Chronic Intermittent Hypoxia Induces Hypoxia Evoked Catecholamine Efflux In Adult Rat Adrenal Medulla Via Oxidative Stress
Authors: Ganesh K. Kumar, Vandana Rai, Suresh D. Sharma, Devi Prasadh Ramakrishnan, Ying-Jie Peng, Dangjai Souvannakitti and Nanduri R. Prabhakar
DOI / Source: https://doi.org/10.1113/jphysiol.2006.112524
Date: 14 June 2006
Reading level: Advanced
Why This Matters for Freedivers
This paper supports the idea that repeated low-oxygen exposures can change how your stress systems respond, and that the pattern (intermittent bursts) matters more than total hypoxia time. While it’s a rat study (so it doesn’t map 1:1 to training), it’s a strong reminder that stacking frequent hypoxic stress can push the body toward higher catecholamines and blood-pressure effects — and that recovery and overall stress load (sleep, illness, fatigue) likely matter more than divers sometimes assume.
Synopsis
Freedivers often use repeated breath-holds as training, and many people also experience repeated low-oxygen episodes in real life through sleep apnea. This study looks at what repeated intermittent hypoxia (short bursts of low oxygen over many days) does to a key stress organ: the adrenal medulla, which releases adrenaline and noradrenaline. In adult animals, the adrenal medulla normally doesn’t respond directly to acute hypoxia very much — it typically needs nerve input. The researchers asked: can chronic intermittent hypoxia “rewire” it so it starts reacting directly to low oxygen? 
They exposed adult rats to intermittent hypoxia cycles (very low oxygen for 15 seconds, then normal oxygen for 5 minutes, repeated over 8 hours/day) for either 3 or 10 days, and compared this with rats exposed to a similar total amount of continuous hypoxia. Then they tested adrenal glands outside the body and measured how much adrenaline/noradrenaline “leaked out” when the tissue was exposed to acute hypoxia. The key result was striking: after 10 days of intermittent hypoxia, acute hypoxia suddenly triggered strong catecholamine release, but this did not happen after 3 days and did not happen with continuous hypoxia. So it wasn’t “hypoxia in general” — it was the intermittent pattern that caused the change. 
They then chased the mechanism and found evidence pointing to oxidative stress, especially superoxide (a reactive oxygen species). Aconitase activity (a classic oxidative-stress-sensitive enzyme) dropped in the adrenal tissue after intermittent hypoxia, suggesting more reactive oxygen species were being generated. Most convincing: when rats were treated with antioxidants (including a superoxide-dismutase mimetic or N-acetylcysteine), the “new” hypoxia-triggered catecholamine release was prevented, and the associated rise in blood pressure and plasma catecholamines was reduced or abolished. In short, intermittent hypoxia caused a stress-system “upgrade” driven by oxidative stress — making the adrenal medulla more reactive to low oxygen episodes.
Abstract
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 μM) 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.