Circadian rhythmicity and sleep homeostasis interact to regulate sleep-wake cycles [1-4], but the genetic basis of individual differences in sleep-wake regulation remains largely unknown [5]. PERIOD genes are thought to contribute to individual differences in sleep timing by affecting circadian rhythmicity [6], but not sleep homeostasis [7, 8]. We quantified the contribution of a variable-number tandem-repeat polymorphism in the coding region of the circadian clock gene PERIOD3 (PER3) [9, 10] to sleep-wake regulation in a prospective study, in which 24 healthy participants were selected only on the basis of their PER3 genotype. Homozygosity for the longer allele (PER3(5/5)) had a considerable effect on sleep structure, including several markers of sleep homeostasis: slow-wave sleep (SWS) and electroencephalogram (EEG) slow-wave activity in non-rapid eye movement (non-REM) sleep and theta and alpha activity during wakefulness and REM sleep were all increased in PER3(5/5) compared to PER3(4/4) individuals. In addition, the decrement of cognitive performance in response to sleep loss was significantly greater in the PER3(5/5) individuals. By contrast, the circadian rhythms of melatonin, cortisol, and peripheral PER3 mRNA expression were not affected. The data show that this polymorphism in PER3 predicts individual differences in the sleep-loss-induced decrement in performance and that this differential susceptibility may be mediated by its effects on sleep homeostasis.

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Viola AU, James LM, Archer SN, Dijk DJ. PER3 polymorphism and cardiac autonomic control: effects of sleep debt and circadian phase. Am J Physiol Heart Circ Physiol 295: H2156 -H2163, 2008; doi:10.1152/ajpheart.00662.2008.-A variable number tandem repeat polymorphism in the coding region of the circadian clock PERIOD3 (PER3) gene has been shown to affect sleep. Because circadian rhythms and sleep are known to modulate sympathovagal balance, we investigated whether homozygosity for this PER3 polymorphism is associated with changes in autonomic nervous system (ANS) activity during sleep and wakefulness at baseline and after sleep deprivation. Twenty-two healthy participants were selected according to their PER3 genotype. ANS activity, evaluated by heart rate (HR) and HR variability (HRV) indexes, was quantified during baseline sleep, a 40-h period of wakefulness, and recovery sleep. Sleep deprivation induced an increase in slow-wave sleep (SWS), a decrease in the global variability, and an unbalance of the ANS with a loss of parasympathetic predominance and an increase in sympathetic activity. Individuals homozygous for the longer allele (PER3 5/5 ) had more SWS, an elevated sympathetic predominance, and a reduction of parasympathetic activity compared with PER3 4/4 , in particular during baseline sleep. The effects of genotype were strongest during nonrapid eye movement (NREM) sleep and absent or much smaller during REM sleep. The NREM-REM cycle-dependent modulation of the low frequency-to-(low frequency ϩ high frequency) ratio was diminished in PER3 5/5 individuals. Circadian phase modulated HR and HRV, but no interaction with genotype was observed. In conclusion, the PER3 polymorphism affects the sympathovagal balance in cardiac control in NREM sleep similar to the effect of sleep deprivation. clock gene; autonomic nervous system; cardiovascular risk; slow wave activity GENETIC FACTORS have been identified as playing an important role in many physiological processes, especially those involved in cardiovascular control (5,10,34,46,57). Heart rate (HR) variability (HRV), defined as the variation in the interval between consecutive heart beats, is modulated by the autonomic nervous system and is an indicator of clinically relevant cardiovascular phenotypes. Reduced HRV is an independent predictor of cardiac disease and cardiac mortality (3,14,15,23,27,33,40,51). The primary explanation for this predictive effect is that reduced HRV reflects a shift in the cardiac sympathovagal balance from parasympathetic to sympathetic control over the autonomic nervous system (35, 45). Vigilance state and endogenous circadian phase are major modulators of the autonomic nervous system. Sympathetic activity is higher during wakefulness than sleep, and, within sleep, the sympathetic contribution is greater in rapid eye movement (REM) sleep than in deep non-REM (NREM) sleep (7, 56). During continuous wakefulness under controlled behavioural conditions, HRV is not constant but varies with circadian phase such that global HRV is great...

