Effects of a Seven‐Day Continuous Infusion of Ropivacaine on Circadian Rhythms in the Rat

The present study was conducted to evaluate the effect of a 7 d continuous infusion of ropivacaine on the 24 h rhythms of body temperature, heart rate, and locomotor activity. After an initial 7 d baseline, rats were randomly divided into two groups of 4 rats each to receive ropivacaine or saline via an osmotic pump for 7 consecutive days. The pumps were removed thereafter and observed during a 7 d recovery span. The studied circadian rhythms were measured by radiotelemetry throughout each of the 7 d periods. An additional group of 4 rats was studied under the same experimental conditions to assess the plasma levels of ropivacaine on days 3 and 8 following pump implantation. Our results indicate that ropivacaine does not induce loss of the circadian rhythms of body temperature, heart rate, or locomotor activity; a prominent period of 24 h was found for all variables in all animals, before, during, and after ropivacaine treatment. However, ropivacaine treatment did modify some characteristics of the rhythms; it increased the MESOR (24 h mean) of the heart rate and locomotor activity rhythms and advanced the acrophase (peak time) of the locomotor activity circadian rhythm. The present study indicates that the circadian rhythms of heart rate and locomotor activity are modified after continuous infusion of ropivacaine, which is of particular interest, given the potential cardiotoxicity of this local anesthetic agent.     

Effects of suprachiasmatic nuclei lesions on circadian and ultradian rhythms in body temperature in ocular enucleated rats

Abstract

To test the hypothesis that an oscillator located outside the suprachiasmatic nuclei (SCN) controls the circadian rhythm of body temperature, we conducted a study with 14 blinded rats, 10 of which receiving a SCN lesion. Body temperature was automatically and continuously recorded for about one month by intraperitoneal radio transmitters. Food intake, drinking and locomotor activity were also recorded. Periodograms revealed that 3 rats with histologically verified total bilateral SCN lesions did not exhibit any circadian rhythmicity. The 7 other rats appeared to have partial lesions. They showed shortening of period and severe amplitude reduction in all functions. Thus, no support was found for the hypothesis of a separate circadian ‘temperature oscillator’ located outside the SCN. Nevertheless, after large partial lesions body temperature showed more persistency than some of the other behavioral rhythms.

Ultradian rhythms in temperature persisted after partial and total lesions. Other functions showed parallel ultradian rhythms. In intact rats the ultradian peaks were restricted predominantly to the subjective night. After total lesions these peaks became more or less homogeneously distributed in time but more heterogeneously after partial lesions. So the SCN plays a role in the temporal structure of ultradian rhythms but does not generate them. Non‐24‐hour actograms showed instabilities of period and phase of ultradian rhythms. Intact and lesioned rats were similar with respect to the mean (about 3.5 hrs) and standard deviation (about 1.5 hrs) of ultradian periods in temperature. These features indicate that a mechanism outside the SCN is underlying ultradian rhythmicity, capable of generating short‐term oscillations. Two approaches, homeostatic sleep‐wake relaxation oscillations and multiple circadian oscillators, are discussed.     

Effects of differences in the availability of light upon the circadian rhythms of institutionalized elderly

The aim of this study was to compare the availability of diurnal and nocturnal light in two residences for aged persons (R1 and R2, Palma de Mallorca, Illes Balears, Spain). We found that the R1 inmates were exposed to lower amounts of light during waking time and higher amounts during sleeping time. The main traits of the circadian rhythms and the quality of sleep in the inmates of the two residences were found to be positively related to the availability of light during waking time and negatively to the increased light exposure during bed time. In addition, the sleep of R1 inmates suffered higher disturbances as a consequence of the different policy for nocturnal diapers check and change. Altogether, these two factors may explain the differences observed in the two residences regarding the circadian rhythms, health status and quality of life. Two conclusions stem from these results: (1) the circadian rhythms of aged people are particularly sensitive to the contrast between diurnal and nocturnal light and (2) the nursing staff of institutions for aged people must receive specific formation on the best practices for maintaining the circadian health of aged people.     

