A circadian rhythm in heart rate variability contributes to the increased cardiac sympathovagal response to awakening in the morning

Morning hours are associated with a heightened risk of adverse cardiovascular events. Recent evidence suggests that the sleep-wake cycle and endogenous circadian system modulate cardiac function in humans and may contribute to these epidemiological findings. The aim of the present study was to investigate the interaction between circadian and sleep-wake-dependent processes on heart rate variability (HRV). Fifteen diurnally active healthy young adults underwent a 72-h ultradian sleep-wake cycle (USW) procedure (alternating 60-min wake episodes in dim light and 60-min nap opportunities in total darkness) in time isolation. The present study revealed a significant main effect of sleep-wake-dependent and circadian processes on cardiac rhythmicity, as well as a significant interaction between these processes. Turning the lights off was associated with a rapid increase in mean RR interval and cardiac parasympathetic modulation (high-frequency [HF] power), whereas low-frequency (LF) power and sympathovagal balance (LF:HF ratio) were reduced (p?≤?.001). A significant circadian rhythm in mean RR interval and HRV components was observed throughout the wake and nap episodes (p?≤?.001). Sleep-to-wake transitions occurring in the morning were associated with maximal shifts towards sympathetic autonomic activation as compared to those occurring during the rest of the day. Namely, peak LF:HF ratio was observed in the morning, coincidental with peak salivary cortisol levels. These results contribute to our understanding of the observed increase in cardiovascular vulnerability after awakening in the morning.     

Stress-induced susceptibility to sudden cardiac death in mice with altered serotonin homeostasis

In humans, chronic stressors have long been linked to cardiac morbidity. Altered serotonergic neurotransmission may represent a crucial pathophysiological mechanism mediating stress-induced cardiac disturbances. Here, we evaluated the physiological role of serotonin (5-HT) 1A receptors in the autonomic regulation of cardiac function under acute and chronic stress conditions, using 5-HT(1A) receptor knockout mice (KOs). When exposed to acute stressors, KO mice displayed a higher tachycardic stress response and a larger reduction of vagal modulation of heart rate than wild type counterparts (WTs). During a protocol of chronic psychosocial stress, 6 out of 22 (27%) KOs died from cardiac arrest. Close to death, they displayed a severe bradycardia, a lengthening of cardiac interval (P wave, PQ and QRS) duration, a notched QRS complex and a profound hypothermia. In the same period, the remaining knockouts exhibited higher values of heart rate than WTs during both light and dark phases of the diurnal rhythm. At sacrifice, KO mice showed a larger expression of cardiac muscarinic receptors (M2), whereas they did not differ for gross cardiac anatomy and the amount of myocardial fibrosis compared to WTs. This study demonstrates that chronic genetic loss of 5-HT(1A) receptors is detrimental for cardiovascular health, by intensifying acute, stress-induced heart rate rises and increasing the susceptibility to sudden cardiac death in mice undergoing chronic stress.     

Heart rate variability changes in business process outsourcing employees working in shifts

Background and Objectives

Irregular and poor quality sleep is common in business process outsourcing (BPO) employees due to continuous shift working. The influence of this on the cardiac autonomic activity was investigated by the spectral analysis of heart rate variability (HRV).

Methods

36 night shift BPO employees (working from 22:00 to 06:00h) and 36 age and sex matched day shift BPO employees (working from 08:00 to 16:00h) were recruited for the study. Five minute electrocardiogram (ECG) was recorded in all the subjects. Heart rate variability was analyzed by fast Fourier transformation using RMS Vagus HRV software. The results were analyzed using Mann Whitney U test, Student t-test, Wilcoxon signed rank test and were expressed as mean ± SD.

Results

Sleepiness was significantly higher among night shift workers as measured by Epworth Sleepiness Scale (p<0.001). Night shift BPO employees were found to have a trend towards lower values of vagal parameters - HF power (ms²), and higher values of sympathovagal parameters like LF Power (ms²) and the LF/HF power (%) suggesting decreased vagal activity and sympathetic over activity, when compared to day shift employees. However, HRV parameters did not vary significantly between the day shift employees and night shift workers baseline values, and also within the night shift group.

