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Sleep and the Peripheral Vascular System☆
Sleep and the Peripheral Vascular Systemq G Zoccoli, A Silvani, and C Franziniy, University of Bologna, Bologna, Italy Ó 2017 Elsevier Inc. All rights reserved.
Cerebral Circulation Cerebral BF Changes During Sleep Mechanisms of Cerebral BF Regulation During Sleep: Beyond Flow-Activity Coupling Cutaneous Circulation Renal and Splanchnic Circulation Skeletal Muscle Circulation Coronary Circulation OSA and Peripheral Circulation Sleep Loss and Peripheral Circulation Further Reading
2 2 2 3 4 4 4 5 5 5
Glossary Arterial blood pressure surges Phasic increases of arterial blood pressure appearing in physiologic conditions during rapid eye movement (REM) sleep and depending on central neural mechanisms. Blood-brain barrier (BBB) Interface between the peripheral circulation and the central nervous system consisting of the cerebral microvascular endothelium with tight junctions between endothelial cells and of surrounding astrocytes, pericytes, and neurons. It controls the exchange of substances between blood and brain tissue. Cerebral autoregulation Mechanisms maintaining cerebral blood flow stable in the face of changes in arterial blood pressure by adjusting cerebrovascular resistance. Flow-activity coupling Mechanism linking changes in neuronal activity and energy usage of the tissue with changes in cerebral blood flow.
Hypocretins (orexins) Neuropeptides produced by neurons in the lateral hypothalamus that are involved in stimulating food intake and wakefulness and controlling energy metabolism. Obstructive sleep apnea (OSA) Repetitive pauses in breathing occurring during sleep because of upper airway obstruction. Episodes of sleep apnea are usually associated with a reduction in blood oxygen saturation. Peripheral vascular system A system of intertwining arteries, capillaries, and veins which carries blood from and to the heart and the lungs. Sleep inertia A physiological transitional state characterized by a lowered arousal occurring immediately after awakening from sleep and producing a temporary decrement in performance.
Sleep processes involve the body as well as the brain. Blood flow (BF) to different organs matches specific metabolic requirements, which vary with behavioral states of the wake-sleep cycle: wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. On the other hand, changes in BF are obtained through changes in arterial blood pressure (ABP) and vascular resistance, which, in turn, depend on autonomic output to heart and blood vessels. Autonomic cardiovascular control results from the interaction between reflex mechanisms, such as the baroreflex, the chemoreflex, and thermoregulation, and central autonomic commands specific to each sleep state. Thus, sleep-related changes in peripheral circulation depend jointly on changes in organ metabolic rate and on autonomic activity to the heart and blood vessels. The direction and magnitude of sleep-dependent changes in BF to a given vascular bed result from the complex interaction among local systemic reflex, and central autonomic mechanisms. In the following paragraphs, the physiological sleep-dependent changes in the cerebral circulation and in extracerebral vascular districts will be reviewed. Whenever possible, the focus will be aimed at translation from animal models to humans and at the mechanisms of the observed circulatory changes. Effects of sleep-related respiratory derangements and sleep loss on the peripheral circulation will also be summarized.
q
Change History: November 2015. Prof. Carlo Franzini, one of the co-authors passed away in 2015.
y
Carlo Franzini is now deceased.
Reference Module in Neuroscience and Biobehavioral Psychology
http://dx.doi.org/10.1016/B978-0-12-809324-5.00964-0
1
2
Sleep and the Peripheral Vascular System
Cerebral Circulation Cerebral BF Changes During Sleep A substantial body of evidence on animal models and humans demonstrates that overall cerebral BF differs widely between the behavioral states of the wake-sleep cycle. The key mechanism involved is probably a coupling between cerebral vascular resistance and neural activity because cerebral BF is tightly related to glucose and oxygen consumption, which, in turn, mainly reflects synaptic activity during sleep as well as during wakefulness (flow-activity coupling). On the other hand, sleep-dependent changes in cerebral BF are largely independent of systemic hemodynamic changes, which redistribute BF among other systemic vascular beds (cerebral autoregulation). In humans, cerebral BF decreases during NREM sleep compared with previous wakefulness. Results on animal models are less consistent: cerebral BF decreases during NREM sleep in lambs, while no significant differences or even BF increases have been reported during NREM sleep in rats and rabbits. These inconsistencies probably depend on the lack of stringent criteria to discriminate very quiet wakefulness from sleep onset in animal models. In humans, the decrease in cerebral BF during NREM sleep is more pronounced in the thalamus and brainstem, which are involved either actively or permissively in the generation of electroencephalographic (EEG) slow waves. BF also significantly decreases during NREM sleep in the basal forebrain and hypothalamus, which are involved in sleep generation and modulation of cortical activation. At the cortical level, the BF reduction during NREM sleep is most pronounced in the orbital prefrontal and anterior cingulated cortex. At least in part, these reductions in BF appear related to the reduced metabolic cost of synchronized bursting patterns of activation during NREM sleep. Accordingly, BF in the ventromedial prefrontal regions is negatively correlated with EEG d-power during NREM sleep. During REM sleep, studies on different species and with different techniques consistently report that cerebral BF tonically increases with respect to NREM sleep. Interestingly, evidence on rabbits suggests that this BF increase is achieved preferentially by increasing vertebral artery BF at the expense of common carotid artery BF, which actually decreases during REM sleep in this species. On the other hand, experiments performed at high temporal resolution on lambs reveal that during REM sleep, phasic surges of cerebral BF are superimposed on a tonic cerebral BF increase. These BF surges are initiated by cerebrovascular dilatation and sustained by surges of ABP, which are a physiological feature of REM sleep in different animal models and humans. At a regional level, the increase in BF during REM sleep is most prominent in the pontine tegmentum, dorsal mesencephalon, thalamic nuclei, amygdala, and in the anterior cingulated and entorhinal cortex. The BF increase in the dorsal ponto-mesencephalic region during REM sleep points to the role of this area in REM sleep generation. Interestingly, some neurons of this region project monosynaptically to thalamic nuclei, which are also activated in REM sleep. On the other hand, amygdaloid complexes interact with the anterior cingulated and entorhinal cortex, and their activation may contribute to emotional memory processing during REM sleep. Conversely, BF in the precuneus and the posterior cingulated, parietal, and dorsolateral prefrontal cortex is lower than average during REM sleep. Thus, deactivation involving higher-order heteromodal association cortices appears a defining characteristic of sleep itself, being common to both NREM and REM states. The process of awakening entails a rapid restoration of BF to wakefulness levels in the brain stem and thalamus, suggesting that reactivation of these regions is involved in the reestablishment of consciousness. In heteromodal neocortical areas, conversely, BF takes 5–20 min to rise to wakefulness levels after awakening from sleep. This time lag may be linked to dissipation of sleep inertia. However, the fact that BF values in cortical and limbic structures are lower during wakefulness more than 15 min after sleep than during wakefulness before sleep appears in accordance with a restorative function of sleep, at least as far as these brain structures are concerned. While brain circulation has been extensively studied during sleep in humans and animal models, spinal cord circulation during sleep has received much less attention. Available data indicate that sleep-dependent changes in spinal cord BF are substantial and generally parallel those in cerebral BF. In particular, spinal cord BF increases during REM sleep with respect to NREM sleep in rabbits and rats, whereas it decreases during NREM sleep with respect to quiet wakefulness in rats only. This discrepancy concerning NREM sleep may depend on behavioral species differences, with rats being more active than rabbits during wakefulness. Flow-activity coupling is not as well documented in the spinal cord as it is in the brain during sleep. Lumbar motor neurons undergo a modest hyperpolarization on passing from wakefulness to NREM sleep, with further hyperpolarization occurring in REM sleep. This hyperpolarization results from increased activity of inhibitory spinal interneurons. Clearly, it is not possible to infer overall sleepdependent changes in spinal cord neural activity from these data, and no data are available on spinal cord metabolic activity during sleep. These issues are worth experimental clarification, as they may lead to the demonstration that sleep modulates the activity of the central nervous system as a whole.
