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. 2017 Dec 1;313(6):H1075-H1086.
doi: 10.1152/ajpheart.00822.2016. Epub 2017 Jun 30.

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

Affiliations

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

Michael J Huber et al. Am J Physiol Heart Circ Physiol. .

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.NEW & NOTEWORTHY 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.

Keywords: orexin; paraventricular nucleus; salt-sensitive hypertension; sympathetic nerve activity; vasopressin.

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Figures

Fig. 1.
Fig. 1.
Mean arterial pressure (MAP) of Sprague-Dawley (SD) rats and Dahl salt-sensitive (Dahl S) rats on 4 wk of a normal-salt (NS; 0.4% Nacl) or high-salt (HS; 8% NaCl) diet detected by radiotelemetry. HS diet increases MAP of Dahl S rats but not SD rats. n = 5 for each group. *P ≤ 0.05 vs. NS diet.
Fig. 2.
Fig. 2.
Real-time PCR analysis of orexin receptor 1 (OX1R), orexin receptor 2 (OX2R), and arginine vasopressin (AVP) mRNA expression levels in the paraventricular nucleus (PVN) between normal salt (NS; 0.4% NaCl) and high salt (HS; 8% NaCl) diet-fed Sprague-Dawley (SD) rats and Dahl salt-sensitive (Dahl S) rats. HS diet did not change OX1R or OX2R but significantly increased AVP PVN mRNA expression in SD rats. HS diet increased mRNA levels of OX1R, OX2R, and AVP in the PVN in Dahl S rats. The mRNA level in the control sample was assigned to equal 1 arbitrary unit. n = 4–8 for each group. *P ≤ 0.05 vs. NS diet.
Fig. 3.
Fig. 3.
A: representative immunostaining images of orexin receptor 1 (OX1R) in the paraventricular nucleus (PVN) between normal-salt (NS; 0.4% NaCl; left) and high-salt (HS; 8% NaCl; right) diet-fed Dahl salt-sensitive (Dahl S) rats. HS diet increased PVN OX1R immunoreactivity in Dahl S rats. The top row shows low-magnification images; the bottom row shows high-magnification images. B: representative immunostaining images of arginine vasopressin (AVP) in the PVN between NS and HS diet-fed Dahl S rats. HS diet increased PVN AVP immunoreactivity in Dahl S rats. The top row shows low-magnification images; the bottom row shows high-magnification images (contrasts were adjusted to enhance immunostained clusters).
Fig. 4.
Fig. 4.
A: real-time PCR analysis of paraventricular nucleus (PVN) arginine vasopressin (AVP) mRNA expression levels at 3 h after acute intracerebroventricular (ICV) infusion of vehicle control (0.9% saline) and orexin A (0.2 nmol) using male adult Sprague-Dawley (SD) rats. Intracerebroventricular injection of orexin A increased PVN AVP mRNA expression in SD rats. The mRNA level in the control sample was assigned to equal 1 arbitrary unit. n = 7–9 for each group. *P ≤ 0.05 vs. vehicle control. B: representative immunostaining images showing PVN AVP expression at 3 h after acute intracerebroventricular infusion of vehicle control (0.9% saline; left) and orexin A (0.2 nmol; right) using male adult SD rats. Intracerebroventricular infusion of orexin A increased AVP immunoreactivity in SD rats (contrast was adjusted to enhance immunostained clusters). C, left: incubation of primary neuronal cultures from the hypothalamus of newborn SD rats containing the PVN with increasing concentrations of orexin A for 6 h. Neurons were then collected, RNA was purified, and real-ime PCR was performed to assay mRNA levels of AVP. n = 4 for each group. *P ≤ 0.05 vs. control. Right, incubation of primary neuronal cultures from the hypothalamus of newborn SD rats containing the PVN with orexin A alone or coincubated with the orexin receptor 1 (OX1Ra) antagonist SB-408124 or the orexin receptor 2 antagonist (OX2Ra) TCS-OX2-29 for 6 h. Real-time PCR was performed to measure AVP mRNA levels. Orexin A-induced increases in mRNA levels of AVP were attenuated by orexin receptor 1 but not orexin receptor 2 blockade in hypothalamic neurons. The mRNA level in the control sample was assigned to equal 1 arbitrary unit. n = 4 for each group. *P ≤ 0.05 vs. control; #P ≤ 0.05 vs. orexin.