Interpretation and Conclusion

Night shift working increased the heart rate and shifted the sympathovagal balance towards sympathetic dominance and decreased vagal parameters of HRV. This is an indicator of unfavorable change in the myocardial system, and thus shows increased risk of cardiovascular disease among the night shift employees.     

Low-frequency oscillation of sympathetic nerve activity decreases during development of tilt-induced syncope preceding sympathetic withdrawal and bradycardia

Sympathetic activation during orthostatic stress is accompanied by a marked increase in low-frequency (LF, approximately 0.1-Hz) oscillation of sympathetic nerve activity (SNA) when arterial pressure (AP) is well maintained. However, LF oscillation of SNA during development of orthostatic neurally mediated syncope remains unknown. Ten healthy subjects who developed head-up tilt (HUT)-induced syncope and 10 age-matched nonsyncopal controls were studied. Nonstationary time-dependent changes in calf muscle SNA (MSNA, microneurography), R-R interval, and AP (finger photoplethysmography) variability during a 15-min 60 degrees HUT test were assessed using complex demodulation. In both groups, HUT during the first 5 min increased heart rate, magnitude of MSNA, LF and respiratory high-frequency (HF) amplitudes of MSNA variability, and LF and HF amplitudes of AP variability but decreased HF amplitude of R-R interval variability (index of cardiac vagal nerve activity). In the nonsyncopal group, these changes were sustained throughout HUT. In the syncopal group, systolic AP decreased from 100 to 60 s before onset of syncope; LF amplitude of MSNA variability decreased, whereas magnitude of MSNA and LF amplitude of AP variability remained elevated. From 60 s before onset of syncope, MSNA and heart rate decreased, index of cardiac vagal nerve activity increased, and AP further decreased to the level at syncope. LF oscillation of MSNA variability decreased during development of orthostatic neurally mediated syncope, preceding sympathetic withdrawal, bradycardia, and severe hypotension, to the level at syncope.     

Increased sympathetic and decreased parasympathetic cardiovascular modulation in normal humans with acute sleep deprivation.

Cardiovascular autonomic modulation during 36 h of total sleep deprivation (SD) was assessed in 18 normal subjects (16 men, 2 women, 26.0 +/- 4.6 yr old). ECG and continuous blood pressure (BP) from radial artery tonometry were obtained at 2100 on the first study night (baseline) and every subsequent 12 h of SD. Each measurement period included resting supine, seated, and seated performing computerized tasks and measured vigilance and executive function. Subjects were not supine in the periods between measurements. Spectral analysis of heart rate variability (HRV) and BP variability (BPV) was computed for cardiac parasympathetic modulation [high-frequency power (HF)], sympathetic modulation [low-frequency power (LF)], sympathovagal balance (LF/HF power of R-R variability), and BPV sympathetic modulation (at LF). All spectral data were expressed in normalized units [(total power of the components/total power-very LF) x 100]. Spontaneous baroreflex sensitivity (BRS), based on systolic BP and pulse interval powers, was also measured. Supine and sitting, BPV LF was significantly increased from baseline at 12, 24, and 36 h of SD. Sitting, HRV LF was increased at 12 and 24 h of SD, HRV HF was decreased at 12 h SD, and HRV LF/HF power of R-R variability was increased at 12 h of SD. BRS was decreased at 24 h of SD supine and seated. During the simple reaction time task (vigilance testing), the significantly increased sympathetic and decreased parasympathetic cardiac modulation and BRS extended through 36 h of SD. In summary, acute SD was associated with increased sympathetic and decreased parasympathetic cardiovascular modulation and decreased BRS, most consistently in the seated position and during simple reaction-time testing.     