Chronopharmacokinetics of imipenem in the rat

There are no studies indicating a possible modification of imipenem pharmacokinetics related to the hour (i.e., circadian time) of its administration. The aim of this study was to evaluate the influence of different times of intramuscular imipenem administration on its disposition in Wistar AF EOPS rats. Four groups of eight animals were given a single intramuscular injection of 140 mg/kg of imipenem either at 10:00, 16:00, 22:00, or 04:00 h. Blood samples were collected 0.5, 1, 2, 3, 4, 6, and 8 h after drug injection, and the main pharmacokinetic parameters determined were C_max, T_max, elimination half-life (t_1/2), area under the concentration-versus-time curve (AUC), total serum clearance (CL/F), and volume of distribution (V/F). Circadian variation of C_max (49%), T_max (92%), and AUC (19%) was observed leading to variability of imipenem exposure. Clearance and volume of distribution were modified according to the circadian time of drug injection but did not reach statistical significance. The results suggest that varying the time of administration induces intra-individual variability.     

Exogenous corticosteroid and shifts of circadian rhythms in hamsters

We tested the hypothesis that glucocorticoid stimulation mediates the effect of exercise on circadian clock resetting in hamsters. We injected animals with 1 and 5 mg dexamethasone—a potent glucocorticoid agonist—at zeitgeber time (ZT) 4 and ZT6, circadian phases at which vigorous exercise induces maximal phase advances of about 3h. Neither dose of dexamethasone induced phase shifts that were significantly larger than those induced by injections of saline vehicle at either of the phases tested. Some animals, however, showed quite large and consistent phase shifts to repeated injections whether with saline or dexamethasone, such that there was a statistically significant correlation between individuals' responses to the two treatments. The data indicate no role for increased glucocorticoid activity in mediating the effects of exercise on circadian phase shifting, but suggest a modest role for nonspecific stimulation, independent of exercise, in inducing phase shifts at ZT4-ZT6. (Chronobiology International, 18(2), 203-213, 2001)     

Sleep and circadian rhythms: key components in the regulation of energy metabolism

In this review, we present evidence from human and animal studies to evaluate the hypothesis that sleep and circadian rhythms have direct impacts on energy metabolism, and represent important mechanisms underlying the major health epidemics of obesity and diabetes. The first part of this review will focus on studies that support the idea that sleep loss and obesity are "interacting epidemics." The second part will discuss recent evidence that the circadian clock system plays a fundamental role in energy metabolism at both the behavioral and molecular levels. These lines of research must be seen as in their infancy, but nevertheless, have provided a conceptual and experimental framework that potentially has great importance for understanding metabolic health and disease.     

Presence of circadian rhythms in the locomotor activity of a cave-dwelling millipede Glyphiulus cavernicolus sulu (Cambalidae, Spirostreptida)

The locomotor activity of the millipede Glyphiulus cavernicolus (Spirostreptida), which occupies the deeper recesses of a cave, was monitored in light-dark (LD) cycles (12h light and 12h darkness), constant darkness (DD), and constant light (LL) conditions. These millipedes live inside the cave and are apparently never exposed to any periodic factors of the environment such as light-dark, temperature, and humidity cycles. The activity of a considerable fraction of these millipedes was found to show circadian rhythm, which entrained to a 12:12 LD cycle with maximum activity during the dark phase of the LD cycle. Under constant darkness (DD), 56.5% of the millipedes (n = 23) showed circadian rhythms, with average free-running period of 25.7h ± 3.3h (mean ± SD, range 22.3h to 35.0h). The remaining 43.5% of the millipedes, however, did not show any clear-cut rhythm. Under DD conditions following an exposure to LD cycles, 66.7% (n = 9) showed faint circadian rhythm, with average free-running period of 24.0h ± 0.8h (mean ± SD, range 22.9h to 25.2h). Under constant light (LL) conditions, only 2 millipedes of 11 showed free-running rhythms, with average period length of 33.3h ± 1.3h. The results suggest that these cave-dwelling millipedes still possess the capacity to measure time and respond to light and dark situations. (Chronobiology International, 17(6), 757-765, 2000)     