Fig. 5.
Fig. 5.
Real-time PCR analysis of paraventricular nucleus (PVN) orexin receptor 1 (OX1R), orexin receptor 2 (OX2R), and arginine vasopressin (AVP) mRNA expression levels at 3 h after acute intracerebroventricular (ICV) infusion of vehicle control (0.9% saline) and hypertonic saline (4 μmol) using male adult Sprague-Dawley (SD) rats. Acute intracerebroventricular injection of hypertonic saline increased PVN OX1R and AVP mRNA levels in SD rats. The mRNA level in the control sample was assigned to equal 1 arbitrary unit. n = 4–7 for each group. *P ≤ 0.05 vs. vehicle control.
Fig. 6.
Fig. 6.
A: representative images showing immunoreactivity of paraventricular nucleus (PVN) orexin receptor 1 (OX1R) 3 h after acute intracerebroventricular (ICV) infusion of vehicle control (0.9% saline; left) and hypertonic saline (4 μmol; right) using male adult Sprague-Dawley SD rats. Intracerebroventricular hypertonic saline infusion increased PVN OX1R immunoreactivity. The top row shows low-magnification images; the bottom row shows high-magnification images. B: representative images showing PVN arginine vasopressin (AVP) expression 3 h after acute intracerebroventricular infusion of vehicle control (0.9% saline; left) and hypertonic saline (4 μmol; right) using male adult SD rats. Intracerebroventricular NaCl solution increased PVN AVP immunoreactivity. The top row shows low-magnification images; the bottom row showss high-magnification images (contrast was adjusted to enhance immunostained clusters).
Fig. 7.
Fig. 7.
A: representative traces showing splanchnic sympathetic nerve activity (SSNA), renal sympathetic nerve activity (RSNA), and mean arterial pressure [blood pressure (BP)] responses to bilateral paraventricular nucleus (PVN) microinjections of the orexin receptor 1 antagonist (OX1Ra) SB-408124 (30 pmol/50 nl per side) into Dahl salt-sensitive (Dahl S) rats fed a normal-salt (NS; 0.4% NaCl; left) or high-salt (HS; 8% NaCl; right) diet. PVN orexin receptor 1 blockade reduced blood pressure in Dahl S rats with HS intake. B, left: 2.5-s specimen traces of SSNA (top) and RSNA (bottom) before injection of OX1Ra into the PVN and after microinjection of OX1Ra into the PVN of a Dahl S rat on NS diet. Right, 2.5-s specimen traces of SSNA (top) and RSNA (bottom) before injection of OX1Ra into the PVN and after microinjection of OX1Ra into the PVN of a Dahl S rat on the HS diet. Avg, average; ∫, integrated.
Fig. 8.
Fig. 8.
A: summary data showing changes in splanchnic sympathetic nerve activity (ΔSSNA), renal sympathetic nerve activity (ΔRSNA), mean arterial pressure (ΔMAP), and heart rate [ΔHR; in beats/min (BPM)] in response to bilateral paraventricular nucleus (PVN) microinjections of the orexin receptor 1 antagonist SB-408124 (30 pmol/50 nl per side) in normal-salt (NS; 0.4% NaCl, n = 5–6) and high-salt (HS; 8% NaCl) diet-fed Dahl salt-sensitive (Dahl S) rats (n = 5). *P < 0.05 vs. NS diet. B: representation of a single injection (50 nl) of ink showing the injection site within the PVN.

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