Mechanisms of Cerebral BF Regulation During Sleep: Beyond Flow-Activity Coupling Brain metabolism depends on a continuous circulatory supply of glucose and oxygen to neurons and astrocytes. In astrocytes, glucose is partly converted to lactate, which is then released in the extracellular space and taken up by neurons. In neurons, pyruvate arising from both glucose and lactate is used oxidatively. With neuronal activity, lactate oxidation increases. Glutamate reuptake by astrocytes activates glucose utilization and lactate production and release. Lactate produced by astrocytes during neuronal activation may therefore sustain neuronal energy needs as activation persists. To be transported into the brain, blood glucose must cross the blood–brain barrier (BBB) through specific carriers. It has been hypothesized that with physiological brain activation, such as occurs in REM sleep, glucose supply to the brain is increased by promoting glucose transport across the BBB. Contrary to this hypothesis,
Sleep and the Peripheral Vascular System
3
neither the capillary surface area available for blood–brain diffusion nor BBB permeability to glucose is higher in REM sleep than in wakefulness in rats despite a 29% increase in cerebral BF. Therefore, a modulation of glucose transport through the BBB is not a mechanism that provides energy on demand during the physiological brain activation that characterizes REM sleep. Glutamate signaling processes may play a role in the local regulation of cerebral BF during sleep. In particular, glutamateevoked calcium influx in postsynaptic neurons may activate production of nitric oxide (NO), adenosine, and arachidonic acid metabolites, which, in turn, cause vasodilation. Accordingly, experiments performed on lambs demonstrate that the NO synthase inhibitor N-nitro-L-arginine (L-NNA) reduces cerebral BF during all wake-sleep states and particularly (24%) during REM sleep. Intriguingly, the physiological sleep-dependent differences in cerebral BF are abolished within 1–3 h of L-NNA infusion, to reappear by 24 h. NO is also key in mediating the early cerebral vasodilation, which initiates phasic surges of cerebral BF during REM sleep. These data indicate that NO promotes cerebral vasodilation during sleep as well as during wakefulness, that the role played by NO is greatest during REM sleep, and that NO is a major, although not the sole, determinant of the sleep-dependent differences in cerebral BF. Cerebral blood vessels receive a rich sympathetic innervation. Recent evidence on lambs indicates that activity of these sympathetic fibers strongly increases during REM sleep and, particularly, during phasic episodes of this sleep state, when phasic increases in sympathetic activity to cerebral blood vessels precede the onset of ABP surges by 12 s. These phasic increases in sympathetic activity do not prevent the early cerebrovascular dilatation that initiates cerebral BF surges in phasic REM sleep, likely because of the substantial time delay and time constant of sympathetic control of vascular resistance. However, the phasic increases in sympathetic activity do limit cerebrovascular dilatation at the time of maximum ABP increase, thus protecting against potentially dangerous phasic rises in microcirculatory pressure and perfusion during REM sleep. As far as the neural control of the cerebral circulation is concerned, it is worth remembering that diffuse aminergic and cholinergic projections to the cerebral cortex may drive widespread vasoconstriction or vasodilation. These projections originate from brain structures, such as the locus coeruleus, brainstem raphe nuclei, and basal forebrain, which differ widely in activity between wake and sleep states. These diffuse aminergic and cholinergic projections may thus play a role in modulating BF in wide cortical areas as a function of the wake-sleep behavior. The effects of changes in systemic ABP on cerebral BF are buffered by cerebral autoregulation during sleep, although the effectiveness of these local regulatory mechanisms varies between wake-sleep states. Accordingly, in newborn lambs, a 50% reduction in cerebral perfusion pressure induces cerebral vasodilation both in NREM sleep and in REM sleep, as expected as a result of autoregulation of cerebral BF. However, the speed and magnitude of this vascular response are lower during REM sleep than either in NREM sleep or wakefulness. During REM sleep, moreover, the lower breakpoint of the autoregulation curve is shifted to the right relative to NREM sleep and wakefulness. This peculiar vulnerability of the cerebral circulation to hypotension during REM sleep may be because tonic cerebral vasodilation in this state limits the vasodilatatory reserve available for BF autoregulation. On the other hand, experiments on lambs indicate that during REM sleep, cerebral BF follows tightly the variability in cerebral perfusion pressure, which, in turn, is the greatest during this sleep state. During quiet wakefulness and particularly during NREM sleep, conversely, spontaneous fluctuations in cerebral BF are largely independent and in excess of those in cerebral perfusion pressure, suggesting the occurrence of synchronized vasomotor fluctuations in the cerebral circulation. These results are of interest because mathematical modeling demonstrates that synchronized vasomotion may facilitate oxygen diffusion to the tissue, thus helping to match perfusion to local metabolic needs during wakefulness and NREM sleep. During wakefulness, cerebral BF is very sensitive to changes in the arterial partial pressures of oxygen and carbon dioxide: a decrease in the former and an increase in the latter cause reductions in cerebrovascular resistance and, hence, increases in cerebral BF. During sleep, however, the cerebrovascular responses to hypercapnia and isocapnic hypoxia are drastically reduced, placing the brain at risk for hypoperfusion. This is particularly relevant considering that nocturnal hypoxia and hypercapnia are characteristic of cardiorespiratory diseases such as obstructive sleep apnea (OSA) or congestive heart failure. Arousal from sleep may thus represent a protective response, but it has been demonstrated that repeated hypoxia and even hypercapnic hypoxia become ineffective in evoking arousal during REM sleep. In contrast, hypercapnia per se appears not to become less effective as an arousing stimulus with repetition.