Circadian rhythm of atrioventricular conduction predicts long-term survival in patients with chronic atrial fibrillation

The R-R interval of the electrocardiogram during atrial fibrillation (AF) appears absolutely irregular. However, the Poincaré plot of the R-R interval reveals a sector shape of distribution that is unique to AF. Furthermore, the height of lower envelope (LE1.0) of the distribution and the degree of scatter above the envelope (scattering index) may reflect the refractoriness and concealment of atrioventricular (AV) conduction, respectively. We previously observed that both the LE1.0 and scattering index show clear circadian rhythms in patients with chronic AF and that the rhythms are blunted in those with congestive heart failure and chronic AF. In the present study, we examined if the blunted circadian rhythm of the AV conduction has prognostic value in patients with chronic AF. We studied a retrospective cohort of 120 patients who underwent 24h Holter monitoring at baseline. During an observation period of 33 +/- 16 mon, there were 25 deaths (21%) including 13 cardiac and 8 stroke deaths. All patients showed significant circadian rhythms in both LE1.0 and scattering index with acrophases occurring at night; however, patients dying subsequently from cardiac causes, but not those from fatal stroke were blunted in the circadian rhythms (the amplitudes were < 55% of those in surviving patients). Furthermore, the reduced circadian amplitude of scattering index was an increased risk for cardiac death even after adjustment of coexisting cardiovascular risks [adjusted relative risk (95% confidence interval) per 1-SD decrement, 4.24 (1.54-11.6)]. When patients were divided by the circadian amplitude of the scattering index of 36.5 msec (mean minus 1-SD), the 5yr cardiac mortality below and above the cutoff was 57 and 6%, respectively (log-rank test, p < 0.001). We conclude that the blunted circadian rhythm of AV conduction is an independent risk for cardiac death in patients with chronic AF.     

Repeated psychosocial stress at night,but not day,affects the central molecular clock

We have recently demonstrated that the outcome of repeated social defeat (SD) on behavior, physiology and immunology is more negative when applied during the dark/active phase as compared with the light/inactive phase of male C57BL/6 mice. Here, we investigated the effects of the same stress paradigm, which combines a psychosocial and novelty stressor, on the circadian clock in transgenic PERIOD2::LUCIFERASE (PER2::LUC) and wildtype (WT) mice by subjecting them to repeated SD, either in the early light phase (social defeat light?=?SDL) or in the early dark phase (social defeat dark?=?SDD) across 19 days. The PER2::LUC rhythms and clock gene mRNA expression were analyzed in the suprachiasmatic nucleus (SCN) and the adrenal gland, and PER2 protein expression in the SCN was assessed. SDD mice showed increased PER2::LUC rhythm amplitude in the SCN, reduced Per2 and Cryptochrome1 mRNA expression in the adrenal gland, and increased PER2 protein expression in the posterior part of the SCN compared with single-housed control (SHC) and SDL mice. In contrast, PER2::LUC rhythms in the SCN of SDL mice were not affected. However, SDL mice exhibited a 2-hour phase advance of the PER2::LUC rhythm in the adrenal gland compared to SHC mice. Furthermore, plasma levels of brain-derived neurotrophic factor (BDNF) and BDNF mRNA in the SCN were elevated in SDL mice. Taken together, these results show that the SCN molecular rhythmicity is affected by repeated SDD, but not SDL, while the adrenal peripheral clock is influenced mainly by SDL. The observed increase in BDNF in the SDL group may act to protect against the negative consequences of repeated psychosocial stress.     

Spectral analysis of the heart rate variability in sleep

Spectral analysis of heart rate variability (HRV) during overnight polygraphic recording was performed in 11 healthy subjects. The total spectrum power, power of the VLF, LF and HF spectral bands and the mean R-R were evaluated. Compared to Stage 2 and Stage 4 non-REM sleep, the total spectrum power was significantly higher in REM sleep and its value gradually increased in the course of each REM cycle. The value of the VLF component (reflects slow regulatory mechanisms, e.g. the renin-angiotensin system, thermoregulation) was significantly higher in REM sleep than in Stage 2 and Stage 4 of non-REM sleep. The LF spectral component (linked to the sympathetic modulation) was significantly higher in REM sleep than in Stage 2 and Stage 4 non-REM sleep. On the contrary, a power of the HF spectral band (related to parasympathetic activity) was significantly higher in Stage 2 and Stage 4 non-REM than in REM sleep. The LF/HF ratio, which reflects the sympathovagal balance, had its maximal value during REM sleep and a minimal value in synchronous sleep. The LF/HF ratio significantly increased during 5-min segments of Stage 2 non-REM sleep immediately preceding REM sleep compared to 5-min segments of Stage 2 non-REM sleep preceding the slow-wave sleep. This expresses the sympathovagal shift to sympathetic predominance occurring before the onset of REM sleep. A significant lengthening of the R-R interval during subsequent cycles of Stage 2 non-REM sleep was documented, which is probably related to the shift of sympathovagal balance to a prevailing parasympathetic influence in the course of sleep. This finding corresponds to a trend of a gradual decrease of the LF/HF ratio in subsequent cycles of Stage 2 non-REM sleep.     

