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nTS ROS contribute to acute intermittent hypoxia-induced phrenic and sympathetic LTF

      Cardiorespiratory neural networks undergo alterations in function (plasticity) that are critical to homeostasis but can be deleterious, as in obstructive sleep apnea. Intermittent exposure to acute hypoxia (AIH) in rats produces prolonged increases in ventilatory/phrenic and sympathetic activity (pLTF, sLTF) and augmented hypoxia (Hx) responses post-AIH. LTF involves local spinal cord mechanisms. However, carotid body denervation decreases pLTF suggesting chemoafferent input contributes. The nTS integrates and modulates cardiorespiratory input and undergoes plasticity due to changes in afferent input, including to Hx. nTS reactive oxygen species (ROS) are increased by intermittent Hx and important for plasticity. We hypothesized the nTS is critical to generation and maintenance of LTF via increased ROS. Anesthetized, vagotomized, paralyzed, ventilated rats were exposed to AIH (10X; 10% O2, 45s, every 5 min); arterial pressure and phrenic and splanchnic sympathetic nerve activity were recorded. AIH was preceded or followed by inhibition of nTS activity by bilateral microinjection of the GABA receptor agonist muscimol, or aCSF. To assess effects of nTS ROS, separate rats underwent AIH following bilateral nTS microinjection of antioxidant catalase (CAT, 500 U/ml; 60nl) prior to each Hx bout or following chronic nTS overexpression of human catalase (AdCAT). Under control, AIH produced pLTF and sLTF, and augmented Hx responses. Overall nTS inhibition with muscimol significantly reversed AIH-induced LTF and blunted its development. Furthermore, reducing nTS ROS acutely (CAT microinjection) or chronically (CAT overexpression) attenuated pLTF, sLTF and augmented Hx responses. Data suggest nTS ROS contribute to phrenic and sympathetic LTF. HL98602.
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