Sensitivity of Heart Rate and Blood Pressure to Spontaneous Activity in Transgenic Rats

Spontaneous changes in heart rate (HR), activity and systolic (SBP) and diastolic (DBP) blood pressure have been measured in 3 groups of 7 transgenic [TGR(mRen-2)27] rats for 4 weeks, starting at 12 weeks of age, and living on a 12:12 L:D schedule (light on at 07:00 h). Group TG-ENA was given enalapril, an angiotensin-converting enzyme inhibitor, in its drinking water; group TG-AMLO was given the calcium-channel blocker, amlodipine, by the same route; and group TG-VEH had no addition to its drinking water and so acted as a control. The sensitivity of the cardiovascular variables (CV's) to spontaneous activity was assessed throughout the study period by measuring the gradient of [CV / activity]. For the control (TG-VEH) group, mean HR was highest during the dark phase, at which time the sensitivity to spontaneous activity was least. By contrast, the circadian rhythms of SBP and DBP were inverted, peaking in the light (resting) phase, and there was no reliable difference between the light and dark phases with regard to the sensitivity of SBP or DBP to the effects of spontaneous activity. Enalapril reduced SBP and DBP, but did not alter their phase inversion with respect to HR. However, in SBP and DBP, as well as HR, sensitivities to spontaneous activity were now greater in the light phase. Amlodipine also reduced SBP and DBP and, in addition, greatly reduced the amplitude of their circadian rhythms. With this treatment also, sensitivity to spontaneous activity was greatest in the light phase for HR, SBP and DBP. A simple explanation of these results is that, in the absence of treatment, transgenic rats of this age have DBP and, particularly, SBP values that are too high in the light (resting) phase to permit much further rise due to spontaneous activity, and that this "ceiling effect" no longer holds if SBP and DBP have been reduced pharmacologically.     

Effects of photoperiod reduction on rat circadian rhythms of BP, heart rate, and locomotor activity

The effects of a photoperiod reduction in the entrainment of circadian rhythms of systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and spontaneous locomotor activity (SLA) were determined in conscious Wistar rats by using radiotelemetry. Two groups of seven rats were maintained in a 12:12-h light-dark (12L/12D) photoperiod for 11 wk and then placed in a reduced photoperiod of 8:16-h light-dark (8L/16D) by advancing a 4-h darkness or by advancing and delaying a 2-h darkness for 6 wk. Finally, they were resynchronized to 12L/12D. Advancing a 4-h dark phase induced a 1-h advance of acrophase for SBP, DBP, and HR, but not for SLA. The percent rhythm, amplitude, and the 12-h mean values of all parameters were significantly decreased by the photoperiod reduction. When symmetrically advancing and delaying a 2-h dark phase, a 1 h 20 min delay of acrophases and a decrease in percent rhythms and amplitudes of SBP, DBP, HR, and SLA were observed. Only the 12-h mean values of HR and SLA were decreased. Our findings show that the cardiovascular parameters differ from SLA in phase-shift response to photoperiod reduction and that the adjustment of circadian rhythms to change from 12L/12D to 8L/16D photoperiod depends on the direction of the extension of the dark period.     

The Correlation Between Activity, Blood Pressure and Heart Rate in Freely Mobile Sprague-Dawley and Transgenic Rats

Systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR) and locomotor activity have been measured at 1-min intervals for 24 h in Sprague-Dawley (N = 5) and for 2x24 h in transgenic hypertensive (N = 4) rats. The animals were freely mobile and entrained to a 12:12 LD cycle (lights on at 0700). The endogenous circadian component of the cardiovascular variables was removed from the raw data, and then correlations between activity and the residual component (raw data minus the endogenous component) of SBP, DBP and HR were calculated. This calculation was performed twice, in the mid-light and mid-dark phases. We have investigated if the mean size of the correlation coefficients depended on cardiovascular variable (SBP, DBP or HR), phase (D or L) or strain (Sprague-Dawley, SPD, or Transgenic, TG, rats). Nearly all correlations were positive and ANOVA's showed a significant effect of cardiovascular variable for both strains, with correlations for HR being significantly higher than those for SBP and DBP. The mean correlations in the SPD strain were significantly higher than in the TG strain for variables SBP and DBP, but not for HR. The correlations between activity and blood pressure were more marked for SPD rats in the light (inactive) than dark (active) phase. Both strains showed ultradian rhythms in all variables, particularly in the light phase. If the analysis was repeated using deviations of the cardiovascular variables from a 1-h moving average rather than the endogenous circadian component, then the results were very similar. The results are discussed in terms of the links between the rhythms of activity and cardiovascular variables, with particular reference to differences between the two strains.     