Heart Rate Variability as an Indicator of Chronic Stress Caused by Lameness in Dairy Cows

Most experimental studies on animal stress physiology have focused on acute stress, while chronic stress, which is also encountered in intensive dairy cattle farming–e.g. in case of lameness–, has received little attention. We investigated heart rate (HR) and heart rate variability (HRV) as indicators of the autonomic nervous system activity and fecal glucocorticoid concentrations as the indicator of the hypothalamic–pituitary–adrenal axis activity in lame (with locomotion scores 4 and 5; n = 51) and non-lame (with locomotion scores 1 and 2; n = 52) Holstein-Friesian cows. Data recorded during the periods of undisturbed lying–representing baseline cardiac activity–were involved in the analysis. Besides linear analysis methods of the cardiac inter-beat interval (time-domain geometric, frequency domain and Poincaré analyses) non-linear HRV parameters were also evaluated. With the exception of standard deviation 1 (SD1), all HRV indices were affected by lameness. Heart rate was lower in lame cows than in non-lame ones. Vagal tone parameters were higher in lame cows than in non-lame animals, while indices of the sympathovagal balance reflected on a decreased sympathetic activity in lame cows. All geometric and non-linear HRV measures were lower in lame cows compared to non-lame ones suggesting that chronic stress influenced linear and non-linear characteristics of cardiac function. Lameness had no effect on fecal glucocorticoid concentrations. Our results demonstrate that HRV analysis is a reliable method in the assessment of chronic stress, however, it requires further studies to fully understand the elevated parasympathetic and decreased sympathetic tone in lame animals.     

Poincaré plot interpretation using a physiological model of HRV based on a network of oscillators

In this paper, we develop a physiological oscillator model of which the output mimics the shape of the R-R interval Poincaré plot. To validate the model, simulations of various nervous conditions are compared with heart rate variability (HRV) data obtained from subjects under each prescribed condition. For a variety of sympathovagal balances, our model generates Poincaré plots that undergo alterations strongly resembling those of actual R-R intervals. By exploiting the oscillator basis of our model, we detail the way that low- and high-frequency modulation of the sinus node translates into R-R interval Poincaré plot shape by way of simulations and analytic results. With the use of our model, we establish that the length and width of a Poincaré plot are a weighted combination of low- and high-frequency power. This provides a theoretical link between frequency-domain spectral analysis techniques and time-domain Poincaré plot analysis. We ascertain the degree to which these principles apply to real R-R intervals by testing the mathematical relationships on a set of data and establish that the principles are clearly evident in actual HRV records.     

