Sleep and bodily functions: the physiological interplay between body homeostasis and sleep homeostasis.

Body homeostasis and sleep homeostasis may both rely on the complex integrative activity carried out by the hypothalamus. Thus, the three main wake-sleep (WS) states (i.e. wakefulness, NREM sleep, and REM sleep) may be better understood if the different cardio-respiratory and metabolic parameters, which are under the integrated control of the autonomic and the endocrine systems, are studied during sleep monitoring. According to this view, many physiological events can be considered as an expression of the activity that physiological regulations should perform in order to cope with the need to fulfill body and sleep homeostasis. This review is aimed at making an assessment of data showing the existence of a physiological interplay between body homeostasis and sleep homeostasis, starting from the spontaneous changes observed in the somatic and autonomic activity during sleep, through evidence showing the deep changes occurring in the central integration of bodily functions during the different WS states, to the changes in the WS states observed when body homeostasis is challenged by the external environment and when the return to normal ambient conditions allows sleep homeo- stasis to run without apparent physiological restrictions. The data summarized in this review suggest that an approach to the dichotomy between NREM and REM sleep based on physiological regulations may offer a framework within which observations that a traditional behavioral approach may overlook can be interpreted. The study of the interplay between body and sleep homeostasis appears, therefore, to be a way to understand the function of complex organisms beyond that of the specific regulations.

Central and baroreflex control of heart rate during the wake-sleep cycle in rat.

UNLABELLED: Spontaneous fluctuations in Heart Period (HP) and Mean Arterial Pressure (MAP) make it possible to evaluate baroreceptor-heart rate reflex sensitivity (BRS). 30-s sequences of HP and MAP beat-to-beat values were considered in the different wake-sleep states (Wake, W; Quiet Sleep, QS; Active Sleep, AS) in rats to assess whether 1) BRS changes between states and 2) the different indexes supply consistent BRS measures. BRS indexes were calculated according to validated literature procedures as regression coefficients of HP vs. MAP 1) within all ramps of increasing or decreasing MAP of four beats or more, with HP and MAP changing in the same direction (baroreflex-mediated fluctuations, BRSp), 2) within all such ramps irrespective of the relative direction of HP and MAP changes (baroreflex + non-baroreflex, i.e. non-homeostatic centrally driven, fluctuations, BRSA). HP vs. MAP regression coefficient along the entire 30-s sequence (bHPMAP) was also calculated. RESULTS: BRSp did not change among states, BRSA decreased from QS to W to AS, bHPMAP decreased from QS to W and became negative in AS. CONCLUSIONS: 1) as indicated by BRSp, baroreflex sensitivity is state independent, 2) BRSp to BRS(A) to bHPMAP are increasingly affected by non-baroreflex fluctuations, BRSp being most apt to measure BRS, 3) non-homeostatic MAP and HP fluctuations increase from QS to W and prevail in AS. These potentially harmful fluctuations are normally buffered by baroreflexes: in the case of baroreflex impairment, circulatory risk may arise in conditions like AS, when they prevail.

Nitric oxide inhibition abolishes sleep-wake differences in cerebral circulation.

Nitric oxide (NO), being produced by active neurones and also being a cerebral vasodilator, may couple brain activity and blood flow in sleep, particularly during active sleep (AS), which is characterized by widespread neural activation and markedly elevated cerebral blood flow (CBF) compared with quiet wakefulness (QW) and quiet sleep (QS). This study examined CBF and cerebral vascular resistance (CVR) in lambs (n = 6) during spontaneous sleep-wake cycles before and after infusion of N(omega)-nitro-L-arginine (L-NNA), an inhibitor of NO synthase. L-NNA infusion produced increases in CVR and decreases in CBF during all sleep-wake stages, with the greatest changes occurring in AS (DeltaCVR, 88 +/- 19%; DeltaCBF -24 +/- 8%). The characteristic CVR and CBF differences among AS, QS, and QW disappeared within 1-3 h of L-NNA infusion, but had reappeared by 24 h despite persisting cerebral vasoconstriction. These experiments show that NO promotes cerebral vasodilatation during sleep as well as wakefulness, particularly during AS. Additionally, NO is the major, although not sole, determinant of the CBF differences that exist between sleep-wake states.

