Orexin and its receptors are critical regulating sympathetic vasomotor tone under physiological and pathophysiological conditions. Orexin receptor 1 (OXR1) is upregulated in the paraventricular nucleus (PVN) in the hypothalamus and contributes to increased sympathetic outflow in obese Zucker rats (OZRs). We hypothesized that silencing OXR1 expression in the PVN decreases heightened blood pressure and elevated sympathetic outflow in OZRs.An adeno-associated virus (AAV) vector containing a short hairpin RNA (shRNA) targeting rat OXR1 was designed to silence OXR1 expression in the PVN. The AAV-OXR1-shRNA or scrambled shRNA was injected into the PVN in OZRs. The arterial blood pressure in free-moving OZRs 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 OZRs treated with AAV-OXR1-shRNA had markedly lower OXR1 expression and lower mean arterial blood pressure, heart rate, and ratio of low- to high-frequency components of heart rate variability compared with OZRs treated with scrambled shRNA. Furthermore, AAV-OXR1-shRNA 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-OXR1-shRNA substantially decreased the basal firing activity of spinally projecting PVN neurons in OZRs and attenuated the excitatory effect of orexin A on the firing activity of these neurons.These data suggest that chronic downregulation of OXR1 expression in the PVN reduces sympathetic vasomotor tone in obesity-related hypertension.

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