Wiley: The Journal of Physiology: Table of Contents

Amino acid modulation of the carotid body selectively modulates peripheral chemoreceptor respiratory reflex

Wed, 15 Jul 2026 00:00:00 -0700

Abstract figure legend When the carotid body (CB) detects low oxygen levels (hypoxia), this leads to: (1) depolarization of the chemosensory cells (glomus cells) within the CB – the resulting increase in intracellular Ca²⁺ stimulates the exocytotic co-release of vesicles containing ATP and glutamate; (2) synaptic ATP acts on postsynaptic petrosal neuron P2X2/3 receptors, and activation initiates the depolarization of petrosal afferent fibres; (3) glutamate acts on ionotropic NMDA receptors on adjacent glomus cells (paracrine) and back on the cell from which it was released (autoreceptor); and (4) increases in intracellular Ca²⁺ due to NMDA activation trigger the mobilization of GABA vesicles. GABA binds to GABA_A receptors on adjacent glomus cells, inhibiting their excitation and dampening the CB chemoreflex response. This intrinsic ‘accelerator–brake’ mechanism sets the chemoreflex gain and modulates breathing.

Abstract

Cardiorespiratory homeostasis is maintained by carotid body (CB) peripheral chemoreceptors that monitor blood oxygen and stimulate breathing. While proportionality between peripheral chemoreflex sensitivity and respiratory response is relative to hypoxia severity, the fundamental regulatory mechanisms remain unknown. We hypothesized that intercellular amino acid transmission between glomus cells modulates CB sensitivity. We identified a full complement of glutamate and gamma-aminobutyric acid (GABA) synaptic signalling machinery in the CB. During hypoxia stimulation, glutamate acting via NMDA receptors (NMDA-R) stimulated CB afferents while releasing GABA, which acted on GABA_A receptors to rapidly attenuate afferent drive mediated by purinergic P2X receptors. We propose that this intrinsic ‘accelerator–brake’ mechanism regulates CB sensitivity to hypoxia. Further, glutamate and NMDA-R were essential for long-term facilitation (LTF) of respiratory chemoreflex responses induced by repeated hypoxia or glutamate exposures. The accelerator–brake mechanism establishes the set-point of chemoreflex gain and provides plasticity for modulation, explaining ventilatory LTF to repeated bouts of hypoxia.

Key points

An intra-carotid body interaction between glutamate and GABA transmission is crucial for the generation of the biphasic carotid body afferent nerve response when stimulated with low doses of sodium cyanide. Glutamate stimulates the carotid body chemoreflex to increase inspiratory drive without affecting sympathetic activity, heart rate or perfusion pressure, indicating selective activation of a carotid body respiratory reflex arc. Repetitive application of glutamate to the carotid body sensitizes chemoreflex phrenic nerve responses producing long-term facilitation.

APOE4 negates the effects of ovarian hormones on cerebrovascular endothelial and mitochondrial function

Wed, 15 Jul 2026 00:00:00 -0700

Abstract figure legend We examined the interaction effect of ovarian hormones and APOE genotype on cerebrovascular and mitochondrial function. Our data revealed that APOEε3 mice that were ovariectomized exhibited impaired endothelial function and greater oxidative stress and inflammation compared to sham controls. Oestradiol improved endothelial and mitochondrial function and reduced oxidative stress and inflammation in APOEε3 mice following ovariectomy. In contrast APOEε4 mice were resistant to ovarian hormones on cerebrovascular and mitochondrial function, as well as on mechanisms of oxidative stress and inflammation.

Abstract

The APOEε4 allele and oestrogen deficiency independently predispose females to an increased risk of vascular and metabolic impairments, but their cerebrovascular effects are less understood. The purpose of this study was to determine the interaction between APOE genotype and oestrogen on cerebrovascular endothelial and mitochondrial function. We studied young female homozygous APOEε3 and APOEε4 mice (n = 19–20/group; ∼6 months old) that were fed a high-fat diet and were ovariectomized (OVX), OVX and supplemented with 17β-oestradiol, or left intact. In APOEε3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilatation, which was rescued by 17β-oestradiol. However, in APOEε4 mice, there was no effect of OVX or 17β-oestradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17β-oestradiol treatment in APOEε3 mice, but there was no impact of OVX or 17β-oestradiol in the APOEε4 mice. In cerebral arteries and arterioles, 17β-oestradiol led to higher mitochondrial complex I respiration in APOEε3 but not APOEε4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes and pro-inflammatory factors. Overall these results indicate that the APOE genotype modulates the impact of OVX and oestradiol on the cerebral vasculature. We found that 17β-oestradiol enhances cerebrovascular endothelial and mitochondrial function in OVX APOEε3 mice but not in APOEε4 mice. This suggests that 17β-oestradiol supplementation may have more cerebrovascular benefits for APOEε4 non-carriers.

