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Chronic lack of hypocretin signaling may entail consequences on blood pressure that are potentially adverse and that vary widely among wake-sleep states.

Cortelli P. Sleep-dependent changes in the coupling between heart period and blood pressure in human subjects. We investigated whether in human subjects, the pattern of coupling between the spontaneous fluctuations of heart period (HP) and those of systolic blood pressure (SBP) differs among wake-sleep states. Polysomnographic recordings and finger blood pressure measurements were performed for 48 h in 15 nonobese adults without sleep-disordered breathing. The cross-correlation function (CCF) between the fluctuations of HP and SBP at frequencies Ͻ0.15 Hz was computed during quiet wakefulness (QW), light (stages 1 and 2) and deep (stages 3 and 4) nonrapid-eye-movement sleep (NREMS), and rapid-eye-movement sleep (REMS). A positive correlation between HP and the previous SBP values, which is the expected result of baroreflex feedback control, was observed in the sleep states but not in QW. In deep NREMS, the maximum CCF value was significantly higher than in any other state, suggesting the greatest baroreflex contribution to the coupling between HP and SBP. A negative correlation between HP and the subsequent SBP values was also observed in each state, consistent with the mechanical feed-forward action of HP on SBP and with central autonomic commands. The contribution of these mechanisms to the coupling between HP and SBP, estimated from the minimum CCF value, was significantly lower in deep NREMS than either in light NREMS or QW. These results indicate that the pattern of coupling between HP and SBP at low frequencies differs among wake-sleep states in human subjects, with deep NREMS entailing the highest feedback contribution of the baroreflex and a low effectiveness of feed-forward mechanisms.feedback and feed-forward mechanisms; baroreflex; central autonomic commands; cross-correlation analysis; sequence technique THE PATTERN OF COUPLING BETWEEN the spontaneous fluctuations of heart period (HP) and those of blood pressure indicates the contribution of different mechanisms to cardiovascular control during real-life behavior. In particular, a positive correlation between HP and the previous pressure values is the expected result of the arterial baroreflex, which acts as a delayed negative-feedback control (37). In turn, the fluctuations of HP may alter cardiac output, eliciting pressure fluctuations that are negatively correlated with them. Central autonomic commands (15) cause opposite changes in HP and vascular resistance (13), thereby apparently enhancing this feed-forward interaction.In animal models, the pattern of coupling between HP and blood pressure suggests a variable contribution of central and baroreflex mechanisms to cardiovascular control in different wake-sleep states (33,34,39). The baroreflex contribution appears most prominent during quiet sleep in lambs (33) and during nonrapid-eye-movement sleep (NREMS) in rats (34,39). On the other hand, in rapid-eye-movement sleep (REMS), the contribution of feed-forward mechanisms prevails in rats due to central autonomic commands (6,34,39), which manifest a...

The central neural pathways underlying the physiological coordination between thermoregulation and the controls of the wake-sleep behavior and cardiovascular function remain insufficiently understood. Growing evidence supports the involvement of hypocretin (orexin) peptides in behavioral, cardiovascular, and thermoregulatory functions. We investigated whether the effects of ambient temperature on wake-sleep behavior and cardiovascular control depend on the hypothalamic neurons that release hypocretin peptides. Orexin-ataxin3 transgenic mice with genetic ablation of hypocretin neurons (n = 11) and wild-type controls (n = 12) were instrumented with electrodes for sleep scoring and a telemetric blood pressure transducer. Simultaneous sleep and blood pressure recordings were performed on freely-behaving mice at ambient temperatures ranging between mild cold (20°C) and the thermoneutral zone (30°C). In both mouse groups, the time spent awake and blood pressure were higher at 20°C than at 30°C. The cold-related increase in blood pressure was significantly smaller in rapid-eye-movement sleep (REMS) than either in non-rapid-eye-movement sleep (NREMS) or wakefulness. Blood pressure was higher in wakefulness than either in NREMS or REMS at both ambient temperatures. This effect was significantly blunted in orexin-ataxin3 mice irrespective of ambient temperature and particularly during REMS. These data demonstrate that hypocretin neurons are not a necessary part of the central pathways that coordinate thermoregulation with wake-sleep behavior and cardiovascular control. Data also support the hypothesis that hypocretin neurons modulate changes in blood pressure between wakefulness and the sleep states. These concepts may have clinical implications in patients with narcolepsy with cataplexy, who lack hypocretin neurons.

Abstract-Leptin increases sympathetic activity, possibly contributing to hypertension in obese subjects. Hypertension increases cardiovascular mortality, with nighttime (sleep) blood pressure having a substantial prognostic value. We measured blood pressure in male leptin-deficient obese mice (ob/ob; nϭ7) and their lean wild-type littermates (ϩ/ϩ; nϭ11) during wakefulness, non-rapid-eye-movement sleep, and rapid-eye-movement sleep to investigate whether, in the absence of leptin, derangements of blood pressure are still associated with obesity and depend on the wake-sleep state. Mice were implanted with a telemetric pressure transducer and electrodes for discriminating wake-sleep states. Mean blood pressure was significantly higher in ob/ob than in ϩ/ϩ mice during wakefulness (7.3Ϯ2.6 mm Hg) and non-rapid-eye-movement sleep (6.7Ϯ2.8 mm Hg) but not during rapid-eye-movement sleep (2.6Ϯ2.6 mm Hg). In ob/ob and ϩ/ϩ mice, mean blood pressure was substantially higher during wakefulness than during non-rapid-eye-movement sleep. On passing from non-rapid-eye-movement sleep to rapid-eye-movement sleep, mean blood pressure decreased significantly in ob/ob but not in ϩ/ϩ mice. The time spent during wakefulness was lower in ob/ob than in ϩ/ϩ mice during the dark (active) period, whereas the opposite occurred during the light (rest) period. Consequently, mean blood pressure was significantly higher in ob/ob than in ϩ/ϩ mice during the light (8.2Ϯ2.4 mm Hg) but not during the dark (3.0Ϯ2.9 mm Hg) period. These data suggest that, in the absence of leptin, obesity may entail hypertensive derangements of blood pressure, which are substantially modulated by the cardiovascular effects of the wakesleep states. Key Words: arterial pressure Ⅲ behavior Ⅲ heart rate Ⅲ hypertension Ⅲ obesity Ⅲ investigative techniques Ⅲ mice O besity is a threat to health care because it is rapidly increasing in prevalence 1 and is associated with hypertension and cardiovascular risk. 2 The hormone leptin signals the abundance of fat stores and acts on the hypothalamus to mount adaptive adjustments of energy balance. 3 Leptin also increases sympathetic activity and blood pressure (BP). 4 -6 Diet-induced obesity entails hyperleptinemia and resistance to the anorectic but not to the cardiovascular effects of leptin, 7 which may, thus, contribute to obesityrelated hypertension. 8,9 Mutations that cause a lack of leptin or leptin receptors cause morbid obesity, 3 allowing us to disentangle the cardiovascular correlates of obesity from those of hyperleptinemia. Although values of BP in the hypertensive range have been reported in obese subjects with congenital leptin deficiency, 10 evidence of hypertension is not consistent in this rare form of obesity. 11 Evidence is inconsistent also on obese mice with congenital impairment of leptin signaling, in which either hypotensive 12-14 or hypertensive 15-17 derangements of BP have been reported. In these mice, the occurrence 15 or severity 17 of hypertension vary between the light and dark periods, which entail ...