Aging and the circadian rhythm of melatonin: a cross-sectional study of Chinese subjects 30-110 yr of age

Although previous reports indicate that nocturnal plasma melatonin secretion declines with age, some recent findings do not support this point. In the present cross-sectional study, we documented serum melatonin concentrations at two time points, 02:00 and 08:00 h, in 144 persons aged 30-110 yr and found a significant age-related decline. It began around the age of 60 and reached a very significantly lower level in subjects in their 70s and over 80 yr of age (P < 0.01, when compared with age <60 yr). Nocturnal melatonin levels were higher among (post-menopausal only) women than men overall (P < 0.05). In the older age-groups, nocturnal melatonin levels did not differ between healthy controls and subjects with high blood pressure or ischemic heart disease. To further check these results, we also assessed the circadian pattern of serum melatonin in four subgroups of healthy men, aged 30-39, 40-49, 50-59, and 60-69 yr: blood samples were taken at 2 h intervals from 08:00 to 22:00 h and hourly from 22:00 to 08:00 h. Our results showed generally similar circadian melatonin patterns that peaked at night with very low levels during the daytime. No significant difference was found among the three younger groups, but nocturnal melatonin levels were significantly lower in the men in their 60s.     

AGING AND THE CIRCADIAN RHYTHM OF MELATONIN: A CROSS-SECTIONAL STUDY OF CHINESE SUBJECTS 30–110 YR OF AGE

Although previous reports indicate that nocturnal plasma melatonin secretion declines with age, some recent findings do not support this point. In the present cross-sectional study, we documented serum melatonin concentrations at two time points, 02:00 and 08:00h, in 144 persons aged 30–110 yr and found a significant age-related decline. It began around the age of 60 and reached a very significantly lower level in subjects in their 70s and over 80 yr of age (P<0.01, when compared with age <60 yr). Nocturnal melatonin levels were higher among (post-menopausal only) women than men overall (P<0.05). In the older age-groups, nocturnal melatonin levels did not differ between healthy controls and subjects with high blood pressure or ischemic heart disease. To further check these results, we also assessed the circadian pattern of serum melatonin in four subgroups of healthy men, aged 30–39, 40–49, 50–59, and 60–69 yr: blood samples were taken at 2h intervals from 08:00 to 22:00h and hourly from 22:00 to 08:00h. Our results showed generally similar circadian melatonin patterns that peaked at night with very low levels during the daytime. No significant difference was found among the three younger groups, but nocturnal melatonin levels were significantly lower in the men in their 60s.     

Chronotherapy in Coronary Heart Disease: Comparison of Two Nitrate Treatments

The purpose of this study was to assess the ischemic burden and the hemodynamic changes during daily activities in patients with coronary heart disease. Three exercise tests were performed during the day (10:00 a.m., 2:00 p.m., 6:00 p.m.), recording ST-segment depression, pulmonary artery pressure, pulmonary wedge pressure, and cardiac output as well as heart rate and systemic blood pressure during placebo and nitrate therapy. With placebo as well as nitrate therapy there was a gradual increase of ischemia and preload and a decrease of cardiac output during the day. High nitrate concentrations led to a significant reduction of both preload and ST depression with a marked circadian phase dependency of cardiovascular effects.     

Chronotherapy in Coronary Heart Disease: Comparison of Two Nitrate Treatments

The purpose of this study was to assess the ischemic burden and the hemodynamic changes during daily activities in patients with coronary heart disease. Three exercise tests were performed during the day (10:00 a.m., 2:00 p.m., 6:00 p.m.), recording ST-segment depression, pulmonary artery pressure, pulmonary wedge pressure, and cardiac output as well as heart rate and systemic blood pressure during placebo and nitrate therapy. With placebo as well as nitrate therapy there was a gradual increase of ischemia and preload and a decrease of cardiac output during the day. High nitrate concentrations led to a significant reduction of both preload and ST depression with a marked circadian phase dependency of cardiovascular effects.     

Circadian rhythm gene expression and daily melatonin levels vary in athletes and sedentary males

The circadian rhythm is a 24-h cycle in which cells control metabolic and physiological processes throughout the day. In this study, we compared the expression patterns of major circadian rhythm-related genes: from blood of Bmal1, Ror-α, Cry1, Per2, Per1, and Nr1d1. In addition, changes in patterns of melatonin levels were observed in 16 subjects, eight males rugby players and eight males who did not exercise regularly. Blood was collected at 6:00, 10:00, 18:00, and 22:00. Bmal1, Ror-α, Cry1, Per2 (p < 0.001), Per1 (p < 0.01), and Nr1d1 (p < 0.05) genes related to circadian rhythm was higher in rugby players than in sedentary males. However, melatonin levels were higher in sedentary males than in rugby players (p < 0.05). These results indicate that long-term exercise in athletes can increase the expression of genes related to circadian rhythm and these may have an effect on daily melatonin levels as well.     