Cutaneous Circulation The cutaneous circulation ensures heat exchange between the body and the environment. Skin BF mainly reflects this key role played by the skin in thermoregulation. In rabbits, on passing from wakefulness to NREM sleep, skin vasodilation accompanies the decrease in the set point of body temperature. In humans, skin vasodilator activity is unchanged on passing from wakefulness to NREM sleep. However, skin temperature, which indirectly depends on the control of cutaneous circulation, is higher during the night than during the day, causing skin warming and dissipation of body heat during sleep. Skin temperature during sleep increases especially in the distal skin areas, which are usually cooler than the proximal ones during wakefulness. Interestingly, this pattern of skin vasomotion is impaired in narcoleptic patients, possibly contributing to their low core temperature. Narcolepsy is a rare sleep disorder associated with a selective loss of hypothalamic hypocretin (orexin)-producing neurons. The hypocretin system not only regulates the wake-sleep cycle, but also plays a role in metabolic and autonomic functions, which include sleep-dependent cardiovascular control. These data thus raise the hypothesis that hypothalamic hypocretin neurons are involved not only in mediating the sleep-dependent changes in skin circulation, but also more generally in linking thermoregulation to circulatory control.
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Sleep and the Peripheral Vascular System
A substantial body of evidence indicates that thermoregulation is impaired in REM sleep. In this state, the impairment of thermoregulatory processes entails the loss of vasomotor patterns reflexly driven by ambient temperature and, hence, the occurrence of paradoxical changes in skin BF. In particular, in a cold environment, thermoregulation physiologically causes skin vasoconstriction, which is accompanied by vasoconstriction in the splanchnic and renal beds and by vasodilation in the skeletal muscle bed. However, on passing from NREM sleep to REM sleep, skin BF increases because of the decrease in thermoregulatory neurogenic vasoconstriction combined with an increase in ABP. On the contrary, during exposition to warm ambient temperature, thermoregulation physiologically entails skin vasodilation, which is accompanied by vasoconstriction in the splanchnic and renal beds. However, on passing from NREM sleep to REM sleep, skin BF decreases because of a drop in thermoregulatory neurogenic vasodilation combined with a decrease in ABP.
Renal and Splanchnic Circulation BF measurements in renal and splanchnic districts on animal models do not evidence significant BF changes on passing from quiet wakefulness to NREM sleep. However, it should be noted that in rats, kidney BF is higher during NREM sleep than in active wakefulness despite a decrease in ABP because of a substantial decrease in renal vascular resistance. This difference in renal vascular resistance between NREM sleep and active wakefulness is, at least in part, because of a corresponding difference in renal sympathetic nerve activity. Renal sympathetic nerve activity further decreases in the transition from NREM sleep to REM sleep, together with a further increase in renal BF. Mesenteric vascular resistance and BF also tend to decrease and to increase, respectively, on passing from NREM sleep to REM sleep. It should be kept in mind that as discussed in the previous paragraph, the renal and splanchnic vascular beds play a role in the integrated pattern of vasomotor adjustments resulting from a thermal load. Thus, during REM sleep, when impairment of hypothalamic control disrupts the thermoregulatory distribution of cardiac output that exists in NREM sleep, there is a drop in sympathetic vasomotor tone, increasing splanchnic and renal BF with respect to NREM sleep both at low and high ambient temperatures. Finally, REM sleep entails the disappearance of the negative correlation between arterial and portal blood supply, which guarantees the constancy of total liver BF. Thus, during REM sleep, an increase in hepatic arterial BF is not compensated by a corresponding decrease in portal venous BF, and vice versa, as it physiologically occurs during wakefulness and NREM sleep. The finely tuned regulation of liver blood supply may be lost during REM sleep because of the conspicuous irregularities in respiratory and cardiovascular activity that characterize this sleep state.
Skeletal Muscle Circulation Changes in somatomotor activity are a distinctive feature of sleep: skeletal muscle activity is lower in NREM sleep than in wakefulness, whereas muscle atonia and phasic muscle twitches characterize REM sleep. Accordingly, data on animal models demonstrate that BF to most skeletal muscle groups, and particularly to the diaphragm, is lower during sleep than during wakefulness. Nonetheless, skeletal muscle BF may not change significantly in the transition from quiet wakefulness to NREM sleep. On the other hand, on passing from NREM sleep to REM sleep, iliac vascular resistance and iliac BF increase and decrease, respectively, in rats. These sleepdependent differences in skeletal muscle BF are driven, in part, by local metabolic changes. Skeletal muscles are composed of fibers with different types of metabolic requirements: slow, oxidative red fibers, and fast, glycolytic white fibers. Accordingly, sleepdependent changes in skeletal muscle BF in rabbits and cats depend on muscle fiber composition. In particular, during NREM sleep, BF is high in red fibers and low in white fibers. Conversely, during REM sleep, BF decreases in red fibers and increases or does not show significant changes in white fibers. Changes in muscle BF during REM sleep may be because the increased activity of white fibers secondary to twitching causes local vasodilation, while the decreased activity of red fibers secondary to atonia causes local vasoconstriction, which may or may not be significant with respect to NREM sleep depending on the muscle tone in the latter state. Sympathetic efferent activity to the skeletal muscle vascular bed also plays a major role in driving sleep-dependent changes in skeletal muscle BF. In humans, muscle sympathetic nerve activity decreases on passing from wakefulness to NREM sleep and increases again on passing from NREM sleep to REM sleep. Lumbar sympathetic nerve activity also increases substantially on passing from NREM sleep to REM sleep in rats, this increase explaining most of the corresponding increase in iliac vascular resistance. This evidence thus emphasizes that during REM sleep, sympathetic outflow to different vascular beds is highly heterogeneous. This view is consistent with data obtained during REM sleep-like states in decerebrated cats: a decrease in renal, splanchnic, and cardiac sympathetic activity is accompanied by an increase in sympathetic activity to skeletal muscles irrespective of vagotomy, sino-aortic denervation, or pharmacological paralysis, pointing to a central repatterning of sympathetic activity specific of REM sleep.
