Circadian rhythms in the renin-angiotensin system and adrenal steroids may contribute to the inverse blood pressure rhythm in hypertensive TGR(mREN-2)27 rats

The transgenic TGR(mREN-2)27 rat is not only characterized by fulminant hypertension, but also by a disturbance in circadian blood pressure regulation, resulting in inverse circadian blood pressure profiles. The reasons for these alterations are not very well understood at present. We therefore investigated the circadian rhythms in several hormones participating in blood pressure regulation. From TGR and Sprague-Dawley (SPRD) control rats synchronized to 12h light and 12h dark (LD 12:12) blood was collected at different circadian times (07, 11, 15, 19, 23, 03, and 07 again, 5 rats per strain and time). The activities of plasma renin and converting enzyme, as well as plasma concentrations of corticosterone and aldosterone, were determined by radioimmunoassay (RIA). SPRD rats showed significant circadian rhythms in all variables except plasma renin activity, with maxima occurring during the day. TGR rats showed significant circadian rhythmicity in plasma renin activity and corticosterone and daily variation in aldosterone; angiotensin-converting enzyme (ACE) activity did not reach statistical significance. In TGR rats, 24h means in plasma renin activity and aldosterone were approximately sevenfold and fourfold higher, respectively, than in SPRD rats. Peak concentrations in corticosterone around 15h were more than two times higher in TGR rats than in SPRD rats, whereas no differences were observed during the night. It is concluded that, in TGR rats, the overall increase in plasma renin activity and aldosterone may contribute to the elevated blood pressure. The comparatively high levels in corticosterone and plasma renin activity during daytime may be involved in the inverse circadian blood pressure profiles in the transgenic animals. (Chronobiology International, 17(5), 645-658, 2000)     

CIRCADIAN RHYTHMS IN THE RENIN-ANGIOTENSIN SYSTEM AND ADRENAL STEROIDS MAY CONTRIBUTE TO THE INVERSE BLOOD PRESSURE RHYTHM IN HYPERTENSIVE TGR(mREN-2)27 RATS

The transgenic TGR(mREN-2)27 rat is not only characterized by fulminant hypertension, but also by a disturbance in circadian blood pressure regulation, resulting in inverse circadian blood pressure profiles. The reasons for these alterations are not very well understood at present. We therefore investigated the circadian rhythms in several hormones participating in blood pressure regulation. From TGR and Sprague-Dawley (SPRD) control rats synchronized to 12h light and 12h dark (LD 12:12) blood was collected at different circadian times (07, 11, 15, 19, 23, 03, and 07 again, 5 rats per strain and time). The activities of plasma renin and converting enzyme, as well as plasma concentrations of corticosterone and aldosterone, were determined by radioimmunoassay (RIA). SPRD rats showed significant circadian rhythms in all variables except plasma renin activity, with maxima occurring during the day. TGR rats showed significant circadian rhythmicity in plasma renin activity and corticosterone and daily variation in aldosterone; angiotensin-converting enzyme (ACE) activity did not reach statistical significance. In TGR rats, 24h means in plasma renin activity and aldosterone were approximately sevenfold and fourfold higher, respectively, than in SPRD rats. Peak concentrations in corticosterone around 15h were more than two times higher in TGR rats than in SPRD rats, whereas no differences were observed during the night. It is concluded that, in TGR rats, the overall increase in plasma renin activity and aldosterone may contribute to the elevated blood pressure. The comparatively high levels in corticosterone and plasma renin activity during daytime may be involved in the inverse circadian blood pressure profiles in the transgenic animals. (Chronobiology International, 17(5), 645–658, 2000)     

Young women with major depression live on higher homeostatic sleep pressure than healthy controls

