Contribution of orexin in hypercapnic chemoreflex

Evidence from genetic and pharmacological disruption and supplementation studies in mice

Ben Shiang Deng, Akira Nakamura, Wei Zhang, Masashi Yanagisawa, Yasuichiro Fukuda, Tomoyuki Kuwaki

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

We have previously shown that hypercapnic chemoreflex in prepro-orexin knockout mice (ORX-KO) is attenuated during wake but not sleep periods. In that study, however, hypercapnic stimulation had been chronically applied for 6 h because of technical difficulty in changing the composition of the inspired gas mixture without distorting the animal's vigilance states. In the present study we examined possible involvement of orexin in acute respiratory chemoreflex during wake periods. Ventilation was recorded together with electroencephalography and electromyography before and after intracerebroventricular administration of orexin or an orexin receptor antagonist, SB-334867. A hypercapnic (5 or 10% CO2) or hypoxic (15 or 10% O2) gas mixture was introduced into the recording chamber for 5 min. Respiratory parameters were analyzed only for quiet wakefulness. When mice breathed normal room air, orexin-A and orexin-B but not vehicle or SB-334867 increased minute ventilation in both ORX-KO and wild-type (WT) mice. As expected, hypercapnic chemoreflex in vehicle-treated ORX-KO mice (0.22 ± 0.03 ml·min-1·g-1·% CO 2-1) was significantly blunted compared with that in WT mice (0.51 ± 0.05 ml·min-1·g -1·% CO2-1). Supplementation of orexin-A or -B (3 nmol) partially restored the hypercapnic chemoreflex in ORX-KO mice (0.28 ± 0.03 ml·min-1·g-1·% CO2-1 for orexin-A and 0.32 ± 0.04 ml·min-1·g-1·% CO2 -1 for orexin-B). In addition, injection of SB-334867 (30 nmol) in WT mice decreased the hypercapnic chemoreflex (0.39 ± 0.04 ml·min-1·g-1·% CO2 -1). On the other hand, hypoxic chemoreflex in vehicle-treated ORX-KO and SB-334867-treated WT mice was not different from that in corresponding controls. Our findings suggest that orexin plays a crucial role in CO 2 sensitivity at least during wake periods in mice.

Original languageEnglish (US)
Pages (from-to)1772-1779
Number of pages8
JournalJournal of Applied Physiology
Volume103
Issue number5
DOIs
StatePublished - Nov 2007

Fingerprint

Pharmacology
Knockout Mice
Carbon Monoxide
Ventilation
Gases
Wakefulness
Electromyography
Electroencephalography
Sleep
Air
Orexins
Injections
1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea

Keywords

  • Breathing control
  • Chemostimulation
  • Hypothalamus
  • Orexin receptor antagonist
  • Respiration

ASJC Scopus subject areas

  • Physiology
  • Endocrinology
  • Orthopedics and Sports Medicine
  • Physical Therapy, Sports Therapy and Rehabilitation

Cite this

Contribution of orexin in hypercapnic chemoreflex : Evidence from genetic and pharmacological disruption and supplementation studies in mice. / Deng, Ben Shiang; Nakamura, Akira; Zhang, Wei; Yanagisawa, Masashi; Fukuda, Yasuichiro; Kuwaki, Tomoyuki.

In: Journal of Applied Physiology, Vol. 103, No. 5, 11.2007, p. 1772-1779.

