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An augmented CO 2 chemoreflex and overactive orexin system are linked with hypertension in young and adult spontaneously hypertensive rats
Author(s) -
Li Aihua,
Roy Sarah H.,
Nattie Eugene E.
Publication year - 2016
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/jp272199
Subject(s) - medicine , endocrinology , orexin , hypercapnia , blood pressure , wakefulness , sympathetic nervous system , respiratory system , receptor , neuropeptide , electroencephalography , psychiatry
Key points Activation of central chemoreceptors by CO 2 increases sympathetic nerve activity (SNA), arterial blood pressure (ABP) and breathing. These effects are exaggerated in spontaneously hypertensive rats (SHRs), resulting in an augmented CO 2 chemoreflex that affects both breathing and ABP. The augmented CO 2 chemoreflex and the high ABP are measureable in young SHRs (postnatal day 30–58) and become greater in adult SHRs. Blockade of orexin receptors can normalize the augmented CO 2 chemoreflex and the high ABP in young SHRs and normalize the augmented CO 2 chemoreflex and significantly lower the high ABP in adult SHRs. In the hypothalamus, SHRs have more orexin neurons, and a greater proportion of them increase their activity with CO 2 . The orexin system is overactive in SHRs and contributes to the augmented CO 2 chemoreflex and hypertension. Modulation of the orexin system may be beneficial in the treatment of neurogenic hypertension.Abstract Activation of central chemoreceptors by CO 2 increases arterial blood pressure (ABP), sympathetic nerve activity and breathing. In spontaneously hypertensive rats (SHRs), high ABP is associated with enhanced sympathetic nerve activity and peripheral chemoreflexes. We hypothesized that an augmented CO 2 chemoreflex and overactive orexin system are linked with high ABP in both young (postnatal day 30–58) and adult SHRs (4–6 months). Our main findings are as follows. (i) An augmented CO 2 chemoreflex and higher ABP in SHRs are measureable at a young age and increase in adulthood. In wakefulness, the ventilatory response to normoxic hypercapnia is higher in young SHRs (mean ± SEM: 179 ± 11% increase) than in age‐matched normotensive Wistar–Kyoto rats (114 ± 9% increase), but lower than in adult SHRs (226 ± 10% increase; P < 0.05). The resting ABP is higher in young SHRs (122 ± 5 mmHg) than in age‐matched Wistar–Kyoto rats (99 ± 5 mmHg), but lower than in adult SHRs (152 ± 4 mmHg; P < 0.05). (ii) Spontaneously hypertensive rats have more orexin neurons and more CO 2 ‐activated orexin neurons in the hypothalamus. (iii) Antagonism of orexin receptors with a dual orexin receptor antagonist, almorexant, normalizes the augmented CO 2 chemoreflex in young and adult SHRs and the high ABP in young SHRs and significantly lowers ABP in adult SHRs. (iv) Attenuation of peripheral chemoreflexes by hyperoxia does not abolish the augmented CO 2 chemoreflex (breathing and ABP) in SHRs, which indicates an important role for the central chemoreflex. We suggest that an overactive orexin system may play an important role in the augmented central CO 2 chemoreflex and in the development of hypertension in SHRs.