Intermittent Hypoxia and Its Consequences

Besides the acutely occurring disruptions of both breathing and sleep, OSA is inevitably associated with recurrent periods of hypoxia. We use rats chronically exposed to cyclic variations of ambient oxygen to mimics recurrent hypoxic episodes experienced by OSA patients (chronic-intermittent hypoxia, or IH) to determine the effects of IH on various central and peripheral regulatory functions. The record here shows the acute effect of cyclic hypoxic stimulus on respiratory activity of intercostal muscles and respiratory rate in a urethane-anesthetized rat. In these experiments, we elicit about 20% decrease in oxyhemoglobin saturation which is comparable to the conditions in severe OSA patients.

Kubin Figure 14

We determined that rats exposed to IH of such a pattern and magnitude for 10 h/day for 35 days, have increased levels of mRNAs for several inhibitory receptors in the perifornical region of the posterior hypothalamus, a region that plays an important role in the regulation of both sleep and metabolism.

Kubin Figure 15We also determined that 35 days of IH leads to sprouting of noradrenergic, and to a lesser extent, serotonergic terminals within the hypoglossal (XII) motor nucleus. This may explain the adaptive increase in baseline activity of upper airway muscles that characterizes OSA patients during wakefulness (Rukhadze et al., Am. J. Respir. Crit. Care Med. 182:1321-1329, 2010; full text: PDF).

Kubin Figure 16Importantly, we found that rats exposed to IH for 35 days have profoundly suppressed counter-regulatory release of insulin from the pancreas elicited by a glucose bolus. This phenomenon appears to replicate the glucose intolerance conditions commonly observed in OSA patients (Fenik et al., Front. Neurol. 3 (Article 51):1-13, 2012; full text: PDF).