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

Abstract

Chronic exposure to intermittent hypoxia (CIH) elicits plasticity of the carotid sinus and phrenic nerves via reactive oxygen species (ROS). To determine whether CIH-induced alterations in ventilation, metabolism, and heart rate are also dependent on ROS, we measured responses to acute hypoxia in conscious rats after 14 and 21 d of either CIH or normoxia (NORM), with or without concomitant administration of allopurinol (xanthine oxidase inhibitor), combined allopurinol plus losartan (angiotensin II type 1 receptor antagonist), or apocynin (NADPH oxidase inhibitor). Carotid body nitrotyrosine production was measured by immunohistochemistry. CIH produced an increase in the ventilatory response to acute hypoxia that was virtually eliminated by all three pharmacologic interventions. CIH caused a robust increase in carotid body nitrotyrosine production that was greatly attenuated by allopurinol plus losartan and by apocynin but unaffected by allopurinol. CIH caused a decrease in metabolic rate and a reduction in hypoxic bradycardia. Both of these effects were prevented by allopurinol, allopurinol plus losartan, and apocynin.

Effects of losartan and allopurinol on cardiorespiratory regulation in obstructive sleep apnoea

“…The major finding is that both drugs significantly lowered blood pressure during normoxic, eupnoeic breathing and during acute exposure to hypoxia without reducing sympathetic vasoconstrictor activity. In contrast to our hypotheses, based on previous findings in rats exposed to CIH (Dopp et al., ; Marcus et al., , ; Morgan et al., , b), the slopes of the chemoreflex and vasodilatory responses to acute hypoxia were not altered by losartan or allopurinol.…”

“…slow desaturations followed by rapid resaturations) that is ‘human like’ (Lim et al., ; Morgan et al., , b). Moreover, our CIH protocol is a good model for the cardiorespiratory consequences OSA, because both produce diurnal increases in arterial pressure (Becker et al., ; Fletcher, Lesske, Qian, Miller, & Unger, ; Marcus, Olson, Bird, Philippi, & Morgan, ), sympathetic activation (Carlson et al., ; Marcus et al., ), impaired endothelium‐dependent vasodilatation (Carlson et al., ; Phillips et al., ), increased arterial stiffness (Phillips, Hedner, Berend, & Grunstein, ; Phillips, Olson, Lombard, & Morgan, ), and evidence of oxidative stress (Lavie, ; Morgan et al., ). Accordingly, we believe that hypotheses based on our rat data were not upheld in humans, not because of a failure of the model per se , but rather because the total daily ‘dose’ of intermittent hypoxia in our rat model was more severe than in our human subjects, leading to more pronounced ventilatory and neurocirculatory impairments.…”

“…Chemoreflex sensitivity is enhanced after exposure to chronic intermittent hypoxia (CIH) in experimental animals (Del Rio, Andrade, Lucero, Arias, & Iturriaga, ; Marcus, Li, Bird, Schultz, & Morgan, ; Morgan, Adrian, Wang, Bates, & Dopp, ; Prabhakar, Peng, Kumar, & Nanduri, ), healthy humans (Pialoux et al., ; Tamisier et al., ) and humans with obstructive sleep apnoea (OSA; Mansukhani, Wang, & Somers, ; Narkiewicz et al., ). Increased generation of reactive oxygen species, such as superoxide, is thought to make an important contribution to this sensitization (Del Rio, Moya, & Iturriaga, ; Lim et al., ; Morgan, Bates, Rio, Wang, & Dopp, ; Pialoux et al., ; Semenza & Prabhakar, ). Potential sources of superoxide ion in the carotid body and other components of the extended chemoreflex arc include angiotensin II and xanthine oxidase.…”

“…Increased generation of reactive oxygen species, such as superoxide, is thought to make an important contribution to this sensitization (Del Rio, Moya, & Iturriaga, 2010;Lim et al, 2015;Morgan, Bates, Rio, Wang, & Dopp, 2016b;Pialoux et al, 2009;. Potential sources of superoxide ion in the carotid body and other components of the extended chemoreflex arc include angiotensin II and xanthine oxidase.…”

Contribution of Autonomic Reflexes to the Hyperadrenergic State in Heart Failure

“…In addition, it has been postulated that oxidative stress (i.e., increased ROS emission mainly from enhanced NADPH oxidase activity) is also central in activating chemoreceptors of the carotid bodies (Morgan et al, 2016). Oxidative stress is known to activate the carotid body in HF (Schultz et al, 2015).…”