Coronary Circulation Changes in coronary BF parallel changes in cardiac metabolism. In dogs, significant decreases in heart rate and left coronary BF occur during NREM sleep with respect to previous wakefulness together with increases in coronary vascular resistance. During REM sleep, coronary BF not only returns tonically to wakefulness levels, but also undergoes phasic surges. During intensely phasic periods of REM sleep, these increases in coronary BF may occur after transient pauses in heart rhythm. Phasic bursts of neurogenic cholinergic
Sleep and the Peripheral Vascular System
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vasodilation may underlie these episodes, which show a clear mismatch between coronary BF and myocardial metabolism. Phasic increases in coronary BF during REM sleep are also coupled with bursts of sinus tachycardia. These coronary BF surges are mediated by the sympathetic nervous system, being eliminated by sympathectomy, and their magnitude parallels that of the concomitant heart rate surges. It may thus be hypothesized that during REM sleep, phasic increases in sympathetic efferent activity to the heart trigger a sequence of increased heart rate causing increased myocardiac metabolism, which, in turn, leads to phasic increases in coronary artery BF. However, when tonic coronary BF is experimentally reduced by occluders placed around the left circumflex coronary artery, the phasic bursts of tachycardia during REM sleep do not entail phasic increases in coronary BF, but rather phasic reductions in coronary BF because of reduced diastolic perfusion time.
OSA and Peripheral Circulation In OSA, the upper airways repeatedly become constricted or occluded during sleep, leading to episodes of decreased or absent airflow, hypoxia, and sympathetic activation. OSA may favor the development of hypertension, coronary disease, heart failure, stroke, and cardiac arrhythmias. The prevalence of OSA increases markedly with increasing adiposity, but obesity and OSA are considered independent risk factors for cardiovascular diseases. The physiological hemodynamic changes that occur in normal subjects during sleep do not occur in patients with OSA. The normal decreases in heart rate, ABP, and cardiac output during NREM sleep are lost in OSA patients, who show high sympathetic activity when awake and further increases in ABP and sympathetic activity during sleep. Cerebral hemodynamics are abnormal in patients with OSA. Cerebral BF fluctuates in response to sleep apneas, with an increase in intracranial pressure and a decrease in cerebral perfusion occurring during airways obstruction. Compared with baseline cerebral BF during sleep before apneas, cerebral BF increases up to 15% a few seconds after apnea termination, and decreases 25% 20 s after apnea. Cerebral autoregulation and cerebral vasodilator responses to hypercapnia may also be altered in patients with OSA. Endothelial dysfunction has been identified in pathological conditions such as atherosclerosis, hypertension, and OSA. Mediators produced by the endothelium, and in particular NO, are known to be important in the regulation of coronary BF. The recent development of a model of coronary endothelial dysfunction in lambs may shed light on the role of endothelial-derived vasodilator substances in modulating coronary BF during OSA. These research issues may have clinical relevance. Accordingly, OSA patients show nocturnal changes in electrocardiographic ST segment, which may be related to increased myocardial oxygen demand during postapneic surges in ABP and heart rate at a time when hemoglobin saturation is low. Indeed, the occurrence of a transient uncoupling between coronary BF and myocardial work following OSA has been recently demonstrated in humans, potentially promoting nocturnal myocardial ischemia in patients with OSA.
Sleep Loss and Peripheral Circulation Both sleep deprivation and insomnia have been linked to increased incidence of hypertension and are associated with cardiovascular morbidity and coronary events. Short sleep duration increases the risk for future coronary disease. Recent data indicate that the coronary BF velocity reserve is significantly lower after sleep deprivation (<4 h sleep) than after normal sleep even in healthy subjects without coronary risk factors. Experimental sleep restriction often entails an increase in ABP, which is not associated with muscle sympathetic vasoconstriction, tachycardia, or changes in circulating catecholamine levels. However, as previously discussed with reference to REM sleep, sympathetic outflow to different cardiovascular effectors may be highly heterogeneous. Spectral analysis of heart rate variability indeed indicates that sleep deprivation increases the sympathetic modulation of heart rhythm. Therefore, it remains possible that the cardiovascular effects of sleep deprivation result from increases in sympathetic activity to vascular beds different from skeletal muscles. Finally, it is worth remarking that a growing body of evidence suggests a link between the increased cardiovascular morbidity associated with sleep loss and inflammation. Even in healthy subjects, acute total sleep deprivation induces a significant increase in inflammatory markers, such as tumor necrosis factor, interleukin-1 (IL-1), IL-1 receptor antagonist, IL-6, and C-reactive protein. A high level of these substances could be linked to the development of endothelial dysfunction and consequent cardiovascular disease.
Further Reading Franzini, C., 2005. Cardiovascular physiology: the peripheral circulation. In: Kryger, M.H., Roth, T., Dement, W.C. (Eds.), Principles and Practice of Sleep Medicine, fourth ed., Elsevier Saunders, Philadelphia, PA, pp. 203–212. Maquet, P., 2000. Functional neuroimaging of normal human sleep by positron emission tomography. J. Sleep Res. 9, 207–231. Parmeggiani, P.L., 2005. Physiologic regulation in sleep. In: Kryger, M.H., Roth, T., Dement, W.C. (Eds.), Principles and Practice of Sleep Medicine, fourth ed., Elsevier Saunders, Philadelphia, PA, pp. 185–191. Silvani, A., 2008. Physiological sleep-dependent changes in arterial blood pressure: central autonomic commands and baroreflex control. Clin. Exp. Pharmacol. Physiol. 35, 987–994. Zoccoli, G., Bojic, T., Franzini, C., 2005. Regulation of cerebral circulation during sleep. In: Parmeggiani, P.L., Velluti, R.A. (Eds.), The Physiologic Nature of Sleep. Imperial College Press, London, pp. 351–369.