There is mounting evidence for the involvement of the sleep-wake cycle and the circadian system in the pathogenesis of major depression. However, only a few studies so far focused on sleep and circadian rhythms under controlled experimental conditions. Thus, it remains unclear whether homeostatic sleep pressure or circadian rhythms, or both, are altered in depression. Here, the authors aimed at quantifying homeostatic and circadian sleep-wake regulatory mechanisms in young women suffering from major depressive disorder and healthy controls during a multiple nap paradigm under constant routine conditions. After an 8-h baseline night, 9 depressed women, 8 healthy young women, and 8 healthy older women underwent a 40-h multiple nap protocol (10 short sleep-wake cycles) followed by an 8-h recovery night. Polysomnographic recordings were done continuously, and subjective sleepiness was assessed. In order to measure circadian output, salivary melatonin samples were collected during scheduled wakefulness, and the circadian modulation of sleep spindles was analyzed with reference to the timing of melatonin secretion. Sleep parameters as well as non-rapid eye movement (NREM) sleep electroencephalographic (EEG) spectra were determined for collapsed left, central, and right frontal, central, parietal, and occipital derivations for the night and nap-sleep episodes in the frequency range .75-25 Hz. Young depressed women showed higher frontal EEG delta activity, as a marker of homeostatic sleep pressure, compared to healthy young and older women across both night sleep episodes together with significantly higher subjective sleepiness. Higher delta sleep EEG activity in the naps during the biological day were observed in young depressed women along with reduced nighttime melatonin secretion as compared to healthy young volunteers. The circadian modulation of sleep spindles between the biological night and day was virtually absent in healthy older women and partially impaired in young depressed women. These data provide strong evidence for higher homeostatic sleep pressure in young moderately depressed women, along with some indications for impairment of the strength of the endogenous circadian output signal involved in sleep-wake regulation. This finding may have important repercussions on the treatment of the illness as such that a selective suppression of EEG slow-wave activity could promote acute mood improvement.     

Young Women With Major Depression Live on Higher Homeostatic Sleep Pressure Than Healthy Controls

There is mounting evidence for the involvement of the sleep-wake cycle and the circadian system in the pathogenesis of major depression. However, only a few studies so far focused on sleep and circadian rhythms under controlled experimental conditions. Thus, it remains unclear whether homeostatic sleep pressure or circadian rhythms, or both, are altered in depression. Here, the authors aimed at quantifying homeostatic and circadian sleep-wake regulatory mechanisms in young women suffering from major depressive disorder and healthy controls during a multiple nap paradigm under constant routine conditions. After an 8-h baseline night, 9 depressed women, 8 healthy young women, and 8 healthy older women underwent a 40-h multiple nap protocol (10 short sleep-wake cycles) followed by an 8-h recovery night. Polysomnographic recordings were done continuously, and subjective sleepiness was assessed. In order to measure circadian output, salivary melatonin samples were collected during scheduled wakefulness, and the circadian modulation of sleep spindles was analyzed with reference to the timing of melatonin secretion. Sleep parameters as well as non-rapid eye movement (NREM) sleep electroencephalographic (EEG) spectra were determined for collapsed left, central, and right frontal, central, parietal, and occipital derivations for the night and nap-sleep episodes in the frequency range .75–25?Hz. Young depressed women showed higher frontal EEG delta activity, as a marker of homeostatic sleep pressure, compared to healthy young and older women across both night sleep episodes together with significantly higher subjective sleepiness. Higher delta sleep EEG activity in the naps during the biological day were observed in young depressed women along with reduced nighttime melatonin secretion as compared to healthy young volunteers. The circadian modulation of sleep spindles between the biological night and day was virtually absent in healthy older women and partially impaired in young depressed women. These data provide strong evidence for higher homeostatic sleep pressure in young moderately depressed women, along with some indications for impairment of the strength of the endogenous circadian output signal involved in sleep-wake regulation. This finding may have important repercussions on the treatment of the illness as such that a selective suppression of EEG slow-wave activity could promote acute mood improvement. (Author correspondence: Christian.cajochen@upkbs.ch)     