Altered autonomic cardiac regulation in individuals with Down syndrome

We tested the hypothesis that individuals with Down syndrome, but without congenital heart disease, exhibit altered autonomic cardiac regulation. Ten subjects with Down syndrome (DS) and ten gender-and age-matched healthy control subjects were studied at rest and during active orthostatism, which induces reciprocal changes in sympathetic and parasympathetic traffic to the heart. Autoregressive power spectral analysis was used to investigate R-R interval variability. Baroreflex modulation of sinus node was assessed by the spontaneous baroreflex sequences method. No significant differences between DS and control subjects were observed in arterial blood pressure at rest or in response to standing. Also, R-R interval did not differ at rest. R-R interval decreased significantly less during standing in DS vs. control subjects. Low-frequency (LFNU) and high-frequency (HFNU) (both expressed in normalized units) components of R-R interval variability did not differ between DS and control subjects at rest. During standing, significant increase in LFNU and decrease in HFNU were observed in control subjects but not in DS subjects. Baroreflex sensitivity (BRS) did not differ between DS and control subjects at rest and underwent significant decrease on going from supine to upright in both groups. However, BRS was greater in DS vs. control subjects during standing. These data indicate that subjects with DS exhibit reduced HR response to orthostatic stress associated with blunted sympathetic activation and vagal withdrawal and with a lesser reduction in BRS in response to active orthostatism. These findings suggest overall impairment in autonomic cardiac regulation in DS and may help to explain the chronotropic incompetence typically reported during exercise in subjects with DS without congenital heart disease.     

Fractal and periodic heart rate dynamics in fetal sheep: comparison of conventional and new measures based on fractal analysis

The physiological significance of spectral and fractal components of spontaneous heart rate (HR) variability in the fetus remains unclear. To examine the relationship between circadian rhythms in different measures of HR variability, R-R interval time series obtained by fetal ECGs were recorded continuously over 24 h in five pregnant sheep at 116-125 days gestation. Conventional measures of short-term (STV) and long-term variability (LTV), low-frequency (LF; 0.025-0.15 cycles/beat) and high-frequency (HF; 0.2-0.5 cycles/beat) spectral powers, the LF-to-HF ratio, and fractal dimension values were calculated from 24-h ECG recordings and quantified every 60 min. STV, LTV, and LF and HF spectral powers were minimal during the day but increased significantly to their highest values at night. We found a significant positive correlation between these measures, whereas the cosinor method showed significant similarity between their circadian rhythm patterns. Fetal R-R intervals also exhibited fractal structures. Fetal HR variability had a fractal structure, which was similar between day and night. These results suggested that the circadian rhythms exhibited by STV and LTV during the day were mainly due to changes in frequency components rather than to fractal components of fetal HR fluctuation.     

Inconsistency in the expression of locomotor and ERG circadian rhythms in the German cockroach, Blattella germanica (L.).

ERG recordings from German cockroaches showed that the amplitude of light-evoked responses have a circadian rhythmicity in adult males that coincided with the locomotor circadian rhythm. The peak of the response occurred during the subjective night, and the circadian period was less than 24 h under DD condition. In contrast, although the locomotor circadian rhythm was masked by the development of ovaries and pregnancy in females, their visual responses displayed circadian rhythmicity. This inconsistency in expression of locomotor and visual sensitivity circadian rhythms in females implied separate pacemakers for these two overt rhythms. After severing the optic nerves, changes in ERG amplitude of the operated cockroaches still displayed a circadian rhythm under DD condition, demonstrating that the visual sensitive pacemaker was located in the eye and independent from the locomotor pacemaker.     

Fractal properties of human muscle sympathetic nerve activity

Muscle sympathetic nerve activity (MSNA) in resting humans is characterized by cardiac-related bursts of variable amplitude that occur sporadically or in clusters. The present study was designed to characterize the fluctuations in the number of MSNA bursts, interburst interval, and burst amplitude recorded from the peroneal nerve of 15 awake, healthy human subjects. For this purpose, we used the Allan and Fano factor analysis and dispersional analysis to test whether the fluctuations were time-scale invariant (i.e., fractal) or random in occurrence. Specifically, we measured the slopes of the power laws in the Allan factor, Fano factor, and dispersional analysis curves. In addition, the Hurst exponent was calculated from the slope of the power law in the Allan factor curve. Whether the original time series contained fractal fluctuations was decided on the basis of a comparison of the values of these parameters with those for surrogate data blocks. The results can be summarized as follows. Fluctuations in the number of MSNA bursts and interburst interval were fractal in each of the subjects, and fluctuations in burst amplitude were fractal in four of the subjects. We also found that fluctuations in the number of heartbeats and heart period (R-R interval) were fractal in each of the subjects. These results demonstrate for the first time that apparently random fluctuations in human MSNA are, in fact, dictated by a time-scale-invariant process that imparts "long-term memory" to the sequence of cardiac-related bursts. Whether sympathetic outflow to the heart also is fractal and contributes to the fractal component of heart rate variability remains an open question.     