Role of the microbiota in circadian rhythms of the host

ABSTRACT

Life for meta-organisms is based on a strong relationship between gut bacteria and body cells. This review summarizes to what extent the microbiota can influence host circadian rhythms via a literature review on the topic. The results show that microbiota can influence the host’s circadian gene expression through direct interactions via immunoreceptors and microbiota-derived metabolites, especially in peripheral tissues. Noteworthy metabolites that are only attributable to the microbiota are short-chain fatty acids and unconjugated bile acids. The microbiota also serves as a mediator for the interplay between the host’s diet and circadian rhythmicity. This work furthermore displays that the microbiota is subject to diurnal variations in terms of structure and function and that the host and the host’s diet influence these fluctuations. As most of these results originate in mouse models, we hope this work stimulates further research in human derived tissue to verify these conclusions.     

Modeling the influence of circadian rhythms on the acute inflammatory response

A wide variety of modeling techniques have been applied towards understanding inflammation. These models have broad potential applications, from optimizing clinical trials to improving clinical care. Models have been developed to study specific systems and diseases, but the effect of circadian rhythms on the inflammatory response has not been modeled. Circadian rhythms are normal biological variations obeying the 24-h light/dark cycle and have been shown to play a critical role in the treatment and progression of many diseases. Several of the key components of the inflammatory response, including cytokines and hormones, have been observed to undergo significant diurnal variations in plasma concentration. It is hypothesized that these diurnal rhythms are entrained by the cyclic production of the hormones cortisol and melatonin, as stimulated by the central clock in the suprachiasmatic nucleus. Based on this hypothesis, a mathematical model of the interplay between inflammation and circadian rhythms is developed. The model is validated by its ability to reproduce diverse sets of experimental data and clinical observations concerning the temporal sensitivity of the inflammatory response.     

Feeding entrainment of locomotor activity rhythms in the goldfish is mediated by a feeding-entrainable circadian oscillator

Periodic food availability can act as a potent zeitgeber capable of synchronizing many biological rhythms in fishes, including locomotor activity rhythms. In the present paper we investigated entrainment of locomotor rhythms to scheduled feeding under different light and feeding regimes. In experiment 1, fish were exposed to a 12:12?h light/dark cycle and fed one single daily meal in the middle of the light phase. In experiment 2, we tested the effect of random versus scheduled feeding on the daily distribution of activity. During random feeding, meals were randomly scheduled with intervals ranging from 12 to 36?h, while scheduled feeding consisted of one single daily meal set in the middle of the light or dark phase. Finally, in experiment 3, we studied the synchronization of activity rhythms to feeding under constant darkness (DD) and after shifting the feeding cycle by either advancing or delaying the feeding cycle by 9?h. The results revealed that goldfish synchronized to feeding, overcame light entrainment and significantly changed their daily distribution of activity according to their feeding schedule. In addition, the daily activity pattern modulated by feeding differed between layers: a peak of activity being noticeable directly after feeding at the bottom, while an anticipatory behaviour was obvious at the surface of the tank. Under DD and no food, free-running rhythms averaging 25.5?± 1.9?h (mean?±?SD) were detected. In conclusion, some properties of feeding entrainment (e.g. anticipation of the feeding time, free-running rhythms following termination of periodic feeding, and the stability of ø after shifting the feeding cycle) suggested that goldfish have (a) separate but tightly coupled light- and food-entrainable oscillators, or (b) a single oscillator that is entrainable by both light and food (one synchronizer being eventually stronger than the other).     