Homeostatic and circadian regulation of cognitive performance

Cognitive processes are crucial for human performance. Basic cognitive processes, such as attention, working memory, and executive functions, show homeostatic (time awake, sleep deprivation) and circadian (time of day) variations. Each of these cognitive processes includes several components, which contribute sequentially to the homeostatic and circadian modulation of performance. Sudden (lapses) and gradual changes in cognitive performance occur with sleep deprivation or with time of day. The time course of human cognitive processes throughout the day is relevant to the programming of different human activities. The lowest level of cognitive performance occurs during nighttime and early in the morning, a better level occurs around noon, and even higher levels occur during afternoon and evening hours. However, this time course can be modulated by conditions such as chronotype, sleep deprivation, sleep disorders or medication that affects the central nervous system.     

Human mesor-hypertensive chronorisk

Twelve endocrine variables in blood from a small number of clinically healthy adult women were sampled systematically around the clock and the seasons. Pattern discrimination methods singled out certain hormone values in certain seasons as classifiers for a high vs low risk of developing diseases associated with a high blood pressure. Further evidence in support of such classifiers is obtained on data from adolescent, menstrually cycling young adults and post-menopausal women, here analyzed as pool of series, with the scope of the data from any one age group greatly extended by a resampling procedure, namely, by bootstrapping. This mathematical approach was carried out on data series around the clock and seasons on several hormones as well as systolic and diastolic blood pressure. Classifier roles were strongly supported for plasma aldosterone and thyroid stimulating hormone, originally by an analysis of variance and, in the case of aldosterone, by circannual cosinor analysis and by numerical resampling. Circannual bootstrapping, a procedure recommended for broad routine use as a safeguard for hypothesis testing, was also done for plasma cortisol, dehydro-epi-androsterone sulfate and prolactin, variables for which (parametric) analyses of variance and cosinors did not reveal any difference between groups at high and low cardiovascular risk. In these instances, bootstrapping results are tentative and await further analyses. Results show the ability of circannual bootstrapping to detect outliers. Identification of classifiers provides cost-effective endocrine checks complementing the targeted automatic monitoring of blood pressure. Circannual indices for risk evaluation are, however, costly in several ways since it takes at least a year and quite a few samples to estimate them reliably. Accordingly, we also extended the scope of previous results by the application of an added procedure for circadian bootstrapping. With circadian as well as circannual bootstrapping, we here illustrate a major potential component of a system of chrono-engineering for health maintenance. This system should start with focus on the newborn. The results on adults here analyzed are likely to be more prominent in the neonate, to the extent that they are genetic in origin, yet amenable to modification by the extra-uterine environment.     

Sex steroid hormones enhance hypotensive effects of calcitonin gene-related Peptide in aged female rats

The aim of the present study is to investigate whether vascular protective effects of steroid hormones in aged female rats are mediated through calcitonin gene-related peptide (CGRP), a known potent vasodilator. This rat model reflects the postmenopausal state in humans. We examined whether blood pressure lowering effects of CGRP are enhanced in aged female rats when steroid hormone treatments are administered. We observed that 1) continuous infusion of CGRP lowered blood pressures in rats treated with estradiol-17beta and progesterone (P < 0.05), 2) acute hypotensive effects of CGRP were significantly (P < 0.05) greater in the presence of steroid hormones than in vehicle-treated groups, 3) blood pressure decreases in response to CGRP are lower in aged female rats than they are in young adult ovariectomized rats, and 4) age-related differences in the hypotensive effects of CGRP were nullified when animals were treated with steroid hormones. These data suggest that female sex steroid hormones may modulate arterial blood pressure by regulating the CGRP effector system in female rats regardless of age.     

