Chronic intermittent hypoxia alters ventilatory and metabolic responses to acute hypoxia in rats

Abstract

We determined the effects of chronic exposure to intermittent hypoxia (CIH) on chemoreflex control of ventilation in conscious animals. Adult male Sprague-Dawley rats were exposed to CIH [nadir oxygen saturation (SpO2), 75%; 15 events/h; 10 h/day] or normoxia (NORM) for 21 days. We assessed the following responses to acute, graded hypoxia before and after exposures: ventilation (V̇e, via barometric plethysmography), V̇o2 and V̇co2 (analysis of expired air), heart rate (HR), and SpO2 (pulse oximetry via neck collar). We quantified hypoxia-induced chemoreceptor sensitivity by calculating the stimulus-response relationship between SpO2 and the ventilatory equivalent for V̇co2 (linear regression). An additional aim was to determine whether CIH causes proliferation of carotid body glomus cells (using bromodeoxyuridine). CIH exposure increased the slope of the V̇e/V̇co2/SpO2 relationship and caused hyperventilation in normoxia. Bromodeoxyuridine staining was comparable in CIH and NORM. Thus our CIH paradigm augmented hypoxic chemosensitivity without causing glomus cell proliferation.

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia

“…Oxidative stress generated by cyclical hypoxia and reoxgenation is thought to play a causative role in these forms of respiratory plasticity affecting the afferent and efferent arms of the carotid chemoreflex (Del Rio et al, 2010; Peng et al, 2009; Peng and Prabhakar, 2003). CIH-induced augmentations in chemoreflex control of ventilation have also been demonstrated in intact, unanesthetized animals (Julien et al, 2008; Morgan et al, 2016; Peng et al, 2006b; Reeves et al, 2003). …”

“…Ad libitum access was provided to drinking water and standard chow (Harlan Teklad #8604). Data from 10 normoxic control rats included herein were published in a previous report (Morgan et al, 2016). Experiments were carried out in accordance with recommendations set forth in the National Institutes of Health Guide for Care and Use of Laboratory Animals (NIH Publication #8023, revised 1978).…”

“…The effects of daily drug treatments alone (prior to CIH exposure) on ventilatory responses to acute hypoxia were assessed after one wk of treatment. Data from drug-treated, CIH-exposed rats were compared with those from rats exposed to normoxia without drug treatment (n=10) that were previously published (Morgan et al, 2016). To determine whether longer-term treatments would affect ventilatory responses to acute hypoxia, a separate group of normoxic control rats (n=6) received allopurinol plus losartan for 28 d.…”

“…The immunoreactive intensity, averaged from eight fields for each sampled carotid body, was expressed as optical integrated intensity. This analysis was performed on carotid bodies harvested from 5 rats in each treatment and exposure group with the exception of the NORM-exposed, untreated control rats that were part of a previous study (Morgan et al, 2016). …”

HIF1α and physiological responses to hypoxia are correlated in mice but not in rats

“…Mice and rats are commonly used for studies of respiratory control, and while we are not aware of systematic comparisons between the two species, both have been found to show robust respiratory responses mediated by peripheral chemoreceptors upon exposure to acute hypoxia (Izumizaki et al, 2004;Marcouiller et al, 2014;Morgan et al, 2016;Roux et al, 2000;Soliz et al, 2005). In contrast, long-term exposure to hypoxia (days to weeks) induces a long-term plasticity of the respiratory control system (ventilatory acclimatization to hypoxia), in which hypoxia-inducible factor 1 (HIF-1) plays a key role (Kline et al, 2002;Powell and Fu, 2008;Prabhakar and Semenza, 2012).…”