Interindividual differences in the thermoregulatory response to cool exposure in sleeping neonates.

The responses of the thermoregulatory effectors vary greatly among neonates. Therefore, we assume that a small decrease in air temperature from thermoneutrality induces various thermoregulatory responses within neonates that represent an energy cost due to the cold defence processes. To determine the importance of this variability in nursing, 26 neonates were explored at thermoneutrality and in a cool environment (-1.5 degrees C from thermoneutrality) similar to that which occurs currently in clinical procedure. Oxygen consumption (VO2), oesophageal and skin temperatures, as well as sleep parameters were recorded continuously in both conditions. Analysis of all of the data from all of the neonates revealed that the cool exposure induced thermal and sleep disturbances, but VO2 did not increase and was not negatively correlated to body temperature (as might be expected). Analyses of individual data showed large variability in body temperature regulation: the neonates could be assigned to one of three groups according to the direction of the individual slopes of VO2 versus oesophageal or skin temperature. The groups also differed according to the sleep changes recorded in the cool condition. The results show that the definition of thermoneutrality should be revised by incorporating non only changes in the body temperature, but also the sleep disturbances (increased wakefulness and active sleep, decreased quiet sleep), which are criteria that are more sensitive to mild cool exposure. Thermoneutrality should be defined for each individual, since the results stress that the variability does not help to predict a general pattern of thermoregulatory responses in cool-exposed neonates.

Density of perfused brain capillaries in the aged rat during the wake-sleep cycle.

Structural and functional age-related changes in brain vasculature might affect the cerebral microcirculation. The present study evaluated the density of perfused brain capillaries and the perfusion fraction (perfused/existing capillaries) in aged rats (24 months) during the states of the wake-sleep cycle (quiet wakefulness, quiet sleep, active sleep) characterized by different levels of brain activation. The number of perfused capillaries was determined by intravascular injection of the fluorescent marker Evans Blue; histochemical staining of the capillary endothelium identified the alkaline-phosphatase (AP) reactive quota of the anatomical population. No sleep-related changes in perfused capillary density were found, and the perfusion fraction in the AP-stained sub-population was high and stable (95%) across the sleep-wake cycle: changing levels of brain activation during sleep do not affect functional capillary density in aged rats.

Cerebral circulation in REM sleep: is oxygen a main regulating factor?

In the transition from NREM to REM sleep, as in other instances of brain activation, a marked increase in cerebral blood flow and glucose uptake is observed, together with a lesser increase in O2 uptake. Brain activation also entails an increase in capillary PO2 and lactate production. The hypothesis of saturation of the oxidative machinery was advanced to explain anaerobic glycolysis and lactate production in the presence of high PO2, but data are available that cannot be explained by this hypothesis: hypoxic spots exist in the brain, augmenting in arterial hypoxia and disappearing in arterial hyperoxia, while tissue [H+] lowers as arterial PO2 increases beyond 100 mmHg. Additional hypotheses are thus required. We suggest that O2 diffusion limitation exists in the brain: microregions lying at mid-distance between capillaries may become hypoxic and partly resort to anaerobic glycolysis. These microregions are thought to enlarge with increasing metabolic rate or arterial hypoxia and give rise to vasodilatatory signals regulating local blood flow. REM sleep time is strongly reduced by hypoxic and increased by hyperoxic atmosphere, in accordance with the existence of an O2 diffusion limitation. Any pathological decrease in arterial PO2 and/or O2 delivery creates a specific risk in REM sleep.

Cerebral blood flow regulation in REM sleep: a model for flow-metabolism coupling.