Circadian and Ultradian Rhythms in Blood Glucose and Plasma Insulin of Healthy Adults

The circadian and ultradian variations of blood glucose and plasma insulin have been characterized individually and as a group phenomenon in five healthy young adults studied while adhering as closely as possible to their usual routine of sleep, activity, meal content and timing. Three complementary methods were used to analyze the data: displaying raw data as a function of time; cosinor method according to Nelson and Halberg; and time series analyses as proposed by De Prins and Malbecq. The subjects were studied in the laboratory and their life routine were controlled, but very close to that of their habitual routine. They had mainly ultradian rhythms of blood glucose (mainly about 6 hr) and circadian rhythms of immunoreactive insulin (I.R.I.). Blood glucose ultradian rhythms seem to be mainly but not exclusively mealtime dependent, while I.R.I, circadian rhythms appear to be primarily endogenous in origin. Therefore, the role played by insulin in the control of blood glucose levels seems to be programmed on a circadian basis rather than by a time independent feedback phenomenon as postulated by the conventional homeostatic hypothesis. The advantage of this chronophysiologic approach is to consider circadian rhythms of both I.R.I. and insulin effectiveness as an adaptive phenomenon able to maintain blood sugar changes in the ultradian domain of rhythms.     

A neural theory of circadian rhythms: split rhythms, after-effects and motivational interactions

A neural theory of the circadian pacemaker within the hypothalamic suprachiasmatic nuclei (SCN) is used to explain parametric data about mammalian operant behavior. The intensity, duration, and patterning of ultradian activity-rest cycles and the duration of circadian periods due to parametric (LL) and nonparametric (LD) lighting regimes are simulated. Paradoxical data about split rhythms and after-effects are explained using homeostatic and nonhomeostatic neural mechanisms that modulate pacemaker activity. These modulatory mechanisms enable the pacemaker to adjust to pervasive changes in its lighting regime, as during the passage of seasons, and to ultradian changes in internal metabolic conditions. The model circadian mechanisms are homologous to mechanisms that model hypothalamically mediated appetitive behaviors, such as eating. The theory thus suggests that both circadian and appetitive hypothalamic circuits are constructed from similar neural components. Mechanisms of transmitter habituation, opponent feedback interactions between on-cells and off-cells, homeostatic negative feedback, and conditioning are used in both the circadian and the appetitive circuits. Output from the SCN circadian pacemaker is assumed to modulate the sensitivity of the appetitive circuits to external and internal signals by controlling their level of arousal. Both underarousal and overarousal can cause abnormal behavioral syndromes whose properties have been found in clinical data. A model pacemaker can also be realized as an intracellular system.     

Adaptive significance of circadian clocks

Circadian clocks are ubiquitous and are found in organisms ranging from bacteria to mammals. This ubiquity of occurrence implies adaptive significance, but to date there has been no rigorous empirical evidence to support this. It is believed that an organism possessing circadian clocks gains fitness advantage in two ways: (i) by synchronizing its behavioral and physiological processes to cyclic environmental factors (extrinsic adaptive value); (ii) by coordinating its internal metabolic processes (intrinsic adaptive value). There is preliminary circumstantial evidence to support both. Several studies using organisms living in constant environments have shown that these organisms possess functional circadian clocks, suggesting that circadian clocks may have some intrinsic adaptive value. Studies to assess the adaptive value of circadian clocks in periodic environments suggest that organisms may have a fitness advantage in those periodic environments, which closely match their own intrinsic periodicity. Furthermore, evidence from organisms living in the wild, selection studies, and studies on latitudinal clines suggest that circadian clocks may have an extrinsic adaptive value as well. In this paper, I have presented several hypotheses for the emergence of circadian clocks and have reviewed some major empirical studies suggesting adaptive significance of circadian clocks.     