The Correlation Between Activity,Blood Pressure and Heart Rate in Freely Mobile Sprague-Dawley and Transgenic Rats

Systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR) and locomotor activity have been measured at 1-min intervals for 24 h in Sprague-Dawley (N = 5) and for 2x24 h in transgenic hypertensive (N = 4) rats. The animals were freely mobile and entrained to a 12:12 LD cycle (lights on at 0700). The endogenous circadian component of the cardiovascular variables was removed from the raw data, and then correlations between activity and the residual component (raw data minus the endogenous component) of SBP, DBP and HR were calculated. This calculation was performed twice, in the mid-light and mid-dark phases. We have investigated if the mean size of the correlation coefficients depended on cardiovascular variable (SBP, DBP or HR), phase (D or L) or strain (Sprague-Dawley, SPD, or Transgenic, TG, rats). Nearly all correlations were positive and ANOVA's showed a significant effect of cardiovascular variable for both strains, with correlations for HR being significantly higher than those for SBP and DBP. The mean correlations in the SPD strain were significantly higher than in the TG strain for variables SBP and DBP, but not for HR. The correlations between activity and blood pressure were more marked for SPD rats in the light (inactive) than dark (active) phase. Both strains showed ultradian rhythms in all variables, particularly in the light phase. If the analysis was repeated using deviations of the cardiovascular variables from a 1-h moving average rather than the endogenous circadian component, then the results were very similar. The results are discussed in terms of the links between the rhythms of activity and cardiovascular variables, with particular reference to differences between the two strains.     

Endothelial Nitric Oxide Is Not Involved in Circadian Rhythm Generation of Blood Pressure: Experiments in Wild‐Type C57 and eNOS Knock‐Out Mice under Light‐Dark and Free‐Run Conditions

Endothelial nitric oxide synthase knock out mice (eNOS‐/‐) are mildly hypertensive in comparison to wild‐type (WT) mice. Hypertension in eNOS‐/‐ mice is partly the result of an increase in peripheral resistance due to the absence of the vasodilatory action of NO. No data are available for these animals regarding the 24 h blood pressure profile under the 12:12 h light‐dark cycle (LD) and constant dark (DD) conditions. Therefore, this study aimed to investigate by radiotelemetry the circadian rhythms in systolic blood pressure (SBP) and diastolic blood pressure (DBP) of six eNOS‐/‐ mice and five wild‐type mice under LD and DD. Data were collected beginning 3 wks after operation (implantation of sensor) for 2 wks under LD and for another 2 wks thereafter under DD. Our results show that eNOS‐/‐ mice were hypertensive under all experimental conditions. SBP and DBP were significantly higher by about 15% in eNOS‐/‐ mice. No differences were found in the pattern of the circadian rhythms, rhythmicity, or period lengths during LD or DD. The genetic deletion of eNOS seems to lead to higher SBP and DBP, but the circadian blood pressure pattern is still preserved with higher values during the night (active phase) and lower values during the daytime (rest phase). Thus, endothelial‐derived NO plays an important role in the regulation of vascular tone and haemodynamics, but it is not important for the circadian organization of SBP and DBP.     