Cerebral Circulation Cerebral BF Changes During Sleep Mechanisms of Cerebral BF Regulation During Sleep: Beyond Flow-Activity Coupling Cutaneous Circulation Renal and Splanchnic Circulation Skeletal Muscle Circulation Coronary Circulation OSA and Peripheral Circulation Sleep Loss and Peripheral Circulation Further Reading
2 2 2 3 4 4 4 5 5 5
Glossary Arterial blood pressure surges Phasic increases of arterial blood pressure appearing in physiologic conditions during rapid eye movement (REM) sleep and depending on central neural mechanisms. Blood-brain barrier (BBB) Interface between the peripheral circulation and the central nervous system consisting of the cerebral microvascular endothelium with tight junctions between endothelial cells and of surrounding astrocytes, pericytes, and neurons. It controls the exchange of substances between blood and brain tissue. Cerebral autoregulation Mechanisms maintaining cerebral blood flow stable in the face of changes in arterial blood pressure by adjusting cerebrovascular resistance. Flow-activity coupling Mechanism linking changes in neuronal activity and energy usage of the tissue with changes in cerebral blood flow.
Hypocretins (orexins) Neuropeptides produced by neurons in the lateral hypothalamus that are involved in stimulating food intake and wakefulness and controlling energy metabolism. Obstructive sleep apnea (OSA) Repetitive pauses in breathing occurring during sleep because of upper airway obstruction. Episodes of sleep apnea are usually associated with a reduction in blood oxygen saturation. Peripheral vascular system A system of intertwining arteries, capillaries, and veins which carries blood from and to the heart and the lungs. Sleep inertia A physiological transitional state characterized by a lowered arousal occurring immediately after awakening from sleep and producing a temporary decrement in performance.
Sleep processes involve the body as well as the brain. Blood flow (BF) to different organs matches specific metabolic requirements, which vary with behavioral states of the wake-sleep cycle: wakefulness, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. On the other hand, changes in BF are obtained through changes in arterial blood pressure (ABP) and vascular resistance, which, in turn, depend on autonomic output to heart and blood vessels. Autonomic cardiovascular control results from the interaction between reflex mechanisms, such as the baroreflex, the chemoreflex, and thermoregulation, and central autonomic commands specific to each sleep state. Thus, sleep-related changes in peripheral circulation depend jointly on changes in organ metabolic rate and on autonomic activity to the heart and blood vessels. The direction and magnitude of sleep-dependent changes in BF to a given vascular bed result from the complex interaction among local systemic reflex, and central autonomic mechanisms. In the following paragraphs, the physiological sleep-dependent changes in the cerebral circulation and in extracerebral vascular districts will be reviewed. Whenever possible, the focus will be aimed at translation from animal models to humans and at the mechanisms of the observed circulatory changes. Effects of sleep-related respiratory derangements and sleep loss on the peripheral circulation will also be summarized.
q
Change History: November 2015. Prof. Carlo Franzini, one of the co-authors passed away in 2015.
y
Carlo Franzini is now deceased.
Reference Module in Neuroscience and Biobehavioral Psychology
http://dx.doi.org/10.1016/B978-0-12-809324-5.00964-0
1
2
Sleep and the Peripheral Vascular System
Cerebral Circulation Cerebral BF Changes During Sleep A substantial body of evidence on animal models and humans demonstrates that overall cerebral BF differs widely between the behavioral states of the wake-sleep cycle. The key mechanism involved is probably a coupling between cerebral vascular resistance and neural activity because cerebral BF is tightly related to glucose and oxygen consumption, which, in turn, mainly reflects synaptic activity during sleep as well as during wakefulness (flow-activity coupling). On the other hand, sleep-dependent changes in cerebral BF are largely independent of systemic hemodynamic changes, which redistribute BF among other systemic vascular beds (cerebral autoregulation). In humans, cerebral BF decreases during NREM sleep compared with previous wakefulness. Results on animal models are less consistent: cerebral BF decreases during NREM sleep in lambs, while no significant differences or even BF increases have been reported during NREM sleep in rats and rabbits. These inconsistencies probably depend on the lack of stringent criteria to discriminate very quiet wakefulness from sleep onset in animal models. In humans, the decrease in cerebral BF during NREM sleep is more pronounced in the thalamus and brainstem, which are involved either actively or permissively in the generation of electroencephalographic (EEG) slow waves. BF also significantly decreases during NREM sleep in the basal forebrain and hypothalamus, which are involved in sleep generation and modulation of cortical activation. At the cortical level, the BF reduction during NREM sleep is most pronounced in the orbital prefrontal and anterior cingulated cortex. At least in part, these reductions in BF appear related to the reduced metabolic cost of synchronized bursting patterns of activation during NREM sleep. Accordingly, BF in the ventromedial prefrontal regions is negatively correlated with EEG d-power during NREM sleep. During REM sleep, studies on different species and with different techniques consistently report that cerebral BF tonically increases with respect to NREM sleep. Interestingly, evidence on rabbits suggests that this BF increase is achieved preferentially by increasing vertebral artery BF at the expense of common carotid artery BF, which actually decreases during REM sleep in this species. On the other hand, experiments performed at high temporal resolution on lambs reveal that during REM sleep, phasic surges of cerebral BF are superimposed on a tonic cerebral BF increase. These BF surges are initiated by cerebrovascular dilatation and sustained by surges of ABP, which are a physiological feature of REM sleep in different animal models and humans. At a regional level, the increase in BF during REM sleep is most prominent in the pontine tegmentum, dorsal mesencephalon, thalamic nuclei, amygdala, and in the anterior cingulated and entorhinal cortex. The BF increase in the dorsal ponto-mesencephalic region during REM sleep points to the role of this area in REM sleep generation. Interestingly, some neurons of this region project monosynaptically to thalamic nuclei, which are also activated in REM sleep. On the other hand, amygdaloid complexes interact with the anterior cingulated and entorhinal cortex, and their activation may contribute to emotional memory processing during REM sleep. Conversely, BF in the precuneus and the posterior cingulated, parietal, and dorsolateral prefrontal cortex is lower than average during REM sleep. Thus, deactivation involving higher-order heteromodal association cortices appears a defining characteristic of sleep itself, being common to both NREM and REM states. The process of awakening entails a rapid restoration of BF to wakefulness levels in the brain stem and thalamus, suggesting that reactivation of these regions is involved in the reestablishment of consciousness. In heteromodal neocortical areas, conversely, BF takes 5–20 min to rise to wakefulness levels after awakening from sleep. This time lag may be linked to dissipation of sleep inertia. However, the fact that BF values in cortical and limbic structures are lower during wakefulness more than 15 min after sleep than during wakefulness before sleep appears in accordance with a restorative function of sleep, at least as far as these brain structures are concerned. While brain circulation has been extensively studied during sleep in humans and animal models, spinal cord circulation during sleep has received much less attention. Available data indicate that sleep-dependent changes in spinal cord BF are substantial and generally parallel those in cerebral BF. In particular, spinal cord BF increases during REM sleep with respect to NREM sleep in rabbits and rats, whereas it decreases during NREM sleep with respect to quiet wakefulness in rats only. This discrepancy concerning NREM sleep may depend on behavioral species differences, with rats being more active than rabbits during wakefulness. Flow-activity coupling is not as well documented in the spinal cord as it is in the brain during sleep. Lumbar motor neurons undergo a modest hyperpolarization on passing from wakefulness to NREM sleep, with further hyperpolarization occurring in REM sleep. This hyperpolarization results from increased activity of inhibitory spinal interneurons. Clearly, it is not possible to infer overall sleepdependent changes in spinal cord neural activity from these data, and no data are available on spinal cord metabolic activity during sleep. These issues are worth experimental clarification, as they may lead to the demonstration that sleep modulates the activity of the central nervous system as a whole.