The pattern of metabolic and circulatory changes occurring during REM sleep in the whole brain is also observed at a regional level in different instances of functional activation. This pattern is characterized by an increase in metabolic rate, blood flow, glucose and oxygen uptake, the increase in glucose uptake generally exceeding oxygen uptake. A model of interpretation is presented, based on the assumption that substantial limitation to oxygen diffusion exists in the brain. According to the model, microregions lying at mid-distance between capillaries may become hypoxic, depending on metabolic rate and blood-cell PO2 difference. At increasing metabolic rates, O2 consumption in pericapillary microregions increases and the PO2 drop becomes steeper. As a consequence, in microregions far from capillaries a decrease in O2 availability occurs, in concomitance with the increase in metabolic rate, so that non-oxidative glucose metabolism develops locally. A similar spatial PO2 pattern forms in the case of arterial hypoxia, when capillary PO2, and then blood-cell PO2 difference, is reduced. The hypoxic microregions are the source of vasodilatatory messages, the consequent vasodilatation increasing average capillary PO2 and then favoring O2 diffusion to the tissue. Oxygen thus appears to be a better candidate than glucose as a mediator of blood flow-metabolism coupling. This is supported by its higher extraction fraction and by the fact that, in physiologic conditions, arterial hypoxia (and not hypoglycemia) acts on cerebral blood flow. Moreover, the diffusion capacity of glucose in the brain is higher than that of oxygen, so that diffusion limitation is more likely to occur for oxygen. The present model allows consistent organization of the stereotyped changes in cerebral blood flow and glucose and oxygen uptake occurring both in REM sleep and in other instances of brain activation.

Brain capillary perfusion during sleep.

Brain capillary perfusion was evaluated in the different states of the wake-sleep cycle-quiet wakefulness (QW), quiet sleep (QS), and active sleep (AS)-in rats. The extent of the perfused capillary network was determined by intravascular distribution of a fluorescent marker. Evans blue (EB); it remained unchanged across the three behavioral conditions, QW, QS, and AS. The anatomical network was assessed by alkaline phosphatase (AP) endothelial staining, which is known to underestimate the number of existing capillaries. The resulting number of AP profiles were, therefore, significantly lower than the number of EB profiles, but the percentage of AP-stained capillaries that were perfused (96%) was also unchanged across the behavioral conditions. The results indicate that no capillary recruitment accompanies the wake-sleep cycle. Capillary surface area is a relevant factor in determining exchanges across the blood-brain barrier. In the absence of capillary recruitment (relative constancy of the surface area), the CBF changes during sleep should preferentially affect flow-limited with respect to diffusion-limited transport.

Gastric emptying of solids in morbid obesity.

OBJECTIVE: To evaluate the effect of weight loss induced by dietetic treatment, with or without an intragastric balloon, on gastric emptying of obese subjects. SUBJECTS: 20 morbidly obese subjects (21-54 years, 45.3-58.0 kg/m2) and 20 healthy controls (21-56 years, 20.3-24.8 kg/m2). DESIGN: Parallel study of a 4 month, low calorie dietetic treatment with or without a 500 ml intragastric balloon. RESULTS: In basal conditions, obese subjects had accelerated gastric emptying as compared to healthy controls. At the end of the dietetic treatment period, a significant decrease of body weight was obtained. Patients also showed a slowing of gastric emptying. Both the weight loss and the slowing of gastric emptying occurred irrespective of the presence or absence of the intragastric balloon. CONCLUSION: The present findings are compatible with the hypothesis that gastric emptying, food intake and body weight are integrated parameters in subjects with morbid obesity.

Brain blood flow and extracerebral carotid circulation during sleep in rat.

Cerebral blood flow (CBF) and blood flow (BF) in extracerebral head structures were measured during the sleep-wake cycle in rats using radioactive microspheres. While no statistically significant changes occurred in the transition from Waking to quiet sleep (also referred to as synchronized or non-REM Sleep), CBF increased significantly in active sleep (AS, also referred to as desynchronized or REM Sleep) in all structures considered, with the sole exception of the cerebellum. In extracerebral head structures, no significant state-dependent BF changes were found. Factor Analysis however extracted a common factor accounting for BF variability in the external carotid circulation. This factor was uncorrelated with CBF changes in AS, suggesting independent regulation of the two vascular beds in this sleep state.

Spinal cord blood flow changes during the sleep-wake cycle in rat.

Regional spinal cord blood flow was measured in rats during the sleep-wake cycle with the use of radioactive microspheres. Spinal cord blood flow decreases from wakefulness to quiet (synchronized) sleep while increasing in active (desynchronized) sleep. Blood-flow changes depend on changes in vascular resistance whose mechanisms have yet to be elucidated. Blood-gas tension or mean arterial pressure, however, do not play a relevant causal role.

