Circadian rhythms and sleep have additive effects on respiration in the rat

It is well established that sleep and breathing are functionally related. Changes in sleep-wake states are associated with changes in respiratory motor output, lung ventilation and metabolic rate in animals and man, and conversely, chemical and mechanical respiratory stimuli can elicit changes in sleep-wake state (Phillipson et al. 1977; Phillipson & Bowes, 1986). These mechanisms are implicated in a variety of sleep disorders, such as obstructive sleep apnoea and sleep-related hypoventilation, which are now recognised as a significant cause of morbidity and mortality in Western society (NCSDR, 1993; Phillipson, 1993). In some respiratory disorders, such as nocturnal asthma, the circadian timing system plays a substantial role in the aetiology of the disease, with an additional role for sleep-related mechanisms (Chan et al. 1988; Ballard et al. 1989, 1990). Thus, two separate but linked mechanisms may contribute to respiratory function and dysfunction: sleep mechanisms and circadian mechanisms. Little is known, however, about how the circadian system interacts with sleep-related mechanisms in this context. Recent research has implicated the circadian timing system in respiratory control in animals and man. It has been shown that minute ventilation oscillates with a 24 h period in rats maintained under a 12:12 h light:dark (LD) cycle, with sleep-wake state unknown (Seifert et al. 2000). In resting human subjects held under constant routine conditions (i.e. constant light, no sleep, and meals and other activities scheduled to a 2 h cycle), ventilation exhibited a circadian trend that bordered on statistical significance (Spengler et al. 2000). Furthermore, the respiratory chemoreflex, an important component of the respiratory control system, was found to exhibit significant circadian oscillation in awake healthy male subjects under constant routine conditions (Spengler et al. 2000; Stephenson et al. 2000), and in awake adult rats and birds under a LD cycle (Peever & Stephenson, 1997; Woodin & Stephenson, 1998). The amplitude of the circadian rhythm in respiratory control in awake human subjects was of significant magnitude (approximately 25 % of the mean), being comparable to the changes reported by others for transitions from wakefulness to sleep (Gothe et al. 1981; Douglas et al. 1982a; Stradling et al. 1985). Thus, most previous studies either measured ventilation in awake subjects (Raschke, 1987; Raschke & Moller, 1989; Spengler et al. 2000; Stephenson et al. 2000), or did not take sleep-wake state into account (Seifert et al. 2000). Schafer (1998) reported variable changes in hypercapnic ventilatory responses during ‘deep sleep’ from the first to the second half of the night in human subjects, suggesting that the circadian system may also influence respiratory control during non-rapid-eye-movement (NREM) sleep. This question clearly requires further study. Sleep normally occurs at approximately the same time each day, a manifestation of circadian control of sleep-wake timing (Czeisler et al. 1980; Dijk & Czeisler, 1995). This strong correlation between circadian time and sleep makes it difficult to separate their roles in respiratory function (and dysfunction). We chose to study the rat because this species exhibits a polyphasic (ultradian) sleep pattern allowing ventilation to be measured during wakefulness, non-rapid-eye-movement sleep and rapid-eye-movement sleep (REM) at all times of the day, without the need to manipulate behaviour. In the present study, we addressed the hypothesis that sleep and circadian rhythms have synergistic effects on respiration. We measured ventilation and metabolic rate during electrographically defined sleep-wake states as a function of time of day. Preliminary results from this study have been published (Liao et al. 2000).