Adaptive Significance of Circadian Clocks

Circadian clocks are ubiquitous and are found in organisms ranging from bacteria to mammals. This ubiquity of occurrence implies adaptive significance, but to date there has been no rigorous empirical evidence to support this. It is believed that an organism possessing circadian clocks gains fitness advantage in two ways: (i) by synchronizing its behavioral and physiological processes to cyclic environmental factors (extrinsic adaptive value); (ii) by coordinating its internal metabolic processes (intrinsic adaptive value). There is preliminary circumstantial evidence to support both. Several studies using organisms living in constant environments have shown that these organisms possess functional circadian clocks, suggesting that circadian clocks may have some intrinsic adaptive value. Studies to assess the adaptive value of circadian clocks in periodic environments suggest that organisms may have a fitness advantage in those periodic environments, which closely match their own intrinsic periodicity. Furthermore, evidence from organisms living in the wild, selection studies, and studies on latitudinal clines suggest that circadian clocks may have an extrinsic adaptive value as well. In this paper, I have presented several hypotheses for the emergence of circadian clocks and have reviewed some major empirical studies suggesting adaptive significance of circadian clocks.     

Time-Related Behaviour of Endocrine Secretion: Circannual Variations of FT3, Cortisol,Hgh and Serum Basal Insulin in Healthy Subjects

Four healthy young male volunteers were submitted to the study of circadian and circannual bioperiodicities of several hormones: FT3, FT4, Cortisol, HGH, prolactin, PTh and plasma insulin levels. They were observed for a whole year and their blood samples were collected six times a day, every other month. The results were analyzed by two-way ANOVA macroscopic analysis and Student r-test. Our data registered a circannual variation in the mean circadian plasma levels of the following hormones: Cortisol (peak in December), HGH (peak in April), FT3 (peak in April), insulin (peak in February). FT4, prolactin and PTH showed no cyclic variation during the period of observation.     

Time-Related Behaviour of Endocrine Secretion: Circannual Variations of FT3, Cortisol, Hgh and Serum Basal Insulin in Healthy Subjects

Four healthy young male volunteers were submitted to the study of circadian and circannual bioperiodicities of several hormones: FT3, FT4, Cortisol, HGH, prolactin, PTh and plasma insulin levels. They were observed for a whole year and their blood samples were collected six times a day, every other month. The results were analyzed by two-way ANOVA macroscopic analysis and Student r-test. Our data registered a circannual variation in the mean circadian plasma levels of the following hormones: Cortisol (peak in December), HGH (peak in April), FT3 (peak in April), insulin (peak in February). FT4, prolactin and PTH showed no cyclic variation during the period of observation.     

Effect of sex hormones on levels of mRNAs coding for proteins involved in lipid metabolism in macrophages

The effects of sex hormones estradiol (E2), testosterone (Te), and 5α-dihydrotestosterone (DT) on cholesterol accumulation induced by modified low density lipoproteins (LDL) in macrophages differentiated from human peripheral blood monocytes and on the levels of mRNAs coding for proteins involved in lipid metabolism have been studied. All three hormones at physiological concentrations (1 nM) are capable of reducing cholesterol accumulation in cells. The treatment of cells with modified and native (not inducing cholesterol accumulation) LDL results in similar alterations in the expression of several mRNAs aimed primarily at homeostatic regulation of lipid metabolism. These alterations depend on the sex of macrophage donors and in some cases are even reversed in cells obtained from male and female donors. The cells not treated with modified LDL have no significant gender differences in the expression of the examined mRNAs. Hormones, either independently or in combination with the modified LDL, influence the levels of some mRNAs, and each hormone shows an individual range of effects. Correlation analysis of changes in mRNA content in the cells showed that the hormones may interfere with coordination of gene expression. Hormone action leads to: (1) reduced coupling of the content of individual mRNAs with their initial levels in the control cells; (2) reduced coupling of different mRNA levels; (3) regrouping of mRNAs between the clusters; and (4) changes in the number of factors that determine the correlation links between mRNAs. The data show that sex hormones may have impact on the level of expression of certain genes and, in particular, on the coordination of gene expression in macrophages.     

