Control Of Cardiorespiratory Function Research Articles

Orexin facilitates the hypoxic ventilatory response in rats

Orexin is a hypothalamic neuropeptide involved in a variety of functions including arousal, body temperature regulation, and feeding. Orexin neurons are active in wakefulness (or the dark phase in rats) and mostly silent in sleep (light phase), implying the effects of orexin are greater in wakefulness and/or dark phase. Recent evidence implicates orexin in the control of cardiorespiratory function, including the respiratory response to CO2 and blood pressure regulation. Whether orexin influences normal breathing in a state-dependent manner is unresolved. In addition, although the role of orexin in the hypercapnic ventilatory response is well established, its effects on the acute hypoxic ventilatory response (HVR) has not been investigated. We hypothesized that orexin receptor blockade would lead to hypoventilation in wakefulness but not sleep and would reduce the HVR. To test these hypotheses, we conducted two separate experiments, both of which were performed in the light phase. First, we used whole-body plethysmography to measure the ventilation of adult rats in room air. Rats were implanted with EEG and EMG electrodes to determine vigilance state, which was confirmed by applying Fast Fourier Transform on the EEG signals. After a 1hr baseline period, we injected i.p. either suvorexant (an OxR1 and OxR2 antagonist, 20 mg/kg i.p.) or vehicle (100% DMSO, i.p.) and allowed the rats to freely behave for 4 hours in the chamber while breathing room air. Separate groups of rats, also instrumented with EEG and EMG electrodes, were exposed to graded hypoxia (15%, 13%, 11%, and 9% O2) following administration of either 20 mg/kg i.p. suvorexant or vehicle. We found that, irrespective of state of vigilance, OxR1 and OxR2 blockade had no effect on baseline breathing, but significantly reduced the HVR (treatment × O2 level: p=0.03). The effect on the HVR was especially evident at 13% and 11% O2 when the response was reduced by ~30%. We show that orexin facilitates the HVR in the light phase, even though the orexin neurons are silent. Whether orexin has a larger effect on the HVR during the dark phase, when orexin neurons are active, has yet to be determined.

Catecholaminergic neurons projecting to the paraventricular nucleus of the hypothalamus are essential for cardiorespiratory adjustments to hypoxia.

Brainstem catecholamine neurons modulate sensory information and participate in control of cardiorespiratory function. These neurons have multiple projections, including to the paraventricular nucleus (PVN), which contributes to cardiorespiratory and neuroendocrine responses to hypoxia. We have shown that PVN-projecting catecholaminergic neurons are activated by hypoxia, but the function of these neurons is not known. To test the hypothesis that PVN-projecting catecholamine neurons participate in responses to respiratory challenges, we injected IgG saporin (control; n = 6) or anti-dopamine β-hydroxylase saporin (DSAP; n = 6) into the PVN to retrogradely lesion catecholamine neurons projecting to the PVN. After 2 wk, respiratory measurements (plethysmography) were made in awake rats during normoxia, increasing intensities of hypoxia (12, 10, and 8% O2) and hypercapnia (5% CO2-95% O2). DSAP decreased the number of tyrosine hydroxylase-immunoreactive terminals in PVN and cells counted in ventrolateral medulla (VLM; -37%) and nucleus tractus solitarii (nTS; -36%). DSAP produced a small but significant decrease in respiratory rate at baseline (during normoxia) and at all intensities of hypoxia. Tidal volume and minute ventilation (VE) index also were impaired at higher hypoxic intensities (10-8% O2; e.g., VE at 8% O2: IgG = 181 ± 22, DSAP = 91 ± 4 arbitrary units). Depressed ventilation in DSAP rats was associated with significantly lower arterial O2 saturation at all hypoxic intensities. PVN DSAP also reduced ventilatory responses to 5% CO2 (VE: IgG = 176 ± 21 and DSAP = 84 ± 5 arbitrary units). Data indicate that catecholamine neurons projecting to the PVN are important for peripheral and central chemoreflex respiratory responses and for maintenance of arterial oxygen levels during hypoxic stimuli.