Circadian Rhythm of Blood Pressure and Heart Rate in Healthy Persons and Kidney Transplant Patients: Correlations with Activity

Fourteen diurnally active (07: 00–22: 39 h) normotensive healthy control subjects and 14 kidney transplant patients were studied by ambulatory blood pressure monitoring and wrist actigraphy simultaneously during one 24-h period. In the control group, circadian rhythms in systolic (SBP), diastolic (DBP), and mean arterial (MAP) blood pressure, heart rate (HR), and wrist activity were documented by cosinor analysis with comparable afternoon peak times. In contrast, circadian rhythms with afternoon acrophases were detected only in HR and wrist activity in the patient group. The correlation of wrist activity with HR in controls and patients was comparable. Wrist activity and blood pressure were associated (r = 0.65 DBP and 0.54 SBP; p < 0.05) in controls, while in patients the relationship was weak or absent (r ranging from 0.02 SBP to 0.22 DBP). In 6 of 14 patients, BP and wrist activity were negatively correlated, reflecting the existence of nocturnal hypertension. In eight others, the correlation was small but positive. The 24-h pattern in BP and wrist activity in controls was comparably phased; however, this was not the case for the transplant patients, indicating the day-night pattern in blood pressure in this group is strongly dependent on pathologic phenomena rather than activity level and pattern.     

Circadian pattern of blood pressure,heart rate,and double product in liver glycogen storage disease

The objective of this study was to determine systolic, diastolic, and mean arterial blood pressure (SBP, DBP, and MAP), heart rate (HR), double-product (DP: SBP x HR), and activity levels and their 24h pattern in liver glycogen storage disease (LGSD) patients. A case series of 12 (11 pediatric and one adult) diurnally active LGSD (seven type I, three type III, and two type IX) subjects were simultaneously assessed by 24h ambulatory blood pressure monitoring and wrist actigraphy. Nine subjects were judged to be hypertensive based on the criterion of an elevated 24h mean SBP and/or DBP being elevated beyond reference standards or the SBP and/or DBP load (percentage of time BP exceeds normal values) being greater than 25%. Two of the three other subjects, not viewed as hypertensive based on their 24h average SBP or DBP, exhibited daytime or nighttime SBP and/or DBP load hypertension. Each study variables displayed statistically significant (p < 0.001) group circadian rhythmicity. The SBP, DBP, and MAP displayed comparable 24h patterns of appreciable amplitude (total peak-trough variation equal to 17.7, 23.6, and 19.6%, respectively, of the 24h mean) with highest values (orthophase) occurring approximately 11 h after the commencement of daytime activity. The sleep-time trough (bathyphase) occurred approximately 4.5 h before morning awakening. The statistically significant (p < 0.006) circadian rhythms of HR (amplitude equal to 33.2% of the 24h mean) and DP (amplitude equal to 49.4% of the 24h mean) peaked earlier, approximately 7.4 h into the daytime activity span. The sleep-time trough occurred approximately 3 h before morning awakening. The 24h pattern in the cardiovascular variables was correlated with the 24h pattern of activity, with r ranging from 0.50 for DBP to 0.39 for HR.     

Endothelial nitric oxide is not involved in circadian rhythm generation of blood pressure: experiments in wild-type C57 and eNOS knock-out mice under light-dark and free-run conditions

Endothelial nitric oxide synthase knock out mice (eNOS-/-) are mildly hypertensive in comparison to wild-type (WT) mice. Hypertension in eNOS-/- mice is partly the result of an increase in peripheral resistance due to the absence of the vasodilatory action of NO. No data are available for these animals regarding the 24 h blood pressure profile under the 12:12 h light-dark cycle (LD) and constant dark (DD) conditions. Therefore, this study aimed to investigate by radiotelemetry the circadian rhythms in systolic blood pressure (SBP) and diastolic blood pressure (DBP) of six eNOS-/- mice and five wild-type mice under LD and DD. Data were collected beginning 3 wks after operation (implantation of sensor) for 2 wks under LD and for another 2 wks thereafter under DD. Our results show that eNOS-/- mice were hypertensive under all experimental conditions. SBP and DBP were significantly higher by about 15% in eNOS-/- mice. No differences were found in the pattern of the circadian rhythms, rhythmicity, or period lengths during LD or DD. The genetic deletion of eNOS seems to lead to higher SBP and DBP, but the circadian blood pressure pattern is still preserved with higher values during the night (active phase) and lower values during the daytime (rest phase). Thus, endothelial-derived NO plays an important role in the regulation of vascular tone and haemodynamics, but it is not important for the circadian organization of SBP and DBP.     