Rationale: Histamine and dopamine contribute to the maintenance of wakefulness.Objective: Exploratory analysis of the effects of 10 and 50 mg of MK-0249, a novel histamine subtype-3 receptor inverse agonist, and 200 mg of modafinil, a presumed dopaminergic compound, on EEG power spectra during sleep deprivation and subsequent recovery sleep. Methods: 25 healthy men were recruited to a double-blind placebocontrolled cross-over design. EEG power spectra, an electrophysiological marker of changes in sleepiness and vigilance, were obtained at the beginning of wake maintenance tests at 2 hourly intervals throughout a night and day of sleep deprivation, which is an established model of excessive sleepiness. Results: After placebo, sleep deprivation was associated with enhancements in delta, theta and reductions in alpha and beta activity.Following dosing at 02:00, MK-0249 and modafinil reduced delta and theta activity and enhanced alpha and beta activity, compared to placebo. During recovery sleep initiated at 21:00 h, latency to sleep onset, and number of awakenings were not different from placebo for any of the active treatments. Wake after sleep onset and stage 1 % was increased and total sleep time, SWS % and REM% were reduced after both doses of MK-0249. Compared to placebo, MK-0249 and the 50 mg dose in particular, reduced activity in some delta and theta/alpha frequencies and enhanced beta activity during NREM sleep and REM sleep.After modafinil, no changes were observed for power spectra during sleep. Conclusion: both MK-0249 and modafinil exert effects on the EEG which are consistent with wake promotion.

AMPA receptor modulation is a potential novel approach to enhance cognitive performance. CX717 is a positive allosteric modulator of the AMPA receptor that has shown efficacy in rodent and primate cognition models. CX717 (100 mg, 300 mg and 1000 mg) and placebo were studied in 16 healthy male volunteers (18-45 years) in a randomized, crossover study. Cognitive function, arousal and recovery sleep (by polysomnography) were assessed during the extended wakefulness protocol. Placebo condition was associated with significant decrements in cognition, particularly at the circadian nadir (between 03:00 and 05:00). Pre-specified primary and secondary analyses (general linear mixed modelling, GLMM) at each separate time point did not reveal consistent improvements in performance or objective alertness with any dose of CX717. Exploratory repeated measures analysis, a method used to take into account the influence of individual differences, demonstrated an improvement in attention-based task performance following the 1000 mg dose. Analysis of the recovery sleep showed that CX717 1000 mg significantly reduced stage 4 and slow-wave sleep (p ≤ 0.05) with evidence of reduced electroencephalogram (EEG) slow-wave and spindle activity. The study suggests that CX717 only at the 1000 mg dose may counteract effects of sleep deprivation on attention-based tasks and that it may interfere with subsequent recovery sleep.

Background A lung transplant is the last resort treatment for many patients with advanced lung disease. The majority of donated lungs come from donors following brain death (BD). The endothelin axis is upregulated in the blood and lung of the donor after BD resulting in systemic inflammation, lung damage and poor lung graft outcomes in the recipient. Tezosentan (endothelin receptor blocker) improves the pulmonary haemodynamic profile; however, it induces adverse effects on other organs at high doses. Application of ex vivo lung perfusion (EVLP) allows the development of organ-specific hormone resuscitation, to maximise and optimise the donor pool. Therefore, we investigate whether the combination of EVLP and tezosentan administration could improve the quality of donor lungs in a clinically relevant 6-h ovine model of brain stem death (BSD). Methods After 6 h of BSD, lungs obtained from 12 sheep were divided into two groups, control and tezosentan-treated group, and cannulated for EVLP. The lungs were monitored for 6 h and lung perfusate and tissue samples were processed and analysed. Blood gas variables were measured in perfusate samples as well as total proteins and pro-inflammatory biomarkers, IL-6 and IL-8. Lung tissues were collected at the end of EVLP experiments for histology analysis and wet-dry weight ratio (a measure of oedema). Results Our results showed a significant improvement in gas exchange [elevated partial pressure of oxygen (P = 0.02) and reduced partial pressure of carbon dioxide (P = 0.03)] in tezosentan-treated lungs compared to controls. However, the lungs hematoxylin–eosin staining histology results showed minimum lung injuries and there was no difference between both control and tezosentan-treated lungs. Similarly, IL-6 and IL-8 levels in lung perfusate showed no difference between control and tezosentan-treated lungs throughout the EVLP. Histological and tissue analysis showed a non-significant reduction in wet/dry weight ratio in tezosentan-treated lung tissues (P = 0.09) when compared to control. Conclusions These data indicate that administration of tezosentan could improve pulmonary gas exchange during EVLP.

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