Effect of aging on baroreflex function in humans

Arterial blood pressure (BP) is regulated via the interaction of various local, humoral, and neural factors. In humans, the major neural pathway for acute BP regulation involves the baroreflexes. In response to baroreceptor activation/deactivation, as occurs during transient changes in BP, key determinants of BP, such as cardiac period/heart rate (via the sympathetic and parasympathetic nervous system) and vascular resistance (via the sympathetic nervous system), are modified to maintain BP homeostasis. In this review, the effects of aging on both the parasympathetic and sympathetic arms of the baroreflex are discussed. Aging is associated with decreased cardiovagal baroreflex sensitivity (i.e., blunted reflex changes in R-R interval in response to a change in BP). Mechanisms underlying this decrease may involve factors such as increased levels of oxidative stress, vascular stiffening, and decreased cardiac cholinergic responsiveness with age. Consequences of cardiovagal baroreflex impairment may include increased levels of BP variability, an impaired ability to respond to acute challenges to the maintenance of BP, and increased risk of sudden cardiac death. In contrast, baroreflex control of sympathetic outflow is not impaired with age. Collectively, changes in baroreflex function with age are associated with an impaired ability of the organism to buffer changes in BP. This is evidenced by the reduced potentiation of the pressor response to bolus infusion of a pressor drug after compared to before systemic ganglionic blockade in older compared with young adults.     

Sympathovagal imbalance in hyperthyroidism

We assessed sympathovagal balance in thyrotoxicosis. Fourteen patients with Graves' hyperthyroidism were studied before and after 7 days of treatment with propranolol (40 mg 3 times a day) and in the euthyroid state. Data were compared with those obtained in a group of age-, sex-, and weight-matched controls. Autonomic inputs to the heart were assessed by power spectral analysis of heart rate variability. Systemic exposure to sympathetic neurohormones was estimated on the basis of 24-h urinary catecholamine excretion. The spectral power in the high-frequency domain was considerably reduced in hyperthyroid patients, indicating diminished vagal inputs to the heart. Increased heart rate and mid-frequency/high-frequency power ratio in the presence of reduced total spectral power and increased urinary catecholamine excretion strongly suggest enhanced sympathetic inputs in thyrotoxicosis. All abnormal features of autonomic balance were completely restored to normal in the euthyroid state. beta-Adrenoceptor antagonism reduced heart rate in hyperthyroid patients but did not significantly affect heart rate variability or catecholamine excretion. This is in keeping with the concept of a joint disruption of sympathetic and vagal inputs to the heart underlying changes in heart rate variability. Thus thyrotoxicosis is characterized by profound sympathovagal imbalance, brought about by increased sympathetic activity in the presence of diminished vagal tone.     

A pilot investigation of the effect of extremely low frequency pulsed electromagnetic fields on humans' heart rate variability

The question whether pulsed electromagnetic field (PEMF) can affect the heart rhythm is still controversial. This study investigates the effects on the cardiocirculatory system of ELF-PEMFs. It is a follow-up to an investigation made of the possible therapeutic effect ELF-PEMFs, using a commercially available magneto therapeutic unit, had on soft tissue injury repair in humans. Modulation of heart rate (HR) or heart rate variability (HRV) can be detected from changes in periodicity of the R-R interval and/or from changes in the numbers of heart-beat/min (bpm), however, R-R interval analysis gives only a quantitative insight into HRV. A qualitative understanding of HRV can be obtained considering the power spectral density (PSD) of the R-R intervals Fourier transform. In this study PSD is the investigative tool used, more specifically the low frequency (LF) PSD and high frequency (HF) PSD ratio (LF/HF) which is an indicator of sympatho-vagal balance. To obtain the PSD value, variations of the R-R time intervals were evaluated from a continuously recorded ECG. The results show a HR variation in all the subjects when they are exposed to the same ELF-PEMF. This variation can be detected by observing the change in the sympatho-vagal equilibrium, which is an indicator of modulation of heart activity. Variation of the LF/HF PSD ratio mainly occurs at transition times from exposure to nonexposure, or vice versa. Also of interest are the results obtained during the exposure of one subject to a range of different ELF-PEMFs. This pilot study suggests that a full investigation into the effect of ELF-PEMFs on the cardiovascular system is justified.     