CIRCADIAN PATTERN OF BLOOD PRESSURE,HEART RATE,AND DOUBLE PRODUCT IN LIVER GLYCOGEN STORAGE DISEASE

The objective of this study was to determine systolic, diastolic, and mean arterial blood pressure (SBP, DBP, and MAP), heart rate (HR), double-product (DP: SBP×HR), and activity levels and their 24h pattern in liver glycogen storage disease (LGSD) patients. A case series of 12 (11 pediatric and one adult) diurnally active LGSD (seven type I, three type III, and two type IX) subjects were simultaneously assessed by 24h ambulatory blood pressure monitoring and wrist actigraphy. Nine subjects were judged to be hypertensive based on the criterion of an elevated 24h mean SBP and/or DBP being elevated beyond reference standards or the SBP and/or DBP load (percentage of time BP exceeds normal values) being greater than 25%. Two of the three other subjects, not viewed as hypertensive based on their 24h average SBP or DBP, exhibited daytime or nighttime SBP and/or DBP load hypertension. Each study variables displayed statistically significant (p<0.001) group circadian rhythmicity. The SBP, DBP, and MAP displayed comparable 24h patterns of appreciable amplitude (total peak–trough variation equal to 17.7, 23.6, and 19.6%, respectively, of the 24h mean) with highest values (orthophase) occurring ～11 h after the commencement of daytime activity. The sleep-time trough (bathyphase) occurred ～4.5 h before morning awakening. The statistically significant (p<0.006) circadian rhythms of HR (amplitude equal to 33.2% of the 24h mean) and DP (amplitude equal to 49.4% of the 24h mean) peaked earlier, ～7.4 h into the daytime activity span. The sleep-time trough occurred ～3 h before morning awakening. The 24h pattern in the cardiovascular variables was correlated with the 24h pattern of activity, with r ranging from 0.50 for DBP to 0.39 for HR.     

Development of arterial pressure rhythm and cardiac contraction rate and effects of beta-adrenomimetic agents]

Blood pressure (BP) and heart rate (HR) rhythms were studied in premature infants (299 profiles ranged 24-106 h at 20--min intervals) and 11-13-year-old children (19 profiles for 48 h at 15-min intervals) to explore ultradian-to-circannual rhythm characteristics in BP and HR in preterm human infant and to elucidate the influence of antenatal betamimetic (BM) exposure on adolescent BP and HR rhythms. A circannual modulation of the 3-h amplitude (A) or MESOR of systolic BP (SBP) and diastolic BP (DBP) was seen mainly in prematures with a positive family history of high BP on the father's (f+) side or with both a patro linous and matro-linous history (f+m+), the circannual modulation of HR ultradian A was statistically significant only in "f- m-" infants. In urine collected at 3 h intervals for 24-h spans from 21 premature infants Na+,K+ and 11-oxycorticosteroids had a significant circadian rhythm. 9 adolescents (BM+), which were exposed in utero to different BM doses, had a significantly higher SBP and DBP MESOR and numerically higher circadian A as compared to 10 controls (BM-); correlation (P less than 0.05) between BM dose and HR circadian A was found. DBP led SBP in 8 or 10 "BM-" but in 4 of 9 "BM+" (acrophase difference 17 min and 3 min correspondingly).(ABSTRACT TRUNCATED AT 250 WORDS)     

Ultradian rhythmic models of blood pressure variation in normal human daily life

To examine levels and variance structure of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR), we measured those 3 variables every 7.5 min for 24 h (approximately 192 samples each subject) by ambulatory monitoring in 2 nominated groups of normal volunteers: younger (Y; 8 men, 5 women, 24-44 years) and older (O; 13 men, 12 women, 50-95 years). Y and O did not differ in either sleep or wake means for HR and DBP. Mean SBP in O was 17 mm Hg higher than in Y during wakefulness. Thirty-four subjects had significant low frequency variations (presumably the circadian rhythm) in SBP, DBP and HR, regardless of age. A periodic model fitting the time series required a 9 h feature (rhythm) for Y and O in DBP for best reduction of mean square error. In addition, O regularly showed 3 h features in both SBP and DBP, a 6 h feature in DBP and a 9 h feature in SBP, which were absent in Y. Our results suggest that low-power ultradian rhythms may appear in both SBP and DBP after age 50, and possibly serve as dynamic markers of normal cardiovascular aging.     