Seasonal changes in circadian rhythms of body temperatures in humans living in a dry tropical climate

Seven volunteers (3 females and 4 males; 3 Caucasians and 4 Africans) participated in two 24 h sessions during the cool dry (CD) and the hot dry (HD) seasons of the sahelian tropical climate. Body temperatures were taken on portable cassette recorders for 24 h. Rectal (Tre) and mean skin (Tsk) temperatures decreased in the HD compared to the CD conditions, meeting one of the criteria for adaptation to heat. No ethnic differences in thermal responses were found. Males and females differed in their body temperature rhythms and in their reactions to heat. Body temperatures were higher in females than in males. Males reacted to heat with a decrease in Tre, without change in the Tre-Tsk gradient. Females showed a decrease in both Tre and Tsk, more marked for Tsk, with an increase in the Tre-Tsk gradient. It was concluded that males showed seasonal acclimatization to heat via a decrease in metabolism confirmed by a decrease in plasma levels of thyroid stimulating hormone (TSH) in the HD condition. Females showed a mixed metabolic and thermolytic type of acclimatization, with an absence of variation in plasma TSH levels. In conclusion, the steady rise in temperature between the CD and HD conditions was sufficient to trigger an acclimatization to heat similar in Caucasian and African subjects, although exposure to the external climate differed widely.     

Interindividual Differences in Chronopharmacologic Effects of Drugs: A Background for Individualization of Chronotherapy

In order to optimize chronotherapeutic schedules (designs), we examined the interindividual differences in chronopharmacologic effects of drugs with consideration of the following three factors: (a) inherited factors of direct relevance to chronopharmacology (genetic variability, gender-related differences) as well as age-related differences; (b) interindividual difference in chronoeffective-ness related to disease (e.g., various types and stages of cancer, affective disorders, etc.) as well as to drug-dependent alteration (phase shifts, distortion) of biological rhythms; and (c) means to solve problems resulting from the need of individualization in chronotherapy. These involve the use of circadian marker rhythms (MR) whose characteristics (peak or trough time, amplitude, etc.) can be precisely quantified and thus are applicable as a reference system for physiologic, pathologic, pharmacologic, and therapeutic uses. The MR has to be specific and pertinent and must be easily monitored and documented. This approach can be further advanced by the use of a battery of MRs rather than a single MR. Other suggested means relate to the fact that chronobiotics (agents capable of influencing parameters of a set of biological rhythms) should be considered (e.g., corticoids and adrenocorticotropic hormone) and/or to the subject's synchronization should be enforced by “conventional” zeitgebers (e.g., bright light, physical activity).     

Interindividual Differences in Chronopharmacologic Effects of Drugs: A Background for Individualization of Chronotherapy

In order to optimize chronotherapeutic schedules (designs), we examined the interindividual differences in chronopharmacologic effects of drugs with consideration of the following three factors: (a) inherited factors of direct relevance to chronopharmacology (genetic variability, gender-related differences) as well as age-related differences; (b) interindividual difference in chronoeffective-ness related to disease (e.g., various types and stages of cancer, affective disorders, etc.) as well as to drug-dependent alteration (phase shifts, distortion) of biological rhythms; and (c) means to solve problems resulting from the need of individualization in chronotherapy. These involve the use of circadian marker rhythms (MR) whose characteristics (peak or trough time, amplitude, etc.) can be precisely quantified and thus are applicable as a reference system for physiologic, pathologic, pharmacologic, and therapeutic uses. The MR has to be specific and pertinent and must be easily monitored and documented. This approach can be further advanced by the use of a battery of MRs rather than a single MR. Other suggested means relate to the fact that chronobiotics (agents capable of influencing parameters of a set of biological rhythms) should be considered (e.g., corticoids and adrenocorticotropic hormone) and/or to the subject's synchronization should be enforced by “conventional” zeitgebers (e.g., bright light, physical activity).     

