Department of Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, Missouri, United States.
Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, United States.
J Appl Physiol (1985). 2023 Mar 1;134(3):638-648. doi: 10.1152/japplphysiol.00661.2022. Epub 2023 Jan 19.
We recently showed that in male rats, orexin contributes to the hypoxic ventilatory response (HVR), with a stronger effect in the active phase. The effect of orexin on the HVR in females has not been investigated. As estrogen can inhibit orexin neurons, here we hypothesized that orexin neurons are activated by hypoxia and facilitate the HVR only in diestrus, when estrogen is low. We exposed female rats ( = 10) to near-isocapnic hypoxia ([Formula: see text] from 0.21 to 0.09) over ∼5 min, after vehicle and again after suvorexant (a dual OxR antagonist; 20 mg/kg ip), with ventilation measured using whole body plethysmography. Each rat was tested in proestrus or estrus (p/estrus), and again in diestrus, during both inactive and active phases. We also performed immunohistochemistry (IHC) to determine the proportion of orexin neurons activated by acute hypoxia during diestrus ( = 6) or proestrus/estrus ( = 6) in the active phase. In the inactive phase, the HVR was unaffected by OxR blockade, irrespective of estrus stage. In the active phase, the effect of OxR blockade depended on stage: the slope of the HVR was significantly reduced by OxR blockade only during diestrus. IHC revealed that hypoxia activated more orexin neurons during diestrus compared with p/estrus. We conclude that in females, orexin neurons are activated by hypoxia and contribute to the HVR only in diestrus when estrogen levels are low. Stage of the estrus cycle should be considered when examining the physiological function of orexin neurons in females. We previously showed that orexin facilitates the hypoxic ventilatory response (HVR) of adult male rats during the active phase. Others have shown that estrogen inhibits orexin neurons. Here we show that orexin neurons are activated by hypoxia and facilitate the HVR of adult female rats during the active phase, but only in diestrus. These data suggest that orexin neurons facilitate the HVR in females when they are free from the inhibitory effects of estrogen.
我们最近表明，在雄性大鼠中，食欲素有助于低氧通气反应（HVR），在活动期的作用更强。食欲素对雌性 HVR 的影响尚未得到研究。由于雌激素可以抑制食欲素神经元，因此我们假设，在雌激素水平较低的发情间期，缺氧会激活食欲素神经元，并促进 HVR。我们使雌性大鼠（n=10）暴露于近等碳酸缺氧环境中（[Formula: see text]从 0.21 降至 0.09）持续约 5 分钟，期间给予载体，然后再次给予苏沃雷生（双重 OxR 拮抗剂；20 mg/kg ip），使用全身 plethysmography 测量通气。每只大鼠在发情前期或发情期（p/estrus）接受测试，然后在发情间期，在活动期和非活动期再次接受测试。我们还进行了免疫组织化学（IHC）以确定在发情间期（n=6）或发情前期/发情期（n=6）的活动期，急性缺氧激活的食欲素神经元的比例。在非活动期，OxR 阻断对 HVR 没有影响，与发情阶段无关。在活动期，OxR 阻断的作用取决于阶段：OxR 阻断仅在发情间期显著降低 HVR 的斜率。IHC 显示，与发情前期/发情期相比，缺氧在发情间期激活了更多的食欲素神经元。我们的结论是，在雌性中，食欲素神经元在缺氧时被激活，并在雌激素水平较低的发情间期有助于 HVR。在检查雌性食欲素神经元的生理功能时，应考虑发情周期的阶段。我们之前表明，在活动期，食欲素促进成年雄性大鼠的低氧通气反应（HVR）。其他人已经表明，雌激素抑制食欲素神经元。在这里，我们表明，在活动期，食欲素神经元在成年雌性大鼠中被激活，并促进 HVR，但仅在发情间期。这些数据表明，当雌性动物不受雌激素抑制作用的影响时，食欲素神经元会促进 HVR。
