Dual orexin receptor blocker suvorexant attenuates hypercapnic ventilatory augmentation in mice

Suvorexant (Belsomra(R)), a dual orexin receptor antagonist widely used in the treatment of insomnia, inhibits the arousal system in the brain. However, the drug’s ventilatory effects have not been fully explored. This study aims to investigate the expression of orexin receptors in respiratory neurons and the effects of suvorexant on ventilation. Immunohistology of brainstem orexin receptor OX2R expression was performed in adult mice (n = 4) in (1) rostral ventral respiratory group (rVRG) neurons projecting to the phrenic nucleus (PhN) retrogradely labeled by Fluoro-Gold (FG) tracer, (2) neurons immunoreactive for paired like homeobox 2b (Phox2b) in the parafacial respiratory group/retrotra…

Astrocytes play an active role in persistence of respiratory augmentation in the recovery phase after hypoxic exposure

Calcium/calmodulin-dependent protein kinases in the carotid body: an immunohistochemical study

We determined the presence of Ca(2+)/calmodulin-dependent protein kinases (CaMKs), a family of multifunctional proteins engaged in Ca(2+)-linked signaling, in carotid body chemoreceptor cells which are critical for the hypoxia-sensing. Carotid bodies were dissected from anesthetized normoxic adult Wistar rats and were double stained for individual CaMKs and for tyrosine hydroxylase (TH), a marker of chemoreceptor cells. Immunofluorescence was examined by confocal laser scanning microscopy. We found that CaMKI and CaMKII were expressed in chemoreceptor cells, but their distribution and intensity varied. CaMKI immunoreactivity was distributed throughout the cytoplasm, whereas that of CaMKII w…

Role of microglia in blood pressure and respiratory responses to acute hypoxic exposure in rats

AbstractMicroglia modulate cardiorespiratory activities during chronic hypoxia. It has not been clarified whether microglia are involved in the cardiorespiratory responses to acute hypoxia. Here we investigated this issue by comparing cardiorespiratory responses to two levels of acute hypoxia (13% O2 for 4 min and 7% O2 for 5 min) in conscious unrestrained rats before and after systemic injection of minocycline (MINO), an inhibitor of microglia activation. MINO increased blood pressure but not lung ventilation in the control normoxic condition. Acute hypoxia stimulated cardiorespiratory responses in MINO-untreated rats. MINO failed to significantly affect the magnitude of hypoxia-induced bl…

Expression of p11 and TASK1 Channels in Rat Carotid Body Glomus Cells Subjected to Chronic Intermittent Hypoxia

Chronic intermittent hypoxia (CIH) has been used as a model to mimic nocturnal apnea, which is associated with hypertension. One of the mechanisms for hypertension in patients with nocturnal apnea is an enhancement of the plasma membrane response to acute hypoxia in carotid body glomus cells. Hypoxia is known to induce depolarization via inhibiting TWIK-related acid-sensitive K+ (TASK) channels, one type of leak K+ channels, in glomus cells. The present experiment was undertaken to immunocytochemically investigate the effects of CIH on the expression and intracellular localization of TASK1 channels and p11 that critically affect the trafficking of TASK1 to the cell surface. The expression l…

Structural and functional identification of two distinct inspiratory neuronal populations at the level of the phrenic nucleus in the rat cervical spinal cord.

The diaphragm is driven by phrenic motoneurons that are located in the cervical spinal cord. Although the anatomical location of the phrenic nucleus and the function of phrenic motoneurons at a single cellular level have been extensively analyzed, the spatiotemporal dynamics of phrenic motoneuron group activity have not been fully elucidated. In the present study, we analyzed the functional and structural characteristics of respiratory neuron population in the cervical spinal cord at the level of the phrenic nucleus by voltage imaging, together with histological analysis of neuronal and astrocytic distribution in the cervical spinal cord. We found spatially distinct two cellular populations…

Activation of Astrocytes in the Persistence of Post-hypoxic Respiratory Augmentation

Acute hypoxia increases ventilation. After cessation of hypoxia loading, ventilation decreases but remains above the pre-exposure baseline level for a time. However, the mechanism of this post-hypoxic persistent respiratory augmentation (PHRA), which is a short-term potentiation of breathing, has not been elucidated. We aimed to test the hypothesis that astrocytes are involved in PHRA. To this end, we investigated hypoxic ventilatory responses by whole-body plethysmography in unanesthetized adult mice. The animals breathed room air, hypoxic gas mixture (7% O2, 93% N2) for 2min, and again room air for 10min before and after i.p. administration of low (100mg/kg) and high (300mg/kg) doses of a…

Editorial: Hypoxia and Cardiorespiratory Control

To maintain adequate oxygen levels in the body, which is essential for a healthy life, the respiratory and cardiovascular systems play vitally important roles. When the oxygen content is insufficient, i.e., when hypoxia is loaded, respiratory and cardiovascular systems respond to restore, compensate, or adapt to hypoxia, e.g., by increasing ventilation and blood flow to maintain oxygen transport to vital organs. Traditionally, it has been thought that hypoxia is detected solely by carotid and aortic bodies, i.e., by peripheral chemoreceptors, and information from the peripheral chemoreceptors is transmitted to respiratory and cardiovascular centers in the brainstem whose respiratory and car…