Engineering and governmental challenge: 7-day/24-hour chronobiologic blood pressure and heart rate screening: Part I

This review provides evidence that the bioengineering community needs to develop cost-effective, fully unobtrusive, truly ambulatory instrumentation for the surveillance of blood pressure and heart rate. With available instrumentation, we document a disease risk syndrome, circadian blood pressure overswinging (CHAT, short for circadian hyper-amplitude-tension). Circadian hyper-amplitude-tension is defined as a week-long overall increase in the circadian amplitude or otherwise-measured circadian variability of blood pressure above a mapped threshold, corresponding to the upper 95% prediction limit of clinically healthy peers of the corresponding gender and age. A consistently reduced heart rate variability, gauged by a circadian standard deviation below the lower 5% prediction limit of peers of the corresponding gender and age, is an index of a separate yet additive major risk, a deficient heart rate variability (DHRV). The circadian amplitude, a measure of the extent of reproducible variability within a day, is obtained by linear curve-fitting, which yields added parameters: a midline-estimating statistic of rhythm, the MESOR (a time structure or chronome-adjusted mean), the circadian acrophase, a measure of timing of overall high values recurring in each cycle, and the amplitudes and acrophases of the 12-hour (and higher order) harmonic(s) of the circadian variation that, with the characteristics of the fundamental 24-hour component, describe the circadian waveform. The MESOR is a more precise and more accurate estimate of location than the arithmetic mean. The major risks associated with CHAT and/or DHRV have been documented by measurements of blood pressure and heart rate at 1-hour or shorter intervals for 48 hours on populations of several hundred people, but these risks are to be assessed in a 7-day/24-hour record in individuals before a physical examination, for the following reasons. (1) The average derived from an around-the-clock series of blood pressure measurements, computed as its MESOR, the proven etiopathogenetic factor of catastrophic vascular disease, can be above chronobiologic as well as World Health Organization limits for 5 days or longer and can be satisfactory for months thereafter, as validated by continued automatic monitoring. The MESOR can be interpreted in light of clock-hour-, gender-, and age-specified reference limits and thus can be more reliably estimated with a systematic account of major sources of variability than by casual time-unspecified spot checks (that conventionally are interpreted by a fixed and, thus, rhythm, gender-, and age-ignoring limit). With spot checks, in a diagnostically critical range of "borderline" blood pressures, an inference can depend on the clock-hour of the measurement, usually providing a diagnosis of normotension in the morning and of hypertension in the afternoon (for the same diurnally active, nocturnally resting patient!). Long-term treatment must not be based upon the possibility of an afternoon vs a morning appointment. Moreover, the conventional approach will necessarily miss cases of CHAT that are not accompanied by MESOR hypertension. (2) Circadian hyper-amplitude-tension indicates a greater risk for stroke than does an increase in the around-the-clock average blood pressure (above 130/80 mm Hg) or old age, whereas (3) CHAT can be asymptomatic, as can MESOR hyptertension. (4) Deficient heart rate variability, the fall below a threshold of the circadian standard deviation of heart rate, an entity in its own right, is also a chronome alteration of heart rate variability (CAHRV). Deficient heart rate variability can be present together with CHAT, doubling the relative risk of morbid events. In each case--either combined with CHAT or as an isolated CAHRV--a DHRV constitutes an independent diagnostic assessment provided as a dividend by current blood pressure monitors that should be kept in future instrumentation designs. CHAT and DHRV can be screened by systematic focus on variability, preferably by the use of automatic instrumentation and analyses, which are both available (affordably) for research in actual practice, in conjunction with the Halberg Chronobiology Center at the University of Minnesota.     