S20098 AFFECTS THE FREE-RUNNING RHYTHMS OF BODY TEMPERATURE AND ACTIVITY AND DECREASES LIGHT-INDUCED PHASE DELAYS OF CIRCADIAN RHYTHMS OF THE RAT

Mammalian endogenous circadian rhythms are entrained to the environmental day-night cycle by light exposure. Melatonin is involved in this entrainment by signaling the day-night information to the endogenous circadian pacemaker. Furthermore, melatonin is known to affect the circadian rhythm of body temperature directly. A striking property of the endogenous melatonin signal is its synthesis pattern, characterized by long-term elevated melatonin levels throughout the night. In the present study, the influence of prolonged treatment with the melatonin agonist S20098 during the activity phase of free-running rats was examined. This was achieved by giving S20098 in the food. The free-running body temperature and activity rhythms were studied. The present study shows that enhancement of the melatonin signal, using S20098, affected the free-running rhythm by gradual phase advances of the start of the activity phase, consequently causing an increase in length of the activity phase. A well-known feature of circadian rhythms is its time-dependent sensitivity for light. Light pulse exposure of an animal housed under continuous dark conditions can cause a phase shift of the circadian pacemaker. Therefore, in a second experiment, the influence of melatonin receptor stimulation on the sensitivity of the pacemaker to light was examined by giving the melatonin agonist S20098 in the food during 1 day prior to exposure to a 60-min light pulse of 0, 1.5, 15, or 150 lux given at circadian time (CT) 14. S20098 pretreatment caused a diminished lightpulse- induced phase shift when a light pulse of low light intensity (1.5 lux) was given. S20098 treatment via the food was sufficient to exert chronobiotic activity, and S20098 treatment resulting in prolonged overstimulation of melatonin receptors is able to attenuate the effect of light on the circadian timing system. (Chronobiology International, 18(5), 781–799, 2001)     

Rats with minimal hepatic encephalopathy show reduced cGMP-dependent protein kinase activity in hypothalamus correlating with circadian rhythms alterations

Patients with liver cirrhosis show disturbances in sleep and in its circadian rhythms which are an early sign of minimal hepatic encephalopathy (MHE). The mechanisms of these disturbances are poorly understood. Rats with porta-caval shunt (PCS), a model of MHE, show sleep disturbances reproducing those of cirrhotic patients. The aims of this work were to characterize the alterations in circadian rhythms in PCS rats and analyze the underlying mechanisms. To reach these aims, we analyzed in control and PCS rats: (a) daily rhythms of spontaneous and rewarding activity and of temperature, (b) timing of the onset of activity following turning-off the light, (c) synchronization to light after a phase advance and (d) the molecular mechanisms contributing to these alterations in circadian rhythms. PCS rats show altered circadian rhythms of spontaneous and rewarding activities (wheel running). PCS rats show more rest bouts during the active phase, more errors in the onset of motor activity and need less time to re-synchronize after a phase advance than control rats. Circadian rhythm of body temperature is also slightly altered in PCS rats. The internal period length (tau) of circadian rhythm of motor activity is longer in PCS rats. We analyzed some mechanisms by which hypothalamus modulate circadian rhythms. PCS rats show increased content of cGMP in hypothalamus while the activity of cGMP-dependent protein kinase was reduced by 41% compared to control rats. Altered cGMP-PKG pathway in hypothalamus would contribute to altered circadian rhythms and synchronization to light.     