Shivering during sleep: relationship between muscle blood flow and fiber type composition.

The present study considers in rabbit: i) the relationship between muscle blood flow (BF) increase and fiber-type composition during shivering; ii) the influence of the vigilance states (Quiet Wakefulness, QW; Synchronized Sleep, SS; Desynchronized Sleep, DS) on this relationship. The results show that muscle BF increase during shivering is proportional to the slow-twitch oxidative (SO) fiber component in QW and SS; in DS the proportionality is lost. This is in accordance with the disappearance of shivering, together with all thermoregulatory effector responses, in this sleep state. Another muscle circulation pattern occurring at low ambient temperature, the relationship between BF increase and muscle depth, also disappears in DS. This confirms that the integrative control of muscle circulation, like other integrative mechanisms, is impaired during DS.

Loss of integrative control of peripheral circulation during desynchronized sleep.

Regional blood flow (BF) changes during sleep were measured in rabbits at low, neutral, and high ambient temperatures (Ta) with radioactive microspheres. At both low and high Ta, peripheral vasomotor changes at the onset of desynchronized sleep (DS) were incompatible with thermoregulatory homeostasis. At low Ta, BF decreased in muscle (with the disappearance of shivering), whereas it increased in the arteriovenous anastomoses (AVA) and in the splanchnic bed. At high Ta, BF decreased in muscle (with the disappearance of panting) and in the AVA, whereas it increased in the splanchnic bed. An impaired central nervous regulation underlies the disruption of peripheral circulation patterns in this sleep stage. The lack of adaptive vasomotor adjustments in DS, which has little consequence in normal conditions, may become relevant in cardiovascular pathophysiology when BF redistribution through increased neurogenic vasomotor activity becomes a major compensating mechanism.

Mechanisms of action of the intragastric balloon in obesity: effects on hunger and satiety.

We evaluated the effect of a 500-ml intragastric balloon (Ballobes) on some aspects of eating-related behaviour and weight loss on nine massively obese patients. An 800-kcal mixed meal test was performed some days before, 2-3 days and 2 months after the implant of the balloon. A hypocaloric program was started after the second meal test. At hourly intervals, before and after the meal, patients were asked to rate the desire to eat, hunger, satiety and prospective consumption of food. After 2 months, weight loss was 12.0 +/- 5.1 kg. A significant decrease in the balloon diameters was observed, but none completely deflated. During the meal test performed 2-3 days after the implant, subjects rated themselves as significantly less hungry, fuller and desiring to eat less food. These patterns, however, returned to the baseline levels at the meal test performed after 2 months. No relationship was found between weight loss and reduction in the balloon diameters, nor between the latter and the changes in temporal profiles of eating ratings. The effect of a 500-ml balloon on meal-related hunger and satiety therefore seems to disappear with time.

Regional splanchnic blood flow during sleep in the rabbit.

Regional splanchnic blood flow (rSBF) was measured in rabbits with the radioactive microsphere technique. No statistically significant changes occurred in rSBF or vascular conductances in relation to the different states of the sleep-waking cycle (quiet-wakefulness, synchronized sleep, and desynchronized sleep).

Antibodies to Campylobacter pylori in patients with idiopathic dyspepsia.

We used Western Blotting analysis to determine the immune profile to Campylobacter pylori polypeptides in: A) sera from patients with idiopathic dyspepsia and bacteriological evidence of C. pylori gastric colonization, B) sera from patients with the same symptoms but no bacteriological evidence of C. pylori infection and C) healthy subjects. To avoid interference of aspecific reactions due to antigenic cross reactivity with other thermophilic Campylobacter species, antisera were raised in rabbits against C. pylori as well as against C. coli and C. jejuni. Some bands (with an approximate molecular weight of 118, 85, 40, 34, 28, 18 and 12 Kd) which can be considered specific for C. pylori were identified and the IgG reaction to some of them (40, 34, 28 Kd) was shown to be significantly higher in patients with bacteriological evidence of C. pylori infection than in the other two groups. IgM reactivity to two bacterial proteins of molecular weight 118 and 40 Kd was particularly evident in the second group of patients suggesting a possible diagnostic tool to identify C. pylori infection at a very early stage.