Chronic intermittent hypoxia induces hypoxia-evoked catecholamine efflux in adult rat adrenal medulla via oxidative stress
Chronic intermittent hypoxia induces hypoxia-evoked catecholamine efflux in adult rat adrenal medulla via oxidative stress
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DOI：
10.1113/jphysiol.2006.112524
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发表时间：
2006-08-15
影响因子：
5.5
通讯作者：
Prabhakar, Nanduri R.
中科院分区：
文献类型：
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作者：
Kumar, Ganesh K.;Rai, Vandana;Prabhakar, Nanduri R.
慢性间歇性缺氧（CIH）增强了对动脉血中O-2分压低的生理反应。然而，成年大鼠的肾上腺髓质对急性缺氧的直接影响不敏感。在本研究中，我们研究了CIH是否诱导成年大鼠肾上腺髓质缺氧敏感性，如果是，通过何种机制。实验对暴露于CIH的成年雄性大鼠进行(15 s 5% O-2, 5 min 21% O-2, 9次h(-1)；8 h d(-1)；3或10天)或可比较的累积持续缺氧时间（CH: 4小时7% O-2，然后20小时21% O-2，持续1或10天）。从离体肾上腺髓质监测去甲肾上腺素（NA）和肾上腺素（ADR）外排。在暴露于CIH的大鼠肾上腺髓质中，急性缺氧引起了强烈的NA和ADR流出，而在对照大鼠或暴露于CH 1或10天的大鼠中则没有这些反应。高碳酸血症（10% CO2；酸性，pH值6.8或异水，pH值7.4）对诱导对照、CIH或CH大鼠的儿茶酚胺（CA）外排无效。尼古丁（100 μ M）在对照大鼠中引起NA和ADR外排，这种反应在CIH大鼠中被消除，而在CH大鼠中没有。在对照大鼠中，全身给药2-脱氧葡萄糖降低了ADR的含量，而CIH则减弱了这种反应，表明神经调节的CA分泌下调。CIH肾上腺髓质细胞质和线粒体乌头酶活性下降，提示超氧阴离子的产生增加。全身服用抗氧化剂可逆转CIH对肾上腺髓质的影响。暴露于CIH的大鼠表现出血压升高和血浆CA升高，抗氧化剂消除了这些反应。这些观察结果表明，CIH通过增加超氧阴离子产生的机制诱导成年大鼠肾上腺髓质缺氧感知，并表明缺氧引起的肾上腺髓质CA外排部分导致血压升高和血浆CA升高。
Chronic intermittent hypoxia (CIH) augments physiological responses to low partial pressures of O-2 in the arterial blood. Adrenal medullae from adult rats, however, are insensitive to direct effects of acute hypoxia. In the present study, we examined whether CIH induces hypoxic sensitivity in the adult rat adrenal medulla and, if so, by what mechanism(s). Experiments were performed on adult male rats exposed to CIH (15 s of 5% O-2 followed by 5 min of 21% O-2; 9 episodes h(-1); 8 h d(-1); for 3 or 10 days) or to comparable, cumulative durations of continuous hypoxia (CH; 4 h of 7% O-2 followed by 20 h of 21% O-2 for 1 or 10 days). Noradrenaline (NA) and adrenaline (ADR) effluxes were monitored from ex vivo adrenal medullae. In adrenal medullae of rats exposed to CIH, acute hypoxia evoked robust NA and ADR effluxes, whereas these responses were absent in control rats or in those exposed to CH for 1 or 10 days. Hypercapnia (10% CO2; either acidic, pH 6.8, or isohydric, pH 7.4) was ineffective in eliciting catecholamine (CA) efflux from control, CIH or CH rats. Nicotine (100 mu M) evoked NA and ADR effluxes in control rats, and this response was abolished in CIH but not in CH rats. Systemic administration of 2-deoxyglucose depleted ADR content in control rats, and CIH attenuated this response, indicating downregulation of neurally regulated CA secretion. Cytosolic and mitochondrial aconitase enzyme activities decreased in CIH adrenal medullae, suggesting increased generation of superoxide anions. Systemic administration of antioxidants reversed the effect of CIH on the adrenal medulla. Rats exposed to CIH exhibited increased blood pressures and elevated plasma CA, and antioxidants abolished these responses. These observations demonstrate that CIH induces hypoxic sensing in the adult rat adrenal medulla via mechanisms involving increased generation of superoxide anions and suggest that hypoxia-evoked CA efflux from the adrenal medulla contributes, in part, to elevated blood pressure and plasma CA.