Effects of Music Composed by Mozart and Ligeti on Blood Pressure and Heart Rate Circadian Rhythms in Normotensive and Hypertensive Rats

There is continuing discussion on the effect of music (“Mozart effect”) on numerous functions in man and experimental animals. Radiotelemetry now allows one to monitor cardiovascular functions in freely‐moving unrestrained experimental animals. Radiotelemetry was used to monitor systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), and motor activity (MA) in male normotensive WKY and hypertensive SHR animals. Rats were synchronized to a 12 h light (L): 12 h dark (D) regimen in an isolated, ventilated, light‐controlled, sound‐isolated animal container. Music (Mozart, Symphony # 40; Ligeti, String Quartet # 2) were played for 2 h at 75 dB in the animal cabin starting at the onset of L or D in a cross‐over design. Data were collected every 5 min for 24 h under control conditions and during and after music. In addition, plasma concentrations of norepinephrine (NE) were determined in unrestrained animals at 3 h intervals over 24 h. In both WKY and SHR, highly significant circadian rhythms were obtained in SBP, DBP, HR, and MA under control conditions; HR was lower and BP higher in SHR than in WKY. NE was circadian rhythmic in both strains with higher values in D; the increase in NE with immobilization was much more pronounced in SHR than in WKY. The music of Mozart had no effect on either parameter in WKY, neither in L nor in D. In contrast, in SHR, the music of Mozart presented in L significantly decreased HR and left BP unaffected, leading to a small decrease in cardiac output. The music of Ligeti significantly increased BP both in L and in D and reflexively reduced HR in L, the effects being long‐lasting over 24 h. Interestingly, white noise at 75 dB had no effect at all on either function in both strains. The effects of both Mozart and Ligeti cannot be attributed to a stress reaction, as stress due to cage switch increased HR and BP both in WKY and SHR. The study clearly demonstrates that music of different character (tempo, rhythm, pitch, tonality) can modify cardiovascular functions in freely‐moving rats, with SHR being more sensitive than normotensive animals. The relative contribution of the characteristics of the two pieces of music, however, needs further evaluation.     

Geological cycles

Abstract

Deep body temperature (DBT) and heart rate (HR) circadian rhythms were determined by radiotelemetry in 4 mares kept under controlled light and temperature conditions. Ovulations were determined by rectal palpation of their ovaries. Mean DBT values ranged from 35.85 ± .04 to 37.22 ± .02°C The circadian range of oscillation was extremely low, approximately 0.5° C, with time of maximum temperature occurring midway through the dark period. Mean HR values ranged from 36.4 ± 1.7 to 53.0 ±3.6 beats per min. The circadian range of oscillation was also low, less than 15 beats per min with time of maximum HR occurring approximately at the time of lights off. The HR circacadian rhythm peaked before the DBT circadian rhythm by 3 to 8 hrs. Ovulation did not appear to consistently affect DBT and HR circadian rhythms or their phase relationships.     

Age-related changes in circadian responses to dark pulses

Aging involves many alterations in circadian rhythms, including a loss of sensitivity to both photic and nonphotic time signals. This study investigated the sensitivity of young and old hamsters to the phase advancing effect of a 6-h dark pulse on the locomotor activity rhythm. Each hamster was tested four times during a period of approximately 9 mo; periods of exposure to a 14-h photoperiod were alternated with the periods of exposure to constant light (20-80 lx), during which the dark pulses were administered. There was no significant difference in the phase shifts exhibited by the young (4-10 mo) and old hamsters (19-25 mo) or in the amount of wheel running activity displayed during each dark pulse. However, young hamsters had a significantly greater propensity to exhibit split rhythms immediately after the dark pulses. These results suggest that, although aging does not reduce the sensitivity of the circadian pacemaker to this nonphotic signal, it alters one property of the pacemaker, i.e., the flexibility of the coupling of its component oscillators.     

Effect of NO synthase inhibition on cardiovascular circadian rhythms in wild-type and eNOS-knock-out mice

Cardiovascular functions (blood pressure [BP], heart rate [HR]) were radiotelemetrically studied in endothelial nitric oxide synthase (NOS) knock-out mice (eNOS-/-) and their wild type C57BL/6 (WT) controls. Studies were performed with and without inhibition of the NOS with the non-specific inhibitor N(omega)-Nitro-L-Arginin-Methylester (L-NAME). Six eNOS-/-and five WT mice, kept under a light:dark schedule of 12:12 h (lights on 07:00 h), were treated with L-NAME in tap water containing different concentrations (94, 282, and 940 mg/kg) each for three days. Under control conditions, the eNOS-/-mice are mildly hypertensive in comparison to WT. L-NAME increased systolic [SBP] and diastolic [DBP] blood pressures in WT mice to the levels of eNOS-/-mice after two days of L-NAME application with no dose-dependency, whereas L-NAME had no effects on SBP and DBP in eNOS-/-mice. In neither mouse strain were the circadian rhythms in BP and HR affected by drug treatment. The similarity of the 24 h BP profiles in eNOS-/-and L-NAME-treated WT mice support the notion that only the enothelial NOS and not other NOS isoenzymes are of importance for hypertension in the knock-out mouse strain.     