Mechanisms of Cerebral BF Regulation During Sleep: Beyond Flow-Activity Coupling Brain metabolism depends on a continuous circulatory supply of glucose and oxygen to neurons and astrocytes. In astrocytes, glucose is partly converted to lactate, which is then released in the extracellular space and taken up by neurons. In neurons, pyruvate arising from both glucose and lactate is used oxidatively. With neuronal activity, lactate oxidation increases. Glutamate reuptake by astrocytes activates glucose utilization and lactate production and release. Lactate produced by astrocytes during neuronal activation may therefore sustain neuronal energy needs as activation persists. To be transported into the brain, blood glucose must cross the blood–brain barrier (BBB) through specific carriers. It has been hypothesized that with physiological brain activation, such as occurs in REM sleep, glucose supply to the brain is increased by promoting glucose transport across the BBB. Contrary to this hypothesis,
Sleep and the Peripheral Vascular System
3
neither the capillary surface area available for blood–brain diffusion nor BBB permeability to glucose is higher in REM sleep than in wakefulness in rats despite a 29% increase in cerebral BF. Therefore, a modulation of glucose transport through the BBB is not a mechanism that provides energy on demand during the physiological brain activation that characterizes REM sleep. Glutamate signaling processes may play a role in the local regulation of cerebral BF during sleep. In particular, glutamateevoked calcium influx in postsynaptic neurons may activate production of nitric oxide (NO), adenosine, and arachidonic acid metabolites, which, in turn, cause vasodilation. Accordingly, experiments performed on lambs demonstrate that the NO synthase inhibitor N-nitro-L-arginine (L-NNA) reduces cerebral BF during all wake-sleep states and particularly (24%) during REM sleep. Intriguingly, the physiological sleep-dependent differences in cerebral BF are abolished within 1–3 h of L-NNA infusion, to reappear by 24 h. NO is also key in mediating the early cerebral vasodilation, which initiates phasic surges of cerebral BF during REM sleep. These data indicate that NO promotes cerebral vasodilation during sleep as well as during wakefulness, that the role played by NO is greatest during REM sleep, and that NO is a major, although not the sole, determinant of the sleep-dependent differences in cerebral BF. Cerebral blood vessels receive a rich sympathetic innervation. Recent evidence on lambs indicates that activity of these sympathetic fibers strongly increases during REM sleep and, particularly, during phasic episodes of this sleep state, when phasic increases in sympathetic activity to cerebral blood vessels precede the onset of ABP surges by 12 s. These phasic increases in sympathetic activity do not prevent the early cerebrovascular dilatation that initiates cerebral BF surges in phasic REM sleep, likely because of the substantial time delay and time constant of sympathetic control of vascular resistance. However, the phasic increases in sympathetic activity do limit cerebrovascular dilatation at the time of maximum ABP increase, thus protecting against potentially dangerous phasic rises in microcirculatory pressure and perfusion during REM sleep. As far as the neural control of the cerebral circulation is concerned, it is worth remembering that diffuse aminergic and cholinergic projections to the cerebral cortex may drive widespread vasoconstriction or vasodilation. These projections originate from brain structures, such as the locus coeruleus, brainstem raphe nuclei, and basal forebrain, which differ widely in activity between wake and sleep states. These diffuse aminergic and cholinergic projections may thus play a role in modulating BF in wide cortical areas as a function of the wake-sleep behavior. The effects of changes in systemic ABP on cerebral BF are buffered by cerebral autoregulation during sleep, although the effectiveness of these local regulatory mechanisms varies between wake-sleep states. Accordingly, in newborn lambs, a 50% reduction in cerebral perfusion pressure induces cerebral vasodilation both in NREM sleep and in REM sleep, as expected as a result of autoregulation of cerebral BF. However, the speed and magnitude of this vascular response are lower during REM sleep than either in NREM sleep or wakefulness. During REM sleep, moreover, the lower breakpoint of the autoregulation curve is shifted to the right relative to NREM sleep and wakefulness. This peculiar vulnerability of the cerebral circulation to hypotension during REM sleep may be because tonic cerebral vasodilation in this state limits the vasodilatatory reserve available for BF autoregulation. On the other hand, experiments on lambs indicate that during REM sleep, cerebral BF follows tightly the variability in cerebral perfusion pressure, which, in turn, is the greatest during this sleep state. During quiet wakefulness and particularly during NREM sleep, conversely, spontaneous fluctuations in cerebral BF are largely independent and in excess of those in cerebral perfusion pressure, suggesting the occurrence of synchronized vasomotor fluctuations in the cerebral circulation. These results are of interest because mathematical modeling demonstrates that synchronized vasomotion may facilitate oxygen diffusion to the tissue, thus helping to match perfusion to local metabolic needs during wakefulness and NREM sleep. During wakefulness, cerebral BF is very sensitive to changes in the arterial partial pressures of oxygen and carbon dioxide: a decrease in the former and an increase in the latter cause reductions in cerebrovascular resistance and, hence, increases in cerebral BF. During sleep, however, the cerebrovascular responses to hypercapnia and isocapnic hypoxia are drastically reduced, placing the brain at risk for hypoperfusion. This is particularly relevant considering that nocturnal hypoxia and hypercapnia are characteristic of cardiorespiratory diseases such as obstructive sleep apnea (OSA) or congestive heart failure. Arousal from sleep may thus represent a protective response, but it has been demonstrated that repeated hypoxia and even hypercapnic hypoxia become ineffective in evoking arousal during REM sleep. In contrast, hypercapnia per se appears not to become less effective as an arousing stimulus with repetition.
