Estrogen Modulates the Sensitivity of Lung Vagal C Fibers in Female Rats Exposed to Intermittent Hypoxia

Abstract

Obstructive sleep apnea is mainly characterized by intermittent hypoxia (IH), which is associated with hyperreactive airway diseases and lung inflammation. Sensitization of lung vagal C fibers (LVCFs) induced by inflammatory mediators may play a central role in the pathogenesis of airway hypersensitivity. In females, estrogen interferes with inflammatory signaling pathways that may modulate airway hyperreactivity. In this study, we investigated the effects of IH on the reflex and afferent responses of LVCFs to chemical stimulants and lung inflammation in adult female rats, as well as the role of estrogen in these responses. Intact and ovariectomized (OVX) female rats were exposed to room air (RA) or IH for 14 consecutive days. On day 15, IH enhanced apneic responses to right atrial injection of chemical stimulants of LVCFs (e.g., capsaicin, phenylbiguanide, and α,β-methylene-ATP) in intact anesthetized females. Rats subjected to OVX prior to IH exposure exhibited an augmented apneic response to the same dose of stimulants compared with rats subjected to other treatments. Apneic responses to the stimulants were completely abrogated by bilateral vagotomy or perivagal capsaicin treatment, which blocked the neural conduction of LVCFs. Electrophysiological experiments revealed that in IH-exposed rats, OVX potentiated the excitability of LVCFs to stimulants. Moreover, LVCF hypersensitivity in rats subjected to OVX prior to IH exposure was accompanied by enhanced lung inflammation, which was reflected by elevated inflammatory cell infiltration in bronchoalveolar lavage fluid, lung lipid peroxidation, and protein expression of inflammatory cytokines. Supplementation with 17β-estradiol (E2) at a low concentration (30 μg/ml) but not at high concentrations (50 and 150 μg/ml) prevented the augmenting effects of OVX on LVCF sensitivity and lung inflammation caused by IH. These results suggest that ovarian hormones prevent the enhancement of LVCF sensitivity and lung inflammation by IH in female rats, which are related to the effect of low-dose estrogen.

Central Apnea of Prematurity: Does Sex Matter?

“…9 Control of breathing is regulated by central and peripheral chemoreceptors, hormones, autonomic nervous system activation, and other factors that may vary by sex. [10][11][12][13][14] From a pharmacotherapeutic perspective, limited evidence indicates that caffeine efficacy or metabolism may differ in males and females. 15,16 Sex differences in occurrence of the apnea of prematurity or response to caffeine could have broad prognostic and therapeutic implications.…”

Sex Differences in Neurovascular Control: Implications for Obstructive Sleep Apnea

“…Preclinical experiments support this notion, whereby the hypertensive effects of intermittent hypoxia were more pronounced in ovariectomized rodents relative to females that retained their ovaries [81]. A similar study illustrated that intermittent hypoxia sensitizes lung vagal C fibers to a greater extent in ovariectomized rats relative to those with intact ovaries and that this effect was offset with supplemental 17β-estradiol [82]. While the clinical implications of these findings are not immediately apparent, these data clearly indicate that intermittent hypoxia alters sympathetic discharge patterns differently between sexes and that female sex hormones appear to offset the neurophysiological effects of intermittent hypoxia.…”

Subclinical elevated B-type Natriuretic Peptide (BNP) indicates endothelial dysfunction contributing to hypoxia susceptibility in healthy individuals

“…The fraction of exhaled nitric oxide (FeNO) measures pulmonary endothelial NO levels and regulates the homeostasis in endothelium showed no increase in Group 2 post hypoxia similar to HAPE-S [ 16 ]. On the contrary, studies showed females having less hypoxia susceptibility related to relatively more NO production due to a direct action of estrogen on vascular endothelium [ 29 , 30 ]. We found evidence of reduced oxidative phosphorylation in Group 2 as GLUT1 level was high during hypoxia, moreover, elevated baseline lactate and no significant fall in PO 2 on acute hypoxia is in contrast to Group 1.…”