Kumar Ganesh K, Rai Vandana, Sharma Suresh D, Ramakrishnan Devi Prasadh, Peng Ying-Jie, Souvannakitti Dangjai, Prabhakar Nanduri R
Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4935, USA.
J Physiol. 2006 Aug 15;575(Pt 1):229-39. doi: 10.1113/jphysiol.2006.112524. Epub 2006 Jun 15.
Chronic intermittent hypoxia (CIH) augments physiological responses to low partial pressures of O2 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% O2 followed by 5 min of 21% O2; 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% O2 followed by 20 h of 21% O2 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 microM) 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.
慢性间歇性缺氧（CIH）增强了机体对动脉血中低氧分压的生理反应。然而，成年大鼠的肾上腺髓质对急性缺氧的直接作用不敏感。在本研究中，我们探究了CIH是否会诱导成年大鼠肾上腺髓质产生低氧敏感性，如果是，其机制是什么。实验选用成年雄性大鼠，使其暴露于CIH（5%氧气持续15秒，随后21%氧气持续5分钟；每小时9次循环；每天8小时；持续3天或10天）或同等累积时长的持续性缺氧（CH；7%氧气持续4小时，随后21%氧气持续20小时，持续1天或10天）环境中。从离体肾上腺髓质监测去甲肾上腺素（NA）和肾上腺素（ADR）的流出量。在暴露于CIH的大鼠肾上腺髓质中，急性缺氧引发了强烈的NA和ADR流出，而在对照大鼠或暴露于CH 1天或10天的大鼠中则没有这些反应。高碳酸血症（10%二氧化碳；酸性，pH 6.8，或等氢离子浓度，pH 7.4）在引发对照、CIH或CH大鼠的儿茶酚胺（CA）流出方面无效。尼古丁（100微摩尔）在对照大鼠中引发了NA和ADR流出，而这种反应在CIH大鼠中被消除，但在CH大鼠中未被消除。全身给予2 - 脱氧葡萄糖使对照大鼠的ADR含量减少，而CIH减弱了这种反应，表明神经调节的CA分泌下调。CIH肾上腺髓质中的胞质和线粒体乌头酸酶活性降低，提示超氧阴离子生成增加。全身给予抗氧化剂可逆转CIH对肾上腺髓质的作用。暴露于CIH的大鼠血压升高且血浆CA升高，而抗氧化剂消除了这些反应。这些观察结果表明，CIH通过涉及超氧阴离子生成增加的机制诱导成年大鼠肾上腺髓质产生低氧感知，并提示肾上腺髓质缺氧诱发的CA流出部分促成了血压和血浆CA的升高。