Research output: Contribution to journalArticle

Deng, Ben Shiang ; Nakamura, Akira ; Zhang, Wei ; Yanagisawa, Masashi ; Fukuda, Yasuichiro ; Kuwaki, Tomoyuki. / Contribution of orexin in hypercapnic chemoreflex : Evidence from genetic and pharmacological disruption and supplementation studies in mice. In: Journal of Applied Physiology. 2007 ; Vol. 103, No. 5. pp. 1772-1779.
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abstract = "We have previously shown that hypercapnic chemoreflex in prepro-orexin knockout mice (ORX-KO) is attenuated during wake but not sleep periods. In that study, however, hypercapnic stimulation had been chronically applied for 6 h because of technical difficulty in changing the composition of the inspired gas mixture without distorting the animal's vigilance states. In the present study we examined possible involvement of orexin in acute respiratory chemoreflex during wake periods. Ventilation was recorded together with electroencephalography and electromyography before and after intracerebroventricular administration of orexin or an orexin receptor antagonist, SB-334867. A hypercapnic (5 or 10{\%} CO2) or hypoxic (15 or 10{\%} O2) gas mixture was introduced into the recording chamber for 5 min. Respiratory parameters were analyzed only for quiet wakefulness. When mice breathed normal room air, orexin-A and orexin-B but not vehicle or SB-334867 increased minute ventilation in both ORX-KO and wild-type (WT) mice. As expected, hypercapnic chemoreflex in vehicle-treated ORX-KO mice (0.22 ± 0.03 ml·min-1·g-1·{\%} CO 2-1) was significantly blunted compared with that in WT mice (0.51 ± 0.05 ml·min-1·g -1·{\%} CO2-1). Supplementation of orexin-A or -B (3 nmol) partially restored the hypercapnic chemoreflex in ORX-KO mice (0.28 ± 0.03 ml·min-1·g-1·{\%} CO2-1 for orexin-A and 0.32 ± 0.04 ml·min-1·g-1·{\%} CO2 -1 for orexin-B). In addition, injection of SB-334867 (30 nmol) in WT mice decreased the hypercapnic chemoreflex (0.39 ± 0.04 ml·min-1·g-1·{\%} CO2 -1). On the other hand, hypoxic chemoreflex in vehicle-treated ORX-KO and SB-334867-treated WT mice was not different from that in corresponding controls. Our findings suggest that orexin plays a crucial role in CO 2 sensitivity at least during wake periods in mice.",
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N2 - We have previously shown that hypercapnic chemoreflex in prepro-orexin knockout mice (ORX-KO) is attenuated during wake but not sleep periods. In that study, however, hypercapnic stimulation had been chronically applied for 6 h because of technical difficulty in changing the composition of the inspired gas mixture without distorting the animal's vigilance states. In the present study we examined possible involvement of orexin in acute respiratory chemoreflex during wake periods. Ventilation was recorded together with electroencephalography and electromyography before and after intracerebroventricular administration of orexin or an orexin receptor antagonist, SB-334867. A hypercapnic (5 or 10% CO2) or hypoxic (15 or 10% O2) gas mixture was introduced into the recording chamber for 5 min. Respiratory parameters were analyzed only for quiet wakefulness. When mice breathed normal room air, orexin-A and orexin-B but not vehicle or SB-334867 increased minute ventilation in both ORX-KO and wild-type (WT) mice. As expected, hypercapnic chemoreflex in vehicle-treated ORX-KO mice (0.22 ± 0.03 ml·min-1·g-1·% CO 2-1) was significantly blunted compared with that in WT mice (0.51 ± 0.05 ml·min-1·g -1·% CO2-1). Supplementation of orexin-A or -B (3 nmol) partially restored the hypercapnic chemoreflex in ORX-KO mice (0.28 ± 0.03 ml·min-1·g-1·% CO2-1 for orexin-A and 0.32 ± 0.04 ml·min-1·g-1·% CO2 -1 for orexin-B). In addition, injection of SB-334867 (30 nmol) in WT mice decreased the hypercapnic chemoreflex (0.39 ± 0.04 ml·min-1·g-1·% CO2 -1). On the other hand, hypoxic chemoreflex in vehicle-treated ORX-KO and SB-334867-treated WT mice was not different from that in corresponding controls. Our findings suggest that orexin plays a crucial role in CO 2 sensitivity at least during wake periods in mice.

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