Control of cardiorespiratory function in response to hypoxia in an air-breathing fish, the African sharptooth catfish, Clarias gariepinus

We evaluated the role of the first pair of gill arches in the control of cardiorespiratory responses to normoxia and hypoxia in the air-breathing catfish, Clarias gariepinus. An intact group (IG) and an experimental group (EG, bilateral excision of first gill arch) were submitted to graded hypoxia, with and without access to air. The first pair of gill arches ablations reduced respiratory surface area and removed innervation by cranial nerve IX. In graded hypoxia without access to air, both groups displayed bradycardia and increased ventilatory stroke volume (VT), and the IG showed a significant increase in breathing frequency (fR). The EG exhibited very high fR in normoxia that did not increase further in hypoxia, this was linked to reduced O2 extraction from the ventilatory current (EO2) and a significantly higher critical O2 tension (PcO2) than the IG. In hypoxia with access to air, only the IG showed increased air-breathing, indicating that the first pair of gill arches excision severely attenuated air-breathing responses. Both groups exhibited bradycardia before and tachycardia after air-breaths. The fH and gill ventilation amplitude (VAMP) in the EG were overall higher than the IG. External and internal NaCN injections revealed that O2 chemoreceptors mediating ventilatory hypoxic responses (fR and VT) are internally oriented. The NaCN injections indicated that fR responses were mediated by receptors predominantly in the first pair of gill arches but VT responses by receptors on all gill arches. Receptors eliciting cardiac responses were both internally and externally oriented and distributed on all gill arches or extra-branchially. Air-breathing responses were predominantly mediated by receptors in the first pair of gill arches. In conclusion, the role of the first pair of gill arches is related to: (a) an elevated EO2 providing an adequate O2 uptake to maintain the aerobic metabolism during normoxia; (b) a significant bradycardia and increased fAB elicited by externally oriented O2 chemoreceptors; (c) increase in the ventilatory variables (fR and VAMP) stimulated by internally oriented O2 chemoreceptors.

RETRACTED: Mutual antagonism between hypoxia-inducible factors 1α and 2α regulates oxygen sensing and cardio-respiratory homeostasis

Breathing and blood pressure are under constant homeostatic regulation to maintain optimal oxygen delivery to the tissues. Chemosensory reflexes initiated by the carotid body and catecholamine secretion from the adrenal medulla are the principal mechanisms for maintaining respiratory and cardiovascular homeostasis; however, the underlying molecular mechanisms are not known. Here, we report that balanced activity of hypoxia-inducible factor-1 (HIF-1) and HIF-2 is critical for oxygen sensing by the carotid body and adrenal medulla, and for their control of cardio-respiratory function. In Hif2α(+/-) mice, partial HIF-2α deficiency increased levels of HIF-1α and NADPH oxidase 2, leading to an oxidized intracellular redox state, exaggerated hypoxic sensitivity, and cardio-respiratory abnormalities, which were reversed by treatment with a HIF-1α inhibitor or a superoxide anion scavenger. Conversely, in Hif1α(+/-) mice, partial HIF-1α deficiency increased levels of HIF-2α and superoxide dismutase 2, leading to a reduced intracellular redox state, blunted oxygen sensing, and impaired carotid body and ventilatory responses to chronic hypoxia, which were corrected by treatment with a HIF-2α inhibitor. None of the abnormalities observed in Hif1α(+/-) mice or Hif2α(+/-) mice were observed in Hif1α(+/-);Hif2α(+/-) mice. These observations demonstrate that redox balance, which is determined by mutual antagonism between HIF-α isoforms, establishes the set point for hypoxic sensing by the carotid body and adrenal medulla, and is required for maintenance of cardio-respiratory homeostasis.

Role of CNS excitatory amino acids in the control of cardiorespiratory function

Role of CNS excitatory amino acids in the control of cardiorespiratory function