Suppression of circadian rhythms of pineal and testicular hormones following lithium treatment in normal and reversed light-dark cycles, constant light and constant dark in rats

The aim of the current investigation was to study the effect of lithium on circadian rhythms of pineal - testicular hormones by quantitations of pineal and serum serotonin, N-acetylserotonin and melatonin, and serum testosterone at four time points (06.00, 12.00, 18.00 and 24.00) of a 24-hr period under normal photoperiod (L:D), reversed photoperiod (D:L), constant light (L:L) and constant dark phase (D:D) in rats. Circadian rhythms were observed in pineal hormones in all the combinations of photoperiodic regimens, except in constant light, and in testosterone levels in all the photoperiodic combinations. Pineal and serum N-acetylserotonin and melatonin levels were higher than serotonin at night (24.00 hr), in natural L:D cycle, in reversed L:D cycle or similar to normal L:D cycle in constant dark phase, without any change in constant light. In contrast, testosterone level was higher in light phase (12.00 hr through 18.00 hr) than in the dark phase (24.00 hr through 06.00 hr) in normal L:D cycle, in reversed L:D cycle, similar to normal L:D cycle in constant dark (D:D), and reversed to that of the normal L:D cycle in constant light (L:L). Lithium treatment (2 mEq/kg body weight daily for 15 days) suppressed the magnitude of circadian rhythms of pineal and serum serotonin, N-acetylserotonin and melatonin, and testosterone levels by decreasing their levels at four time points of a 24-hr period in natural L:D or reversed D:L cycle and in constant dark (D:D). Pineal indoleamine levels were reduced after lithium treatment even in constant light (L:L). Moreover, lithium abolished the melatonin rhythms in rats exposed to normal (L:D) and reversed L:D (D:L) cycles, and sustained the rhythms in constant dark. But testosterone rhythm was abolished after lithium treatment in normal (L:D)/reversed L:D (D:L) cycle or even in constant light/dark. The findings indicate that the circadian rhythm exists in pineal hormones in alternate light - dark cycle (L:D/D:L) and in constant dark (D:D), but was absent in constant light phase (L:L) in rats. Lithium not only suppresses the circadian rhythms of pineal hormones, but abolishes the pineal melatonin rhythm only in alternate light - dark cycles, but sustains it in constant dark. The testosterone rhythm is abolished after lithium treatment in alternate light - dark cycle and constant light/dark. It is suggested that (a) normal circadian rhythms of pineal hormones are regulated by pulse dark phase in normal rats, (b) lithium abolishes pineal hormonal rhythm only in pulse light but sustains it in constant dark phase, and (c) circadian testosterone rhythm occurs in both pulse light or pulse dark phase in normal rats, and lithium abolishes the rhythm in all the combinations of the photoperiod. The differential responses of circadian rhythms of pineal and testicular hormones to pulse light or pulse dark in normal and lithium recipients are discussed.     

Activity,sleep and ambient light have a different impact on circadian blood pressure,heart rate and body temperature rhythms

