Increased activity of the orexin system in the paraventricular nucleus contributes to salt-sensitive hypertension

Abstract

The orexin system is involved in arginine vasopressin (AVP) regulation, and its overactivation has been implicated in hypertension. However, its role in salt-sensitive hypertension (SSHTN) is unknown. Here, we tested the hypothesis that hyperactivity of the orexin system in the paraventricular nucleus (PVN) contributes to SSHTN via enhancing AVP signaling. Eight-week-old male Dahl salt-sensitive (Dahl S) and age- and sex-matched Sprague-Dawley (SD) rats were placed on a high-salt (HS; 8% NaCl) or normal-salt (NS; 0.4% NaCl) diet for 4 wk. HS intake did not alter mean arterial pressure (MAP), PVN mRNA levels of orexin receptor 1 (OX1R), or OX2R but slightly increased PVN AVP mRNA expression in SD rats. HS diet induced significant increases in MAP and PVN mRNA levels of OX1R, OX2R, and AVP in Dahl S rats. Intracerebroventricular infusion of orexin A (0.2 nmol) dramatically increased AVP mRNA levels and immunoreactivity in the PVN of SD rats. Incubation of cultured hypothalamus neurons from newborn SD rats with orexin A increased AVP mRNA expression, which was attenuated by OX1R blockade. In addition, increased cerebrospinal fluid Na concentration through intracerebroventricular infusion of NaCl solution (4 µmol) increased PVN OX1R and AVP mRNA levels and immunoreactivity in SD rats. Furthermore, bilateral PVN microinjection of the OX1R antagonist SB-408124 resulted in a greater reduction in MAP in HS intake (-16 ± 5 mmHg) compared with NS-fed (-4 ± 4 mmHg) anesthetized Dahl S rats. These results suggest that elevated PVN OX1R activation may contribute to SSHTN by enhancing AVP signaling. To our best knowledge, this study is the first to investigate the involvement of the orexin system in salt-sensitive hypertension. Our results suggest that the orexin system may contribute to the Dahl model of salt-sensitive hypertension by enhancing vasopressin signaling in the hypothalamic paraventricular nucleus.

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

“…Our immunostaining studies showed that OX1R is expressed in the RVLM‐projecting PVN neurons indicating the potential role of OX1R in SNA outflow control. Surprisingly, there is no OX2R in the RVLM‐projecting PVN neurons although weak OX2R immunofluorescence is observed, and real‐time PCR demonstrated OX2R mRNA presence in the PVN . Instead, OX2R is highly expressed in submedius thalamic nucleus and mediodorsal thalamic nucleus.…”

“…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.…”

“…The ICV injection was carried out using the same protocol as our previous study . In brief, 10‐week‐old male adult SD rats were anesthetized with isoflurane (3% in O 2 ).…”

“…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.…”