Cutaneous Circulation The cutaneous circulation ensures heat exchange between the body and the environment. Skin BF mainly reflects this key role played by the skin in thermoregulation. In rabbits, on passing from wakefulness to NREM sleep, skin vasodilation accompanies the decrease in the set point of body temperature. In humans, skin vasodilator activity is unchanged on passing from wakefulness to NREM sleep. However, skin temperature, which indirectly depends on the control of cutaneous circulation, is higher during the night than during the day, causing skin warming and dissipation of body heat during sleep. Skin temperature during sleep increases especially in the distal skin areas, which are usually cooler than the proximal ones during wakefulness. Interestingly, this pattern of skin vasomotion is impaired in narcoleptic patients, possibly contributing to their low core temperature. Narcolepsy is a rare sleep disorder associated with a selective loss of hypothalamic hypocretin (orexin)-producing neurons. The hypocretin system not only regulates the wake-sleep cycle, but also plays a role in metabolic and autonomic functions, which include sleep-dependent cardiovascular control. These data thus raise the hypothesis that hypothalamic hypocretin neurons are involved not only in mediating the sleep-dependent changes in skin circulation, but also more generally in linking thermoregulation to circulatory control.
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Sleep and the Peripheral Vascular System
A substantial body of evidence indicates that thermoregulation is impaired in REM sleep. In this state, the impairment of thermoregulatory processes entails the loss of vasomotor patterns reflexly driven by ambient temperature and, hence, the occurrence of paradoxical changes in skin BF. In particular, in a cold environment, thermoregulation physiologically causes skin vasoconstriction, which is accompanied by vasoconstriction in the splanchnic and renal beds and by vasodilation in the skeletal muscle bed. However, on passing from NREM sleep to REM sleep, skin BF increases because of the decrease in thermoregulatory neurogenic vasoconstriction combined with an increase in ABP. On the contrary, during exposition to warm ambient temperature, thermoregulation physiologically entails skin vasodilation, which is accompanied by vasoconstriction in the splanchnic and renal beds. However, on passing from NREM sleep to REM sleep, skin BF decreases because of a drop in thermoregulatory neurogenic vasodilation combined with a decrease in ABP.
Renal and Splanchnic Circulation BF measurements in renal and splanchnic districts on animal models do not evidence significant BF changes on passing from quiet wakefulness to NREM sleep. However, it should be noted that in rats, kidney BF is higher during NREM sleep than in active wakefulness despite a decrease in ABP because of a substantial decrease in renal vascular resistance. This difference in renal vascular resistance between NREM sleep and active wakefulness is, at least in part, because of a corresponding difference in renal sympathetic nerve activity. Renal sympathetic nerve activity further decreases in the transition from NREM sleep to REM sleep, together with a further increase in renal BF. Mesenteric vascular resistance and BF also tend to decrease and to increase, respectively, on passing from NREM sleep to REM sleep. It should be kept in mind that as discussed in the previous paragraph, the renal and splanchnic vascular beds play a role in the integrated pattern of vasomotor adjustments resulting from a thermal load. Thus, during REM sleep, when impairment of hypothalamic control disrupts the thermoregulatory distribution of cardiac output that exists in NREM sleep, there is a drop in sympathetic vasomotor tone, increasing splanchnic and renal BF with respect to NREM sleep both at low and high ambient temperatures. Finally, REM sleep entails the disappearance of the negative correlation between arterial and portal blood supply, which guarantees the constancy of total liver BF. Thus, during REM sleep, an increase in hepatic arterial BF is not compensated by a corresponding decrease in portal venous BF, and vice versa, as it physiologically occurs during wakefulness and NREM sleep. The finely tuned regulation of liver blood supply may be lost during REM sleep because of the conspicuous irregularities in respiratory and cardiovascular activity that characterize this sleep state.
Skeletal Muscle Circulation Changes in somatomotor activity are a distinctive feature of sleep: skeletal muscle activity is lower in NREM sleep than in wakefulness, whereas muscle atonia and phasic muscle twitches characterize REM sleep. Accordingly, data on animal models demonstrate that BF to most skeletal muscle groups, and particularly to the diaphragm, is lower during sleep than during wakefulness. Nonetheless, skeletal muscle BF may not change significantly in the transition from quiet wakefulness to NREM sleep. On the other hand, on passing from NREM sleep to REM sleep, iliac vascular resistance and iliac BF increase and decrease, respectively, in rats. These sleepdependent differences in skeletal muscle BF are driven, in part, by local metabolic changes. Skeletal muscles are composed of fibers with different types of metabolic requirements: slow, oxidative red fibers, and fast, glycolytic white fibers. Accordingly, sleepdependent changes in skeletal muscle BF in rabbits and cats depend on muscle fiber composition. In particular, during NREM sleep, BF is high in red fibers and low in white fibers. Conversely, during REM sleep, BF decreases in red fibers and increases or does not show significant changes in white fibers. Changes in muscle BF during REM sleep may be because the increased activity of white fibers secondary to twitching causes local vasodilation, while the decreased activity of red fibers secondary to atonia causes local vasoconstriction, which may or may not be significant with respect to NREM sleep depending on the muscle tone in the latter state. Sympathetic efferent activity to the skeletal muscle vascular bed also plays a major role in driving sleep-dependent changes in skeletal muscle BF. In humans, muscle sympathetic nerve activity decreases on passing from wakefulness to NREM sleep and increases again on passing from NREM sleep to REM sleep. Lumbar sympathetic nerve activity also increases substantially on passing from NREM sleep to REM sleep in rats, this increase explaining most of the corresponding increase in iliac vascular resistance. This evidence thus emphasizes that during REM sleep, sympathetic outflow to different vascular beds is highly heterogeneous. This view is consistent with data obtained during REM sleep-like states in decerebrated cats: a decrease in renal, splanchnic, and cardiac sympathetic activity is accompanied by an increase in sympathetic activity to skeletal muscles irrespective of vagotomy, sino-aortic denervation, or pharmacological paralysis, pointing to a central repatterning of sympathetic activity specific of REM sleep.