Circadian rhythm of serum testosterone levels in male beagle dogs--effects of lighting time zone

In a previous study, the author found that serum testosterone (T) levels in male beagle dogs showed a circadian rhythm which was lowest at 12:00, and increased to a peak at 18:00-6:00, thereafter decreasing until 12:00. The reason was thought to be that dogs were breeding under rigid controlled conditions. The present study was performed to investigate the effects of lighting on the circadian rhythm of T level by means of a reversal of the lighting time zone, because lighting is considered an important factor in modulating T levels. Six male beagle dogs of 2 years were used in this study. The routine lighting time (8:00-20:00) and dark time (20:00-8:00) zone in the breeding room was reversed completely and T levels were measured at intervals of 1-5 weeks for up to 54 weeks. Blood samples were collected at 6:00, 12:00, 18:00 and 24:00. The results showed that the circadian rhythm of the T level and the T level at each blood sampling time did not change significantly within 54 weeks. As a result, it was recognized that the circadian rhythm of the T level in male dogs may not be affected by changes in the lighting time zone.     

Differences of behavioral rhythms observed by flat cage and running-wheel cage in female rat

The ambulatory, wheel-running, and drinking activities were measured in Wistar-Imamichi strain female rats under 12 L:12 D condition (6:00-18:00), using Gundai type ambulo-drinkometer (for simultaneous measurements of ambulation and drinking) and wheel-drinkometer (for simultaneous measurements of wheel-running and drinking) to compare the rhythmicities of each behavioral activity. These apparatuses are able to measure the behavioral activities over a long period, successively and automatically. The circadian patterns of ambulatory activity had two large peaks at 21 or 24:00 and at 6:00 (acrophase). Contrary to the above results, the wheel-running activity exhibited clear mono-peak at 21:00 (acrophase). Thus, apparent differences of the pattern were observed between the two activities. However, ambulatory and wheel-running activities fluctuated showing 4-days rhythmicity, and both activities increased in estrus and proestrus stages, respectively. The circadian rhythms of drinking activities measured by both apparatuses showed almost same patterns with acrophases at 6:00, and 4-days rhythmicities were also observed and were characterized by remarkable decrease of activity in every proestrus stages. From these results, it is concluded that circadian pattern of ambulatory activity is different from that of wheel-running activity, but circadian patterns of drinking activities are stable regardless of different methods of the measurement. The ambulatory, wheel-running and drinking activities reflect the behavioral changes in sexual cycles.     

Circadian variations of the effects of ethanol and of blood ethanol values in the healthy adult man. Chronopharmacological study]

Six healthy young men (22 to 26 years) who had fasted for 12 hours volunteered for this study (subject synchronization: diurnal activity from 07(00) to midnight and nocturnal rest). A set dose of ethanol (0.67 g/kg body weight) was ingested at the fixed (and random) hours of 07(00), 11(00), 19(00) and 23(00), with a week between tests. A set of physiological variables: psychological tests (selft-rating of mood, of physical vigor and of ebriety, tempo, random number addition test); physical variables (heart rate, systolic and diastolic blood pressure, peak expiratory flow, oral temperature and grip strength); blood variables (plasma ethanol, cortisol, lactic acid, pyruvic acid, glucose and erythrocyte K+) and urinary variables (volume, epinephrine, nor-epinephrine and 5-HIAA) were documented at least at 4 hourly intervals and set times. The cosinor method was used for chronobiological statistical analyses. The parameters characterizing the ethanol pharmacokinetics (chronopharmacokinetics) demonstrated a circadian rhythm (p less than 0.05): e. g. the peak height of ethanolemia is greater when ethanol is ingested at 07(00) than at other times. Also a circadian rhythm in biosystems susceptibility can be demonstrated (p less than 0.05) (chronesthesy) with a peak time not necessarily corresponding either to that of ethanolemia or to that of other variables. The overall circadian changes in ethanol effects (chronergy) can be viewed as a combination of both ethanol chronesthesy and chronokinetics.     