Clock polymorphisms and circadian rhythms phenotypes in a sample of the Brazilian population

A Clock polymorphism T to C situated in the 3' untranslated region (3'-UTR) has been associated with human diurnal preference. At first, Clock 3111C had been reported as a marker for evening preference. However these data are controversial, and data both corroborating and denying them have been reported. This study hypothesizes that differences in Clock genotypes could be observed if extreme morning-type subjects were compared with extreme evening-type subjects, and the T3111C and T257G polymorphisms were studied. The possible relationship between both polymorphisms and delayed sleep phase syndrome (DSPS) was also investigated. An interesting and almost complete linkage disequilibrium between the polymorphisms T257G in the 5' UTR region and the T3111C in the 3' UTR region of the Clock gene is described. Almost always, a G in position 257 corresponds to a C in position 3111, and a T in position 257 corresponds to a T in position 3111. The possibility of an interaction of these two regions in the Clock messenger RNA structure that could affect gene expression was analyzed using computer software. The analyses did not reveal an interaction between those two regions, and it is unlikely that this full allele correspondence affects Clock gene expression. These results show that there is no association between either polymorphism T3111C or T257G in the Clock gene with diurnal preference or delayed sleep phase syndrome (DSPS). These controversial data could result from the possible effects of latitude and clock genes interaction on circadian phenotypes.     

Modelling circadian rhythms of protein KaiA, KaiB and KaiC interactions in cyanobacteria

Cyanobacteria are the simplest organisms known that exhibit circadian rhythms. The mechanism of circadian rhythm generation in cyanobacteria is different from eukaryotes. Based on the recent experiments about the interaction of KaiA, KaiB, and KaiC proteins with the generation of circadian rhythms in vitro, we developed a mathematical model to describe post-translational oscillations and the possible chemical reactions involved in the circadian clock mechanism of cyanobacteria. In this model, a series of differential equations, with linear kinetics for binding of proteins, Michaelis - Menten kinetics for enzymatic processes and a term including an explicit delay for dissociation of the KaiA/KaiB/phospho-KaiC complex, are proposed describing the dynamics of the chemistry. It is demonstrated that the mathematical system can lead to circadian oscillation within a range of parameter values.     

Effects of physiological cycles of infused melatonin on circadian rhythmicity in pigeons

Summary The role of the hormone melatonin in the circadian system of pigeons (Columba livia) was investigated. Using an automatic infusion system, melatoni at physiological levels was delivered for 10 h each day to cannulated, pinealectomized (P-X) pigeons in constant darkness. These cyclic infusions of melatonin entrained feeding rhythms in P-X pigeons while vehicle infusions were ineffective entraining agents. When the retinae of P-X pigeons were removed (E-X), feeding rhythms were abolished in constant darkness. When cyclic melatonin infusions were delivered to these birds (E-X and P-X), feeding rhythmicity was restored whereas vehicle infusions alone did not restore rhythmicity. When melatonin infusions were terminated in E-X/P-X pigeons, feeding rhythms persisted for several days but eventually decayed. Blood melatonin levels were measured in both P-X and E-X/P-X birds infused cyclically with exogenous melatonin and were found to be within the physiological range both in level and pattern. These results strongly suggest that endogenous melatonin, released by the pineal gland and the retinae, regulates the timing of feeding rhythms by entraining other oscillators in the circadian system of the pigeon.Abbreviations P-X pinealectomized - E-X bilaterally enucleated - T period of infusion cycle - LD light: dark cycle - DD constant darkness     

Chronopharmacokinetics of Imipenem in the Rat

There are no studies indicating a possible modification of imipenem pharmacokinetics related to the hour (i.e., circadian time) of its administration. The aim of this study was to evaluate the influence of different times of intramuscular imipenem administration on its disposition in Wistar AF EOPS rats. Four groups of eight animals were given a single intramuscular injection of 140 mg/kg of imipenem either at 10∶00, 16∶00, 22∶00, or 04∶00 h. Blood samples were collected 0.5, 1, 2, 3, 4, 6, and 8 h after drug injection, and the main pharmacokinetic parameters determined were C_max, T_max, elimination half‐life (t_1/2), area under the concentration‐versus‐time curve (AUC), total serum clearance (CL/F), and volume of distribution (V/F). Circadian variation of C_max (49%), T_max (92%), and AUC (19%) was observed leading to variability of imipenem exposure. Clearance and volume of distribution were modified according to the circadian time of drug injection but did not reach statistical significance. The results suggest that varying the time of administration induces intra‐individual variability.