Coronary Circulation Changes in coronary BF parallel changes in cardiac metabolism. In dogs, significant decreases in heart rate and left coronary BF occur during NREM sleep with respect to previous wakefulness together with increases in coronary vascular resistance. During REM sleep, coronary BF not only returns tonically to wakefulness levels, but also undergoes phasic surges. During intensely phasic periods of REM sleep, these increases in coronary BF may occur after transient pauses in heart rhythm. Phasic bursts of neurogenic cholinergic
Sleep and the Peripheral Vascular System
5
vasodilation may underlie these episodes, which show a clear mismatch between coronary BF and myocardial metabolism. Phasic increases in coronary BF during REM sleep are also coupled with bursts of sinus tachycardia. These coronary BF surges are mediated by the sympathetic nervous system, being eliminated by sympathectomy, and their magnitude parallels that of the concomitant heart rate surges. It may thus be hypothesized that during REM sleep, phasic increases in sympathetic efferent activity to the heart trigger a sequence of increased heart rate causing increased myocardiac metabolism, which, in turn, leads to phasic increases in coronary artery BF. However, when tonic coronary BF is experimentally reduced by occluders placed around the left circumflex coronary artery, the phasic bursts of tachycardia during REM sleep do not entail phasic increases in coronary BF, but rather phasic reductions in coronary BF because of reduced diastolic perfusion time.
OSA and Peripheral Circulation In OSA, the upper airways repeatedly become constricted or occluded during sleep, leading to episodes of decreased or absent airflow, hypoxia, and sympathetic activation. OSA may favor the development of hypertension, coronary disease, heart failure, stroke, and cardiac arrhythmias. The prevalence of OSA increases markedly with increasing adiposity, but obesity and OSA are considered independent risk factors for cardiovascular diseases. The physiological hemodynamic changes that occur in normal subjects during sleep do not occur in patients with OSA. The normal decreases in heart rate, ABP, and cardiac output during NREM sleep are lost in OSA patients, who show high sympathetic activity when awake and further increases in ABP and sympathetic activity during sleep. Cerebral hemodynamics are abnormal in patients with OSA. Cerebral BF fluctuates in response to sleep apneas, with an increase in intracranial pressure and a decrease in cerebral perfusion occurring during airways obstruction. Compared with baseline cerebral BF during sleep before apneas, cerebral BF increases up to 15% a few seconds after apnea termination, and decreases 25% 20 s after apnea. Cerebral autoregulation and cerebral vasodilator responses to hypercapnia may also be altered in patients with OSA. Endothelial dysfunction has been identified in pathological conditions such as atherosclerosis, hypertension, and OSA. Mediators produced by the endothelium, and in particular NO, are known to be important in the regulation of coronary BF. The recent development of a model of coronary endothelial dysfunction in lambs may shed light on the role of endothelial-derived vasodilator substances in modulating coronary BF during OSA. These research issues may have clinical relevance. Accordingly, OSA patients show nocturnal changes in electrocardiographic ST segment, which may be related to increased myocardial oxygen demand during postapneic surges in ABP and heart rate at a time when hemoglobin saturation is low. Indeed, the occurrence of a transient uncoupling between coronary BF and myocardial work following OSA has been recently demonstrated in humans, potentially promoting nocturnal myocardial ischemia in patients with OSA.
Sleep Loss and Peripheral Circulation Both sleep deprivation and insomnia have been linked to increased incidence of hypertension and are associated with cardiovascular morbidity and coronary events. Short sleep duration increases the risk for future coronary disease. Recent data indicate that the coronary BF velocity reserve is significantly lower after sleep deprivation (<4 h sleep) than after normal sleep even in healthy subjects without coronary risk factors. Experimental sleep restriction often entails an increase in ABP, which is not associated with muscle sympathetic vasoconstriction, tachycardia, or changes in circulating catecholamine levels. However, as previously discussed with reference to REM sleep, sympathetic outflow to different cardiovascular effectors may be highly heterogeneous. Spectral analysis of heart rate variability indeed indicates that sleep deprivation increases the sympathetic modulation of heart rhythm. Therefore, it remains possible that the cardiovascular effects of sleep deprivation result from increases in sympathetic activity to vascular beds different from skeletal muscles. Finally, it is worth remarking that a growing body of evidence suggests a link between the increased cardiovascular morbidity associated with sleep loss and inflammation. Even in healthy subjects, acute total sleep deprivation induces a significant increase in inflammatory markers, such as tumor necrosis factor, interleukin-1 (IL-1), IL-1 receptor antagonist, IL-6, and C-reactive protein. A high level of these substances could be linked to the development of endothelial dysfunction and consequent cardiovascular disease.
Further Reading Franzini, C., 2005. Cardiovascular physiology: the peripheral circulation. In: Kryger, M.H., Roth, T., Dement, W.C. (Eds.), Principles and Practice of Sleep Medicine, fourth ed., Elsevier Saunders, Philadelphia, PA, pp. 203–212. Maquet, P., 2000. Functional neuroimaging of normal human sleep by positron emission tomography. J. Sleep Res. 9, 207–231. Parmeggiani, P.L., 2005. Physiologic regulation in sleep. In: Kryger, M.H., Roth, T., Dement, W.C. (Eds.), Principles and Practice of Sleep Medicine, fourth ed., Elsevier Saunders, Philadelphia, PA, pp. 185–191. Silvani, A., 2008. Physiological sleep-dependent changes in arterial blood pressure: central autonomic commands and baroreflex control. Clin. Exp. Pharmacol. Physiol. 35, 987–994. Zoccoli, G., Bojic, T., Franzini, C., 2005. Regulation of cerebral circulation during sleep. In: Parmeggiani, P.L., Velluti, R.A. (Eds.), The Physiologic Nature of Sleep. Imperial College Press, London, pp. 351–369.