Twenty-Four-Hour Blood Pressure Control: An Intraarterial Review

Intraarterial blood pressure monitoring has shown the circadian rhythm of blood pressure control. Blood pressures tend to be highest in the morning before falling gradually during the day to a nadir at 3:00 a.m. There is a slight rise in the late afternoon that may correspond to patients' attendance at hospital for calibration of the equipment. There is a small rise in the blood pressure before awakening, and after arousal there is a rise in blood pressure to the peak level of the morning. In this article, we examine the effect of a variety of antihypertensive agents on this rhythm. In general, β-adrenoceptor blockers appear to have less effect on nocturnal blood pressure and surge in pressure after arousal, while vasodilators, particularly α-adrenoceptor blockers, have a pronounced effect. These findings indicate that the rise in blood pressure before awakening and the rapid rise upon arousal appear to be due to increased α-adrenoceptor activity.     

Twenty-four-hour blood pressure control: an intraarterial review.

Intraarterial blood pressure monitoring has shown the circadian rhythm of blood pressure control. Blood pressures tend to be highest in the morning before falling gradually during the day to a nadir at 3:00 a.m. There is a slight rise in the late afternoon that may correspond to patients' attendance at hospital for calibration of the equipment. There is a small rise in the blood pressure before awakening, and after arousal there is a rise in blood pressure to the peak level of the morning. In this article, we examine the effect of a variety of antihypertensive agents on this rhythm. In general, beta-adrenoceptor blockers appear to have less effect on nocturnal blood pressure and surge in pressure after arousal, while vasodilators, particularly alpha-adrenoceptor blockers, have a pronounced effect. These findings indicate that the rise in blood pressure before awakening and the rapid rise upon arousal appear to be due to increased alpha-adrenoceptor activity.     

Effects of Amlodipine on Orcadian Rhythms in Blood Pressure, Heart Rate, and Motility: A Telemetric Study in Rats

In male Wistar rats [light (L): 07:00-19:00 h, dark (D): 19:00-07:00 h], the effects of the calcium channel blocker amlodipine (1, 3, 10 mg/kg i.p.) on blood pressure, heart rate, and motor activity were studied by telemetric monitoring. Amlodipine was injected either at 07:00 h or at 19:00 h. Systolic and diastolic blood pressure were dose-dependently decreased with more pronounced effects in the dark span, ED₅₀ values in D were about seven times lower than in L. In contrast, the dose-dependent increase in heart rate was more pronounced in L than in D. No significant effects of amlodipine were found on motor activity. The study gives evidence for a circadian phase-dependency in the cardiovascular effects amlodipine in rats.     

Neuro-endocrine correlations of hypothalamic-pituitary-thyroid axis in healthy humans

Neuro-endocrine hormone secretion is characterized by circadian rhythmicity. Melatonin, GRH and GH are secreted during the night, CRH and ACTH secretion peak in the morning, determining the circadian rhythm of cortisol secretion, TRH and TSH show circadian variations with higher levels at night. Thyroxine levels do not change with clear circadian rhythmicity. In this paper we have considered a possible influence of cortisol and melatonin on hypothalamic-pituitary-thyroid axis function in humans. Melatonin, cortisol, TRH, TSH and FT4 serum levels were determined in blood samples obtained every four hours for 24 hours from ten healthy males, aged 36-51 years. We correlated hormone serum levels at each sampling time and evaluated the presence of circadian rhythmicity of hormone secretion. In the activity phase (06:00 h-10:00 h-14:00 h) cortisol correlated negatively with FT4, TSH correlated positively with TRH, TRH correlated positively with FT4 and melatonin correlated positively with TSH. In the resting phase (18:00 h-22:00 h-02:00 h) TRH correlated positively with FT4, melatonin correlated negatively with FT4, TSH correlated negatively with FT4, cortisol correlated positively with FT4 and TSH correlated positively with TRH. A clear circadian rhythm was validated for the time-qualified changes of melatonin and TSH secretion (with acrophase during the night), for cortisol serum levels (with acrophase in the morning), but not for TRH and FT4 serum level changes. In conclusion, the hypothalamic-pituitary-thyroid axis function may be modulated by cortisol and melatonin serum levels and by their circadian rhythmicity of variation.     

General and unspecific damping by malignancy of the circadian amplitude of circulating human melatonin?

