Upregulation of orexin receptor in paraventricular nucleus promotes sympathetic outflow in obese Zucker rats

Abstract

Sympathetic vasomotor tone is elevated in obesity-related hypertension. Orexin importantly regulates energy metabolism and autonomic function. We hypothesized that alteration of orexin receptor in the paraventricular nucleus (PVN) of the hypothalamus leads to elevated sympathetic vasomotor tone in obesity. We used in vivo measurement of sympathetic vasomotor tone and microinjection into brain nucleus, whole-cell patch clamp recording in brain slices, and immunocytochemical staining in obese Zucker rats (OZRs) and lean Zucker rats (LZRs). Microinjection of orexin 1 receptor (OX1R) antagonist SB334867 into the PVN reduced basal arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) in anesthetized OZRs but not in LZRs. Microinjection of orexin A into the PVN produced greater increases in ABP and RSNA in OZRs than in LZRs. Western blot analysis revealed that OX1R expression levels in the PVN were significantly increased in OZRs compared with LZRs. OX1R immunoreactivity was positive in retrogradely labeled PVN-spinal neurons. The basal firing rate of labeled PVN-spinal neurons was higher in OZRs than in LZRs. SB334867 decreased the basal firing activity of PVN-spinal neurons in OZRs but had no effect in LZRs. Orexin A induced a greater increase in the firing rate of PVN-spinal neurons in OZRs than in LZRs. In addition, orexin A induced larger currents in PVN-spinal neurons in OZRs than in LZRs. These data suggest that upregulation of OX1R in the PVN promotes hyperactivity of PVN presympathetic neurons and elevated sympathetic outflow in obesity.

Orexin A increases sympathetic nerve activity through promoting expression of proinflammatory cytokines in Sprague Dawley rats

“…For example, loss of orexin function results in the sleep disorder narcolepsy, and increased CSF orexin levels are found in patients with increased anxiety and panic associated symptoms and in rats at a stress state . Recent studies indicate that brain orexin system is also involved in the regulation of blood pressure and SNA, and its hyperactivity in the brain is associated with hypertension . Thus, the objectives of this study are to investigate whether the PVN orexin signalling is involved in regulating SNA.…”

“…In contrast, prepro‐orexin gene knockout mice show a significant lower blood pressure compared to their wild controls . In addition, the upregulation of orexin signalling has been observed in several animal models of hypertension such as spontaneously hypertensive rats (SHR), stress‐induced hypertensive rats, obesity‐related hypertensive Zucker rats, Dahl salt‐sensitive hypertensive rats and BPH/2J Schlager mice . Furthermore, antagonism of orexin receptors significantly lowers blood pressure in some hypertensive models such as SHR and Dahl salt‐sensitive hypertensive rat .…”

“…Excessive production of PICs in both the periphery and the brain has been demonstrated to contribute to hypertension . OX1R has been found to be expressed in the PVN where orexin‐producing neurons also send projections, and its expression is increased in the hypertensive rats, indicating that PVN orexin signalling may be involved in SNA control. Taken together, we hypothesize that upregulation of orexin signalling in the PVN may stimulate PVN PICs expression and results in excessive production of PICs which in turn increases sympathetic outflow and results in high blood pressure.…”

Acute stress diminishes M-current contributing to elevated activity of hypothalamic-pituitary-adrenal axis

“…Briefly, rats were deeply anesthetized (with sodium pentobarbital 50 mg/kg by intraperitoneal injection) and rapidly perfused transcardially with 0.9% saline followed by 4% paraformaldehyde in 0.1 M phosphate-buffered saline (pH 7.4). The brains were removed and sectioned into 30-µm-thick slices (Zhou et al, 2015). After tissue sections had been treated with blocking agent, they were incubated with the primary antibody mixture (rabbit anti-Kv7.2 from Sigma or rabbit anti-Kv7.3 from Alomone Labs, for CRH: guinea pig anti-corticotrophin-releasing factor antibody, Peninsula Laboratories International, San Carlos, Calif., USA).…”

Sex‐specific differences in cardiovascular and metabolic hormones with integrated signalling in the paraventricular nucleus of the hypothalamus

“…In male obese Zucker rats, microinjection of OX‐A into the PVN increases blood pressure and renal sympathetic nerve activity, presumably through upregulation of OX 1 R in PVN PA neurons projecting to the spinal cord (Zhou et al . ). These results suggest that OX signalling in the PVN contributes to obesity‐related hypertension.…”