Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, University of Chicago, Chicago, Illinois.
J Neurophysiol. 2019 Nov 1;122(5):1874-1883. doi: 10.1152/jn.00435.2019. Epub 2019 Sep 4.
In neonates, catecholamine (CA) secretion from adrenal medullary chromaffin cells (AMC) is an important mechanism for maintaining homeostasis during hypoxia. Nearly 90% of premature infants experience chronic intermittent hypoxia (IH) because of high incidence of apnea of prematurity, which is characterized by periodic stoppage of breathing. The present study examined the effects of repetitive hypoxia, designed to mimic apnea of prematurity, on CA release from AMC of neonatal rats. Neonatal rats were exposed to either control conditions or chronic intermittent hypoxia (IH) from ages postnatal (P0-P5), and CA release from adrenal medullary slices was measured after challenge with repetitive hypoxia (5 episodes of 30-s hypoxia, Po ~35 mmHg). In response to repetitive hypoxia, chronic IH-treated AMC exhibited sustained CA release, and this phenotype was not seen in control AMC. The sustained CA release was associated with long-lasting elevation of intracellular Ca concentration ([Ca]), which was due to store-operated Ca entry (SOCE). 2-Aminoethoxydiphenyl borate, an inhibitor of SOCE, prevented the long-lasting [Ca] elevation and CA release. Repetitive hypoxia increased HO abundance, and polyethylene glycol (PEG)-catalase, a scavenger of HO blocked this effect. PEG-catalase also prevented repetitive hypoxia-induced SOCE activation, sustained [Ca] elevation, and CA release. These results demonstrate that repetitive hypoxia induces long-term facilitation of CA release in chronic IH-treated neonatal rat AMC through sustained Ca influx mediated by SOCE. Apnea of prematurity and the resulting chronic intermittent hypoxia are major clinical problems in neonates born preterm. Catecholamine release from adrenal medullary chromaffin cells maintains homeostasis during hypoxia in neonates. Our results demonstrate that chronic intermittent hypoxia induces a hitherto uncharacterized long-term facilitation of catecholamine secretion from neonatal rat chromaffin cells in response to repetitive hypoxia, simulating hypoxic episodes encountered during apnea of prematurity. The sustained catecholamine secretion might contribute to cardiovascular morbidities in infants with apnea of prematurity.
在新生儿中，肾上腺髓质嗜铬细胞（AMC）中的儿茶酚胺（CA）分泌是在缺氧期间维持体内平衡的重要机制。由于早产儿呼吸暂停的发生率很高，近 90%的早产儿会经历慢性间歇性缺氧（IH），其特征是呼吸周期性停止。本研究检查了重复缺氧的影响，设计用于模拟早产儿呼吸暂停，以测量新生大鼠 AMC 中 CA 的释放。新生大鼠在出生后（P0-P5）接受对照条件或慢性间歇性缺氧（IH）处理，并在重复缺氧（5 个 30 秒的缺氧期，Po~35mmHg）后测量肾上腺髓质切片中的 CA 释放。对重复缺氧的反应，慢性 IH 处理的 AMC 表现出持续的 CA 释放，而对照 AMC 则没有这种表型。持续的 CA 释放与细胞内 Ca 浓度的持久升高（[Ca]）有关，这是由于储存操纵的 Ca 内流（SOCE）所致。SOCE 的抑制剂 2-氨基乙氧基二苯硼酸盐（2-Aminoethoxydiphenyl borate）阻止了持久的[Ca]升高和 CA 释放。重复缺氧增加了 HO 的丰度，HO 的清除剂聚乙二醇（PEG）-过氧化氢酶（catalase）阻止了这种作用。PEG-过氧化氢酶还阻止了重复缺氧诱导的 SOCE 激活、持续的[Ca]升高和 CA 释放。这些结果表明，重复缺氧通过 SOCE 介导的持续 Ca 内流诱导慢性 IH 处理的新生大鼠 AMC 中 CA 释放的长期易化。早产儿呼吸暂停和由此导致的慢性间歇性缺氧是早产儿出生时的主要临床问题。肾上腺髓质嗜铬细胞中的儿茶酚胺释放可在新生儿缺氧期间维持体内平衡。我们的结果表明，慢性间歇性缺氧诱导了一种迄今为止尚未表征的新生大鼠嗜铬细胞对重复缺氧的儿茶酚胺分泌的长期易化作用，模拟了早产儿呼吸暂停期间遇到的缺氧发作。持续的儿茶酚胺分泌可能导致呼吸暂停的婴儿心血管发病率增加。