Key points

Females have twice the risk of Alzheimer's disease than males, and the APOEε4 genetic variant has a greater risk for Alzheimer's disease than the APOEε3 variant. The risk for Alzheimer's disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. There are highly inconsistent results among past studies examining the interaction between APOE genotype and oestrogens on brain outcomes, and their impact on the vasculature has not been studied. We aimed to determine the impact of APOEε4 genotype on the cerebrovascular response to ovariectomy and oestradiol. We found that oestradiol improved cerebral artery endothelial function and mitochondrial respiration in ovariectomized APOEε3 mice following ovariectomy. In contrast APOEε4 mice were resistant to the beneficial effects of ovarian hormones on cerebrovascular and mitochondrial function. This research suggests that APOE genotype may be a consideration when weighing the risks and benefits of prescribing hormone replacement therapy to postmenopausal females.

The influence of metaboreflex activation on pulmonary pressure with combined chemoreflex activation in acute and chronic hypoxia

Wed, 17 Jun 2026 03:38:15 -0700

Abstract figure legend Activation of both the metaboreflex via post-exercise circulatory occlusion and the chemoreflex via acute and chronic hypoxia increased pulmonary artery systolic pressure. Coactivation of these reflexes further increased pulmonary artery pressure in an additive manner.

Abstract

Sympathetic activation arising from both the peripheral chemoreflex in hypoxia and muscle metaboreflex during exercise mediate an increase in pulmonary artery systolic pressure (PASP). We tested the hypothesis that coactivation of the chemoreflex and metaboreflex would augment the PASP response, as has been shown previously for heart rate and ventilation. We conducted two experimental studies: (i) a laboratory study (n = 15) in normoxia and acute isocapnic hypoxia (45 mmHg PETO2${{P}_{{\mathrm{ET}}{{{\mathrm{O}}}_2}}}$) and (ii) a field study (n = 14) at sea level (344 m) and after 4–6 days of acclimatisation to high altitude (3800 m). In both studies, participants performed 3 min of isometric handgrip at 30% of maximal voluntary contraction followed by 3 min of post-exercise circulatory occlusion (PECO). PASP was assessed via transthoracic echocardiography. In Study 1, isocapnic hypoxia reduced PETO2${{P}_{{\mathrm{ET}}{{{\mathrm{O}}}_2}}}$ (44.3 ± 5.3 mHg; P < 0.001) but maintained PETCO2${{P}_{{\mathrm{ETC}}{{{\mathrm{O}}}_2}}}$ (36.8 ± 2.3; P = 0.931) compared to normoxia. Both PECO (+5.3 ± 5.3 mmHg; P = 0.044) and hypoxia (+4.0 ± 2.0 mmHg; P = 0.016) elevated PASP from baseline, whereas combined hypoxic PECO further increased PASP (+8.4 ± 3.7 mmHg, P = 0.009). These responses were unaltered following acclimatisation to 3800 m in Study 2. Importantly, irrespective of the duration of hypoxic exposure and thus the degree of carotid body stimulation, the sum of the individual responses to hypoxia and PECO was not different compared to the combined hypoxic PECO stimulus in either acute (P = 0.806) or chronic hypoxia (P = 0.896). Therefore, although both chemoreflex activation with hypoxia and metaboreflex activation with PECO increase PASP, their coactivation results in an additive, not synergistic, response.

Key points

Activation of the peripheral chemoreflex (e.g. hypoxia) and muscle metaboreflex (e.g. exercise) both increase heart rate, arterial pressure, ventilation and pulmonary pressure. There is evidence of an augmented muscle metaboreflex response for heart rate and ventilation in acute hypoxia, but whether the same effect is seen in the pulmonary vasculature has not been explored. We completed two experimental studies where pulmonary artery systolic pressure (PASP) was assessed during post-exercise circulatory occlusion (PECO) in response to acute isocapnic hypoxia and following acclimatisation to high altitude hypoxia (3800 m). Independent activation of the chemoreflex at rest and metaboreflex during PECO elevated PASP in both acute and chronic hypoxia. When combined, metaboreflex activation with PECO and chemoreflex activation with hypoxia have an additive but not interactive effect on PASP, irrespective of the duration of hypoxic exposure.