Sleep Modulates Hypertension in Leptin-Deficient Obese Mice

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 ...

Control of cardiovascular variability during undisturbed wake-sleep behavior in hypocretin-deficient mice

“…Mice were instrumented with a frontoparietal differential electroencephalographic lead, a differential electromyographic lead from nuchal muscles, and a telemetric blood pressure transducer (TA11PAC10; Data Science International, Tilburg, The Netherlands), as described in detail elsewhere (31). Recordings were performed for 3 days on mice undisturbed and freely behaving in their own cages after a minimum of 11 days of postsurgical recovery and habituation.…”

“…Scoring of wake-sleep states (wakefulness, NREMS, and REMS) was performed visually on the basis of raw electroencephalographic and electromyographic recordings with 4-s resolution as described in detail elsewhere (31). We took care to avoid including even brief arousals within sleep episodes.…”

“…We took care to avoid including even brief arousals within sleep episodes. In particular, episodes of electroencephalographic desynchronization and/or sustained increases in nuchal muscle tone lasting more than 2 s (i.e., half a 4-s epoch) amidst sleep epochs were scored as wakefulness or as an indeterminate state (31). Episodes of REMS at sleep onset representing cataplexy-like states in rodents were scored following consensus criteria (25) and excluded from all analyses.…”

“…Values of HP were computed as the time intervals between the onset of successive systolic upstrokes of blood pressure, i.e., between the minimum value of a pulse wave and the minimum value of the following one. The 4-s epochs, in which errors in the automatic detection of the minima and maxima of the pulse waves produced artifactual values of HP or SBP, were identified and excluded from subsequent analysis with a semiautomated procedure (31). The spontaneous fluctuations of SBP and HP were analyzed on all artifact-free episodes of wakefulness, NREMS, and REMS of duration Ն60 s that occurred during the recording period.…”

Integration of metabolic and cardiovascular diurnal rhythms by circadian clock

“…In leptin-deficient ob/ob mice, which develop obesity, diabetes, and dyslipidemia, the diurnal rhythm in blood pressure is significantly attenuated [48]. Furthermore, leptin receptor-deficient db/db animals exhibit dampened rhythms of Bmal1 expression in the aortic tissue, as well as a disrupted rhythm in blood pressure [49,50].…”