The circadian rhythm of serum melatonin of 39 cancer patients is compared with that of 28 healthy subjects matched by gender and age. Each subject provided 6 blood samples at 4-hour intervals for determination of melatonin by RIA. After log10-transformation, data series were analyzed by single and population-mean cosinor and compared between the two groups and among patients subgrouped by cancer site, stage and treatment. A circadian rhythm (P<0.001) is demonstrated for both groups, with a contributing 12-hour harmonic (P<0.001). In the absence of a difference in MESOR, the circadian amplitude of the cancer patients is smaller than that of the healthy subjects (P=0.003). Numerically, nocturnal (00:00 and 04:00) melatonin concentrations are lower and daytime (08:00-20:00) melatonin concentrations are higher in the cancer patients than in the healthy subjects (P=0.032 at 12:00 and P=0.058 at 16:00). In the age ranges examined, no differences are found with age in either group or by gender in health. No differences are found among cancer patients subgrouped either by site, stage (localized vs. metastasized) or treatment. If these results are validated, other Janus-like (two-faced: stimulation or inhibition, depending on chronome stage) effects of malignancy should be taken into consideration for screening and for timing treatment.     

Effects of Amlodipine on Orcadian Rhythms in Blood Pressure,Heart Rate,and Motility: A Telemetric Study in Rats

In male Wistar rats [light (L): 07:00–19:00 h, dark (D): 19:00–07:00 h], the effects of the calcium channel blocker amlodipine (1, 3, 10 mg/kg i.p.) on blood pressure, heart rate, and motor activity were studied by telemetric monitoring. Amlodipine was injected either at 07:00 h or at 19:00 h. Systolic and diastolic blood pressure were dose-dependently decreased with more pronounced effects in the dark span, ED₅₀ values in D were about seven times lower than in L. In contrast, the dose-dependent increase in heart rate was more pronounced in L than in D. No significant effects of amlodipine were found on motor activity. The study gives evidence for a circadian phase-dependency in the cardiovascular effects amlodipine in rats.     

Development of model based on clock gene expression of human hair follicle cells to estimate circadian time

ABSTRACT

Considering the effects of circadian misalignment on human pathophysiology and behavior, it is important to be able to detect an individual’s endogenous circadian time. We developed an endogenous Clock Estimation Model (eCEM) based on a machine learning process using the expression of 10 circadian genes. Hair follicle cells were collected from 18 healthy subjects at 08:00, 11:00, 15:00, 19:00, and 23:00 h for two consecutive days, and the expression patterns of 10 circadian genes were obtained. The eCEM was designed using the inverse form of the circadian gene rhythm function (i.e., Circadian Time = F(gene)), and the accuracy of eCEM was evaluated by leave-one-out cross-validation (LOOCV). As a result, six genes (PER1, PER3, CLOCK, CRY2, NPAS2, and NR1D2) were selected as the best model, and the error range between actual and predicted time was 3.24 h. The eCEM is simple and applicable in that a single time-point sampling of hair follicle cells at any time of the day is sufficient to estimate the endogenous circadian time.     

Disturbance of circadian rhythms in analgosedated intensive care unit patients with and without craniocerebral injury

Melatonin, cortisol, heart rate, blood pressure, spontaneous motor activity, and body temperature follow stable circadian rhythms in healthy individuals. These circadian rhythms may be influenced or impaired by the loss of external zeitgebers during analgosedation, critical illness, continuous therapeutic intervention in the intensive care unit (ICU), and cerebral injury. This prospective, observational, clinical study examined 24 critically ill analgo-sedated patients, 13 patients following surgery, trauma, or acute respiratory distress (ICU), and 11 patients with acute severe brain injury following trauma or cerebral hemorrhage (CCI). Blood samples for the determination of melatonin and cortisol were obtained from each patient at 2 h intervals for 24 h beginning at 18:00 h on day 1 and ending 16:00 h on day 2. Blood pressure, heart rate, body temperature, and spontaneous motor activity were monitored continuously. Level of sedation was assessed using the Ramsey Sedation Scale. The severity of illness was assessed using the APACHE-II-score. The time series data were analyzed by rhythm analysis with the Chronos-Fit program, using partial Fourier series with up to six harmonics. The 24 h profiles of all parameters from both groups of patients were greatly disturbed/abolished compared to the well-known rhythmic 24 h patterns in healthy controls. These rhythm disturbances were more pronounced in patients with brain injury. The results of this study provide evidence for a pronounced disturbance of the physiological temporal organization in ICU patients. The relative contribution of analgosedation and/or brain injury, however, is a point of future investigation.     

