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

No abstract

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 ...

This study assessed whether sleep-dependent changes in the relationship between heart period (HP) and mean arterial pressure (MAP) occur in newborn life. Electrodes for electrocorticographic, electromyographic, and electrooculographic monitoring and an arterial catheter for blood pressure recordings were implanted in 11 newborn lambs. HP and MAP beat-to-beat values were computed from 120-s blood pressure recordings during quiet wakefulness, active sleep, and quiet sleep. For each recording, the time shift at which the maximum of the HP versus MAP cross-correlation function was attained was identified. For each lamb and wake-sleep state, an average correlation coefficient was then computed corresponding to the median value of such time shifts. The maximum of the cross-correlation function was attained with HP lagging behind MAP. The corresponding mean correlation coefficient was significantly higher in quiet sleep (0.51 Ϯ 0.05) than either in quiet wakefulness (0.31 Ϯ 0.05) or in active sleep (0.29 Ϯ 0.03). Sleep-related differences in the correlation between HP and MAP were maintained after HP and MAP data were low-pass filtered at 0. The regulation of systemic arterial pressure plays an essential role in homeostasis, as it permits coupling of blood flow to tissue metabolic needs while avoiding excessive rises in microvessel transmural pressure. Central autonomic commands, in supporting an actual or expected behavior [e.g. exercise (3), defense reaction (4)], may induce parallel changes in heart rate and in systemic vascular resistance. In adult rats, baroreflex control of heart rate prevails in quiet sleep, whereas central commands prevail in active sleep (5,6). Although effects of central autonomic commands on heart rate and arterial pressure are similar in wakefulness and in active sleep, the cause of such commands is uncertain in the latter state. Thus, central autonomic commands that occur in active sleep give rise to regulatory disturbances rather than to anticipatory regulation, as it occurs during wakefulness. It is unclear whether these conclusions apply to animals during early postnatal development, whose cardiovascular regulation undergoes functional maturation and differs in many respects from that of older animals (7-12).The aim of our study was to assess whether the relationship between heart period (HP) and arterial pressure changes during sleep in newborn lambs. We analyzed the relationship between HP and mean arterial pressure (MAP) in the time domain by Received February 11, 2004; accepted July 6, 2004

We investigated whether the relative contribution of the baroreflex and central commands to the control of heart period differs between spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive rats (WKY) during physiological behavior. Rats were instrumented with an arterial catheter and with electrodes for discriminating wakefulness, nonrapid eye movement sleep (NREMS), and rapid eye movement sleep (REMS). The cross-correlation function (CCF) between spontaneous fluctuations of heart period and mean arterial pressure was computed at frequencies <0.2 Hz. The baroreflex determines a positive correlation between heart period and previous pressure values. This pattern was observed in the CCF during quiet wakefulness (QW) and NREMS, and in QW, it was accompanied by a pronounced negative correlation between heart period and subsequent pressure values. The relative baroreflex contribution to the control of heart period, estimated from the positive peak value of the CCF, was lower in SHR than in WKY during QW but not during NREMS. During REMS, the CCF showed a negative correlation between heart period and both previous and subsequent pressure values, reflecting the prevalence of central autonomic commands. The relative contribution of central commands to the control of heart period, estimated from the negative peak value of the CCF, was lower in SHR than in WKY during REMS. These results suggest that during QW and REMS, the control of heart period exerted by the baroreflex and central commands, respectively, is less effective in SHR than in WKY. This difference is not apparent in a behavioral state of autonomic stability such as NREMS.