Morphology and physiology of capillary systems in subregions of the subfornical organ and area postrema

From recent morphological and physiological studies of capillaries, I shall review four new or revised concepts about blood-tissue communication in the subfornical organ (SFO) and area postrema (AP). First, the capillary systems of SFO and AP exhibit subregional differentiation correlated topographically with cytoarchitecture, densities of immunoreactivity for several peptides and amines, cellular sensitivity to neuroactive substances, afferent neural terminations, and tissue metabolic activity. Thus, contrary to frequent citations, the angioarchitecture and microcirculatory physiology of these small sensory nuclei are not homogeneous. Second, electron microscopic, morphometric, and topographical studies reveal that SFO contains three different types of capillary and AP has two. The differentiated capillary morphology appears to be well organized for specialized functions particularly in SFO subregions. No other body organ or small tissue region is known to have such capillary diversity, further highlighting the complex functions served by SFO. Third, pools of interstitial fluid (Virchow-Robin spaces) surrounding type I and III capillaries in SFO and AP may participate in the receptive properties of these organs as low-resistance pathways for rapid dispersion of blood-borne hormones inside their organ boundaries. The parenchymal walls of Virchow-Robin spaces appear to harbour metabolic mechanisms for hormones such as angiotensin II, and thus could vastly extend the effective blood-brain surface area of permeable capillaries in SFO and AP. Fourth, SFO and AP bear similar physiological characteristics of high blood volume, yet relatively low rates of blood flow. Accordingly, intracapillary blood velocity must be quite slow in these organs, and the duration of transit by blood and circulating messengers rather protracted. This feature of slow blood transit time likely compounds the sensory capability of SFO and AP, rendering increased contact time for blood-borne hormones to penetrate the permeable capillaries of these structures and interact with their known dense populations of receptors for several homeostatic substances involved in regulation of blood pressure and body fluids.     

Development of Inverse Circadian Blood Pressure Pattern in Transgenic Hypertensive Tgr(mREN2)27 Rats

TGR(mREN2)27 (TGR) rats are transgenic animals with an additional mouse renin gene, which leads to overactivity of the renin-angiotensin system. Adult TGR rats are characterized by fulminant hypertension, hypertensive end-organ damage, and an inverse circadian blood pressure pattern. To study the ontogenetic development of cardiovascular circadian rhythms, telemetric blood pressure transmitters were implanted in male Sprague-Dawley (SPRD, n = 5) and heterozygous, transgenic TGR rats before 5 weeks of age. The TGR received either drinking water or enalapril 10 mg/L in drinking water (n = 5 per group). Drug intake was measured throughout the study by computerized monitoring of drinking volume. Circadian patterns in blood pressure and heart rate were analyzed from 5 to 11 weeks of age. In the first week after transmitter implantation, blood pressure did not differ among SPRD, untreated, and enalapril-treated TGR rats. In parallel with the rise in blood pressure of untreated TGR rats, a continuous delay of the circadian acrophase (time of fitted blood pressure maximum) was observed, leading to a complete reversal of the rhythm in blood pressure at an age of 8 weeks. Enalapril reduced blood pressure at night, but was less effective during the day, presumably due to the drinking pattern of the animals, which ingested about 90% of their daily water intake during the nocturnal activity period. After discontinuation of treatment, blood pressure returned almost immediately to values found in untreated TGR rats. In conclusion, the inverse circadian blood pressure profile in TGR rats develops in parallel with the increase in blood pressure. Direct effects of the brain renin-angiotensin system may be involved in the disturbed circadian rhythmicity in TGR(mREN2)27 rats.     