Disturbance of Circadian Rhythms in Analgosedated Intensive Care Unit Patients with and without Craniocerebral Injury

Melatonin, cortisol, heart rate, blood pressure, spontaneous motor activity, and body temperature follow stable circadian rhythms in healthy individuals. These circadian rhythms may be influenced or impaired by the loss of external zeitgebers during analgosedation, critical illness, continuous therapeutic intervention in the intensive care unit (ICU), and cerebral injury. This prospective, observational, clinical study examined 24 critically ill analgo‐sedated patients, 13 patients following surgery, trauma, or acute respiratory distress (ICU), and 11 patients with acute severe brain injury following trauma or cerebral hemorrhage (CCI). Blood samples for the determination of melatonin and cortisol were obtained from each patient at 2 h intervals for 24 h beginning at 18:00 h on day 1 and ending 16:00 h on day 2. Blood pressure, heart rate, body temperature, and spontaneous motor activity were monitored continuously. Level of sedation was assessed using the Ramsey Sedation Scale. The severity of illness was assessed using the APACHE‐II‐score. The time series data were analyzed by rhythm analysis with the Chronos‐Fit program, using partial Fourier series with up to six harmonics. The 24 h profiles of all parameters from both groups of patients were greatly disturbed/abolished compared to the well‐known rhythmic 24 h patterns in healthy controls. These rhythm disturbances were more pronounced in patients with brain injury. The results of this study provide evidence for a pronounced disturbance of the physiological temporal organization in ICU patients. The relative contribution of analgosedation and/or brain injury, however, is a point of future investigation.     

Consistent changes in the circadian rhythms of blood pressure and atrial natriuretic peptide in congestive heart failure.

We demonstrated in previous works that the circadian rhythms of blood pressure (BP) and atrial natriuretic peptide (ANP) are antiphasic in normal subjects and in essential hypertension. The aim of the present study was to assess the circadian rhythms of BP and ANP in 20 patients with stable congestive heart failure (CHF), divided into two groups of 10 according to their New York Heart Association functional class. A matched control group of 10 normal volunteers was also studied. Noninvasive BP monitoring at 15-min intervals was performed for 24 h. Peripheral blood samples were also obtained at 4-h intervals starting from 08:00 h. The mean (+/- SEM) circadian mesors of ANP plasma levels were 13.4 +/- 1.7 pmol/L in the control group, 28.6 +/- 2.4 pmol/L in the group of 10 patients in class II, and 81.5 +/- 12 pmol/L in the group of 10 patients in class III-IV. In normal subjects, plasma ANP concentration was highest at 04:00 h (21.5 +/- 2.7 pmol/L) and lowest at 16:00 h (8.8 +/- 2.4 pmol/L; p less than 0.01). Both groups of patients with CHF showed no significant circadian change in the plasma levels of ANP and also a significantly blunted circadian rhythm of BP. Cosinor analysis confirmed the loss of the circadian rhythms of ANP and BP in CHF patients. Our findings support the existence of a causal relationship between the circadian rhythms of ANP and BP.     

Circadian and seasonal variations of physiological and biochemical determinants of acute myocardial infarction

Almost all cardiovascular events occur according to a circadian rhythm with a greater frequency in the morning on waking and when resuming activity, the mechanism and precise triggering events for myocardial infarction (MI) are not yet fully known. Multiple biologic functions show a diurnal and/or seasonal variation that may contribute to adverse cardiac outomes. Exogenous factors may also modulates these variations. The MI peak usually occurs between 07:00 and 12:00 h. This timing corresponds to the concurrent increase in platelet aggregability, blood concentration of cortisol, catecholamines, angiotensin II, myocardial oxygen demand and coagulation activity, while fibrinolytic activity is decreased. In this review paper we will point out the biological rhythms of a number of functions involved in acute myocardial infarction e.g. blood pressure, hormonal determinants, cholesterol, among others.     

Effects of ultradian lighting and feeding schedules on the circadian rhythm of body temperature in monkeys

In estimating, by use of cosinor-test, the 12- and 24-h component parameters of body temperature circadian rhythm in monkeys under ultradian schedules of lighting and feeding (LD 6:6; DL 6:6) we have shown that an intensive 12-h component is registered in both cases. The presence of a 24-h component of circadian rhythm depends on the zeitgeber phase. This component is present in LD 6:6 (lighting hours 07:00-13:00 and 19:00-01:00) and is absent in DL 6:6 (01:00-07:00 and 13:00-19:00). We hold that the most satisfactory explanation of the phenomena observed is that 12-h component is the result of a masking effect induced by the 12-h schedule (exogenous component) whereas the 24-h component reflects the intrinsic pacemaker work (endogenous component). It should be noted that in our case the masking effect in body temperature rhythm is circadian phase-dependent.