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Antagonism of orexin receptors significantly lowers blood pressure in spontaneously hypertensive rats
Author(s) -
Li Aihua,
Hindmarch Charles C. T.,
Nattie Eugene E.,
Paton Julian F. R.
Publication year - 2013
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2013.256271
Subject(s) - orexin , endocrinology , medicine , orexin receptor , rostral ventrolateral medulla , orexin a , blood pressure , receptor , chemistry , neuropeptide , heart rate
Key points• Orexin is involved in blood pressure regulation. Certain forms of stress or central administration of orexin increases blood pressure and sympathetic nerve activity in normal rats; orexin knockout mice and orexin neuron‐ablated transgenic rats have lower basal blood pressure. The role of orexin in hypertension remains unknown. • RT‐PCR shows a strong trend towards an increased orexin‐A mRNA expression in the rostral ventrolateral medulla in adult spontaneously hypertensive rats. • In adult spontaneously hypertensive rats, blocking orexin receptors by oral administration of an antagonist, almorexant, significantly lowers blood pressure in wakefulness and non‐rapid eye movement sleep during dark and light cycles, an effect accompanied by decreased sympathetic vasomotor tone and noradrenaline levels in cerebrospinal fluid and plasma. • Antagonizing orexin receptors had no effect on resting blood pressure in normal rats. • The orexin system participates in the pathogenesis of high blood pressure in spontaneously hypertensive rats. Modulation of the orexin system could be a potential target in treating some forms of hypertension.Abstract In normal rats, central administration of orexin or exposure to certain forms of stress can induce significant increases in blood pressure and sympathetic nerve activity, which can be blocked by orexin receptor antagonists. The resting blood pressure is, however, unaffected by such antagonists, but is significantly lower in rodents with total loss of orexin, such as prepro‐orexin knockout mice and orexin neuron‐ablated orexin/ataxin‐3 transgenic rats. We hypothesize that orexin is involved in the pathophysiology and maintenance of high blood pressure in the spontaneously hypertensive rat (SHR), a model of primary hypertension. To test this hypothesis, we measured orexin‐A mRNA expression in the rostral ventrolateral medulla and antagonized both orexin receptors using an orally administered potent dual orexin receptor antagonist, almorexant, in SHRs and normotensive Wistar–Kyoto rats. In SHRs, there was a strong trend towards an increased orexin‐A mRNA expression in the rostral ventrolateral medulla, and blocking orexin receptors markedly lowered blood pressure (from 182/152 ± 5/6 to 149/119 ± 9/8 mmHg; P < 0.001), heart rate ( P < 0.001), sympathetic vasomotor tone ( P < 0.001) and the noradrenaline levels in cerebrospinal fluid and plasma ( P < 0.002). The significant antihypertensive effects of almorexant were observed in wakefulness and non‐rapid eye movement sleep during both dark and light phases of the diurnal cycle only in SHRs. Blocking orexin receptors had no effect on blood pressure and sympathetic tone in normotensive Wistar–Kyoto rats. Our study links the orexin system to the pathogenesis of high blood pressure in SHRs and suggests that modulation of the orexin system could be a potential target in treating some forms of hypertension.