Chronophysiology of the cardiovascular system

The development of ambulatory blood pressure monitoring devices and the beat-by-beat measurement of heart rate have enabled it to be established that there are circadian rhythms in heart rate and blood pressure in subjects living normally. Investigations of these variables have led to quantification of their fall at night, and rapid rise on awakening and becoming active in the morning. These changes are of particular interest insofar as abnormalities in them are associated with cardiovascular problems and morbidity in patients and also act as risk factors in otherwise healthy individuals. It has also been shown that there are many other variables of the cardiovascular system. The causes of the circadian rhythms in heart rate and blood pressure are outlined, with particular stress upon the role of the autonomic nervous system, as assessed from low- and high-frequency components of the variation in heart rate measured beat-by-beat. Activity increases blood pressure, but there is evidence that this “reactivity” varies with time of day, and this also might be related to cardiovascular morbidity. Based upon data from several sources, including night work, resting subjects and bed-ridden patients, it is concluded that the contribution of the “body clock” to producing the circadian rhythm in heart rate and blood pressure is relatively small. A bias towards an exogenous cause applies also to most other circadian rhythms in the cardiovascular system. Knowledge of circadian rhythmicity in cardiovascular system, together with an understanding of its causes, provides a rationale for advice to reduce cardiovascular risk and to assess the efficacy of therapies.     

Relationship between disruption of rhythmicity and reentrainment in surgical patients

Urine samples for assay, temperature, heart rate, and blood pressure were collected daily at 2-h intervals from 11 consenting subjects undergoing abdominal surgery, as well as 10 age-and sex-matched control subjects. Alterations in level, and timing of circadian excretion of catecholamine metabolites, adrenal cortical hormones, sodium, potassium, creatinine, and vital signs following surgery were measured. Data were examined to determine if a relationship exists between the degree of circadian alteration and the subject's return to typical circadian profiles. The data suggest that certain circadian rhythms of hospitalized subjects were altered and uncoupled from external stimuli. In addition, subjects with less disruption in some variables following surgery regained rhythmicity more quickly than more disrupted subjects. These findings suggest that health professionals should individualize patient care to promote rhythmicity. In addition, patient assessment should consider individual circadian patterns and disruption following surgery.     

Contribution of circadian physiology and sleep homeostasis to age-related changes in human sleep

The circadian pacemaker and sleep homeostasis play pivotal roles in vigilance state control. It has been hypothesized that age-related changes in the human circadian pacemaker, as well as sleep homeostatic mechanisms, contribute to the hallmarks of age-related changes in sleep, that is, earlier wake time and reduced sleep consolidation. Assessments of circadian parameters in healthy young (∼20-30 years old) and older people (∼65-75 years old)—in the absence of the confounding effects of sleep, changes in posture, and light exposure—have demonstrated that an earlier wake time in older people is accompanied by about a 1h advance of the rhythms of core body temperature and melatonin. In addition, older people wake up at an earlier circadian phase of the body temperature and plasma melatonin rhythm. The amplitude of the endogenous circadian component of the core body temperature rhythm assessed during constant routine and forced desynchrony protocols is reduced by 20-30% in older people. Recent assessments of the intrinsic period of the human circadian pacemaker in the absence of the confounding effects of light revealed no age-related reduction of this parameter in both sighted and blind individuals. Wake maintenance and sleep initiation are not markedly affected by age except that sleep latencies are longer in older people when sleep initiation is attempted in the early morning. In contrast, major age-related reductions in the consolidation and duration of sleep occur at all circadian phases. Sleep of older people is particularly disrupted when scheduled on the rising limb of the temperature rhythm, indicating that the sleep of older people is more susceptible to arousal signals genernpated by the circadian pacemaker. Sleep-homeostatic mechanisms, as assayed by the sleep-deprivation-induced increase of EEG slow-wave activity (SWA), are operative in older people, although during both baseline sleep and recovery sleep SWA in older people remains at lower levels. The internal circadian phase advance of awakening, as well as the age-related reduction in sleep consolidation, appears related to an age-related reduction in the promotion of sleep by the circadian pacemaker during the biological night in combination with a reduced homeostatic pressure for sleep. Early morning light exposure associated with this advance of awakening in older people could reinforce the advanced circadian phase. Quantification of the interaction between sleep homeostasis and circadian rhythmicity contributes to understanding age-related changes in sleep timing and quality. (Chronobiology International, 17(3), 285-311, 2000)