The aim of the present study was to investigate the impact of endogenous and exogenous factors for the expression of the daily rhythms of body temperature (BT), blood pressure (BP) and heart rate (HR). One hundred and seventy-three young adults (YA), 17–24 years old (y.o.), of both genders were studied under a modified constant-routine (CR) protocol for 26 h. Participants were assigned randomly to groups with different lighting regimens: CR-LD, n = 77, lights (>400 l×) on from 09:00 to 17:00 h and off (<10 l×) from 17:00 to 09:00 next morning; CR-LL, n = 81, lights on (>400 l×) during the whole experimental session; CR-DD, n = 15, constant dim light (<10 l×) during the whole experiment. Systolic (SBP) and diastolic (DBP) BP, HR and BT were measured every 2 h. For comparison, the results of the former studies performed under conditions of regular life with an activity period from 07:00 to 23:00 h and sleep from 23:00 till 07:00 h (Control) were reanalyzed. Seven-day Ambulatory Blood Pressure Monitoring (ABPM) records from 27 YA (16–38 y.o.) and BT self-measurement data from 70 YA (17–30 y.o.) taken on ≥ 3 successive days at 08:00, 11:00, 14:00, 17:00, 20:00, 23:00 and 03:00 were available.

The obtained daily patterns were different between Control and CR-DD groups, due to effects of activity, sleep and light. The comparison of Control and CR-LD groups allowed the effects of sleep and activity to be estimated since the lighting conditions were similar. The activity level substantially elevated SBP, but not DBP. Sleep, on the other hand, lowered the nighttime DBP, but has no effect on SBP. HR was affected both by activity and sleep. In accordance with previous studies, these results confirm that the steep BP increase in the morning is not driven by the circadian clock, but rather by sympathoadrenal factors related to awakening and corresponding anticipatory mechanisms. The effect on BT was not significant.

To investigate the impact of light during the former dark time and darkness during the former light time, the CR-LL and CR-DD groups were each compared with the CR-LD group. Light delayed the evening decrease of BT, most likely via a suppression of the melatonin rise. Besides, it had a prominent arousal effect on SBP both in the former light and dark phases, a moderate effect on DBP and no effect on HR. Darkness induced decline in BT. BP values were decreased during the former light time. No effects on HR were found. Altogether, the results of the present paper show that BT, BP and HR are affected by exogenous factors differently. Moreover, the effect was gender-specific. Especially, the response of BT and BP to ambient light was evident only in females.

We suppose that the distinct, gender-specific responses of SBP, DBP and HR to activity, sleep and ambient light do reflect fundamental differences in the circadian control of various cardiovascular functions. Furthermore, the presented data are important for the elaboration of updated reference standards, the interpretation of rhythm disorders and for personalized chronotherapeutic approaches to prevent adverse cardiovascular events more effectively.     

S20098 AFFECTS THE FREE-RUNNING RHYTHMS OF BODY TEMPERATURE AND ACTIVITY AND DECREASES LIGHT-INDUCED PHASE DELAYS OF CIRCADIAN RHYTHMS OF THE RAT

Mammalian endogenous circadian rhythms are entrained to the environmental day-night cycle by light exposure. Melatonin is involved in this entrainment by signaling the day-night information to the endogenous circadian pacemaker. Furthermore, melatonin is known to affect the circadian rhythm of body temperature directly. A striking property of the endogenous melatonin signal is its synthesis pattern, characterized by long-term elevated melatonin levels throughout the night. In the present study, the influence of prolonged treatment with the melatonin agonist S20098 during the activity phase of free-running rats was examined. This was achieved by giving S20098 in the food. The free-running body temperature and activity rhythms were studied. The present study shows that enhancement of the melatonin signal, using S20098, affected the free-running rhythm by gradual phase advances of the start of the activity phase, consequently causing an increase in length of the activity phase. A well-known feature of circadian rhythms is its time-dependent sensitivity for light. Light pulse exposure of an animal housed under continuous dark conditions can cause a phase shift of the circadian pacemaker. Therefore, in a second experiment, the influence of melatonin receptor stimulation on the sensitivity of the pacemaker to light was examined by giving the melatonin agonist S20098 in the food during 1 day prior to exposure to a 60-min light pulse of 0, 1.5, 15, or 150 lux given at circadian time (CT) 14. S20098 pretreatment caused a diminished lightpulse- induced phase shift when a light pulse of low light intensity (1.5 lux) was given. S20098 treatment via the food was sufficient to exert chronobiotic activity, and S20098 treatment resulting in prolonged overstimulation of melatonin receptors is able to attenuate the effect of light on the circadian timing system. (Chronobiology International, 18(5), 781-799, 2001)