level, Ec-SOD activity, GAD67 expression, and GABA level in the PVN compared with the high salt group. Conclusion: Excessive salt intake not only activates oxidative stress but also induces the NLRP3-depensent inflammation and breaks the balance between inhibitory and excitability neurotransmitters in the PVN. Ec-SOD, as an essential anti-oxidative enzyme, eliminates the ROS in the PVN and decreases the blood pressure, probably through inhibiting the NLRP3-dependent inflammation and improving the excitatory neurotransmitter release in the PVN in the salt-induced hypertension.

Dataset Information

Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats.

Publications

Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats.

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