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Spontaneously hypertensive rats have more orexin neurons in the hypothalamus and enhanced orexinergic input and orexin 2 receptor‐associated nitric oxide signalling in the rostral ventrolateral medulla
Author(s) -
Lee YenHsien,
Tsai MinChien,
Li TzuLing,
Dai YuWen E.,
Huang ShangCheng,
Hwang LingLing
Publication year - 2015
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/ep085016
Subject(s) - rostral ventrolateral medulla , orexin , medicine , endocrinology , orexin a , orexin receptor , hypothalamus , chemistry , nitric oxide , receptor , medulla oblongata , central nervous system , neuropeptide
New FindingsWhat is the central question of this study? Our previous study demonstrates that elevated orexin 2 receptor (OX2R) activity within the rostral ventrolateral medulla (RVLM) contributes to hypertension in spontaneously hypertensive rats (SHRs), and a lower OX2R protein level was detected in their RVLM. The present study aims to explore the mechanisms underlying elevated orexinergic activity in the RVLM of SHRs, compared with their normotensive counterparts, Wistar‐Kyoto rats.What is the main finding and its importance? Increased orexinergic input into the RVLM and enhanced OX2R responsiveness in the RVLM, which was mainly mediated by augmented OX2R–neuronal nitric oxide synthase signalling, may underlie the elevated OX2R activity within the RVLM of SHRs.Abstract Our previous study showed that elevated orexin 2 receptor (OX2R) activity within the rostral ventrolateral medulla (RVLM) contributes to hypertension in spontaneously hypertensive rats (SHRs). Herein, we investigated the mechanism(s) underlying the elevated OX2R activity. The following results were found. (i) More hypothalamic orexin A‐immunoreactive (OXA‐IR) cells existed in SHRs than in Wistar‐Kyoto (WKY) rats at either 4 (2217 ± 43 versus 1809 ± 69) or 16 weeks of age (1829 ± 59 versus 1230 ± 84). The number of OXA‐IR cells that project to the RVLM was higher in 16‐week‐old SHRs than in WKY rats (91 ± 11 versus 52 ± 11). (ii) Higher numbers of OXA‐IR and RVLM‐projecting OXA‐IR cells were found in the dorsomedial and perifornical hypothalamus of 16‐week‐old SHRs. (iii) Spontaneously hypertensive rats had higher levels of orexin A and B in the hypothalamus and higher levels of orexin A in the RVLM than did WKY rats. (iv) Unilateral intra‐RVLM application of OX2R agonist, orexin A or [Ala 11 , d ‐Leu 15 ]‐orexin B (50 pmol) induced a larger pressor response in SHRs than in WKY rats. (v) Intra‐RVLM pretreatment with a neuronal nitric oxide synthase (NOS) inhibitor, 7‐nitro‐indazole (2.5 pmol), or a soluble guanylate cyclase inhibitor, methylene blue (250 pmol), reducedthe intra‐RVLM [Ala 11 , d ‐Leu 15 ]‐orexin B‐induced pressor response in both WKY rats and SHRs. In contrast, an inducible NOS inhibitor, aminoguanidine (100 pmol), was ineffective. (vi) Neuronal NOS was co‐expressed with OX2R in RVLM neurons. In conclusion, increased orexinergic input and enhanced OX2R–neuronal NOS signalling may underlie elevated OX2R activity in the RVLM and contribute to the pathophysiology of hypertension in SHRs.