Sleep fragmentation impairs ventilatory long‐term facilitation via adenosine A1 receptors

Abstract

Sleep fragmentation (SF), a primary feature of obstructive sleep apnoea (OSA), impairs hippocampal long-term potentiation and causes cognitive/attention deficits. However, its influence upon respiratory control has hardly been studied. This study examined the effect of SF on ventilatory long-term facilitation (LTF, a persistent augmentation of respiratory activity after episodic hypoxia) and the hypoxic ventilatory response (HVR), and investigated the role of adenosine A1 receptors in these SF effects in conscious adult male Sprague-Dawley rats. SF, confirmed by sleep architecture recordings, was achieved by periodic, forced locomotion in a rotating drum (30 s rotation/90 s stop for 24 h). LTF, elicited by five episodes of 5 min poikilocapnic hypoxia (10% O 2 ) with 5 min intervals, was measured by plethysmography. Resting ventilation and metabolic rate were unchanged, HVR was reduced (150.6 ± 3.5% versus 110.4 ± 12.3%) and LTF was eliminated (22.6 ± 0.5% versus −0.1 ± 1.3%) shortly after 24 h SF. The SF-induced impairments were SF duration dependent, and completely reversible as HVR (< 24 h) and LTF (< 48 h) returned spontaneously to their pre-SF values. The SF-impaired HVR was improved (130.3 ± 4.2%) and SF-eliminated LTF was restored (19.6 ± 0.9%) by systemic injection of the adenosine A1 receptor antagonist 8-CPT (2.5 mg kg −1 ) ∼30 min before LTF elicitation. Both HVR and LTF were also similarly impaired by 24 h total sleep deprivation or 24 h repeated cage tapping-induced SF, but not by a 24 h locomotion control protocol for SF. Collectively, these data suggest that: (1) 24 h SF impairs LTF and poikilocapnic HVR; (2) these impairments require A1 receptors; and (3) SF of OSA may exacerbate OSA via impaired ventilatory control mechanisms.

Sleep fragmentation attenuates the hypercapnic (but not hypoxic) ventilatory responses via adenosine A1 receptors in awake rats

“…The 24 h SF was achieved by periodic, forced locomotion (30 s rotation followed by 90 s stop) at a speed of ~1.5 rotation/min for a 24 h period (started at 08.00 h and ended at 08.00 h on the following morning), as previously described (McGuire et al, 2008b). This SF protocol successfully produced up to ~30 sleep interruptions per hour (McGuire et al, 2008b), a frequency often observed in OSA patients (Wiegand and Zwillich, 1994). Before SF treatment, rats were given 2 days to acclimatize to the drum (~30 min periodic rotation in each day).…”

“…The 24 h LC treatment was also achieved by periodic, forced locomotion in the same drums as previously described (McGuire et al, 2008b). Both rotation and stop times were lengthened (15 min rotation/45 min stop) to allow for deep and consolidated sleep during the 45 min stop periods.…”

“…A recent study in our laboratory has demonstrated that ventilatory long-term facilitation is eliminated and poikilocapnic HVR is attenuated shortly after 24 h SF, and that the SF-impaired ventilatory long-term facilitation and poikilocapnic HVR are restored and improved, respectively, by systemic adenosine A1 receptor antagonism (McGuire et al, 2008b). In that study, however, PaCO 2 was not controlled and HCVR was not measured.…”

The effect of intermittent hypoxia on obstructive sleep apnea: beneficial or detrimental?

“…It has been postulated that repeated hypocapnia between OSA events might inhibit LTF expression in OSA patients (12). However, it should be noted that hypercapnia will always occur concomitant with hypoxia during OSA events, and LTF, if elicited, is quite resilient to various disturbances in rats (13), although recent findings suggest it may be impacted by sleep deprivation/sleep fragmentation (14).…”

Effects of Total Sleep Deprivation on Mouse Cytokine Levels

“…Forty-eight-hour TSD (from 09: 00 to 09: 00) was achieved by slowly rotating the wheels at a constant speed (0.3 m/min) [16][17][18] . Three controls were used in the experiment.…”