Role of parasympathetic overactivity in water immersion stress-induced gastric mucosal lesion in rat.

Stress ulcer is clinically prevalent, but the underlying mechanisms are not well understood. This study aimed to investigate the role of sympathovagal imbalance in the development of water immersion restraint stress (WRS)-induced gastric mucosal lesion. Wistar rats were subjected to either restraint stress (RS) (n = 7) or WRS (n = 7) for 5 h. Linear parameters of heart rate variability and Poincaré plot were analyzed on the basis of the surface ECGs. Gastric mucosal lesion was evaluated by gross anatomy and histology. Mean R-R intervals significantly increased (P < 0.001) in a time-dependent manner in the WRS group but slightly decreased (P < 0.001) in the RS group. Root mean square of successive differences of R-R intervals and high-frequency norm (high-frequency power normalized by the total frequency power) were significantly higher in the WRS group than the RS group (P < 0.001). Low-frequency norm and low-to-high-frequency ratio increased significantly 1 h after stress and then declined to similar levels in both groups. The Poincaré plots of R-R intervals in the WRS group shifted right-upwardly and showed dispersed patterns compared with the RS group. Gastric mucosae showed serious hemorrhage, effusion, and structural collapse in the WRS group but remained normal in the RS group. Bilateral cervical vagotomy suppressed the increase of heart rate variability and prevented the gastric mucosal lesion induced by WRS. We conclude that parasympathetic overactivity is the predominant autonomic response to WRS and is most probably the leading mechanism of WRS-induced gastric mucosal lesion in rat.     

Modeling the influence of chronopharmacological administration of synthetic glucocorticoids on the hypothalamic-pituitary-adrenal axis

ABSTRACT

Natural glucocorticoids, a class of cholesterol-derived hormones, modulate an array of metabolic, anti-inflammatory, immunosuppressive and cognitive signaling. The synthesis of natural glucocorticoids, largely cortisol in humans, is regulated by the hypothalamic-pituitary-adrenal (HPA) axis and exhibits pronounced circadian variation. Considering the central regulatory function of endogenous glucocorticoids, maintenance of the circadian activity of the HPA axis is essential to host survival and chronic disruption of such activity leads to systemic complications. There is a great deal of interest in synthetic glucocorticoids due to the immunosuppressive and anti-inflammatory properties and the development of novel dosing regimens that can minimize the disruption of endogenous activity, while still maintaining the pharmacological benefits of long-term synthetic glucocorticoid therapy. Synthetic glucocorticoids are associated with an increased risk of developing the pathological disorders related to chronic suppression of cortisol rhythmicity as a result of the potent negative feedback by synthetic glucocorticoids on the HPA axis precursors. In this study, a mathematical model was developed to explore the influence of chronopharmacological dosing of exogenous glucocorticoids on the endogenous cortisol rhythm considering intra-venous and oral dosing. Chronic daily dosing resulted in modification of the circadian rhythmicity of endogenous cortisol with the amplitude and acrophase of the altered rhythm dependent on the administration time. Simulations revealed that the circadian features of the endogenous cortisol rhythm can be preserved by proper timing of administration. The response following a single dose was not indicative of the response following long-term, repeated chronopharmacological dosing of synthetic glucocorticoids. Furthermore, simulations revealed the inductive influence of long-term treatment was only associated with low to moderate doses, while high doses generally led to suppression of endogenous activity regardless of the chronopharmacological dose. Finally, chronic daily dosing was found to alter the responsiveness of the HPA axis, such that a decrease in the amplitude of the cortisol rhythm resulted in a partial loss in the time-of-day dependent response to CRH stimulation, while an increase in the amplitude was associated with a more pronounced time-of-day dependence of the response.