The cardiovascular system is highly organised in time; blood pressure (BP), heart rate (HR), peripheral resistance, pressure and the release/activity of vasodilating hormones all display pronounced ...circadian variations. Pathophysiological events within the cardiovascular system are also not random, as shown for instance by sudden cardiac death (SCD), stroke, ventricular arrhythmias (VA), arterial embolism, and symptoms of coronary heart disease (CHD) such as myocardial infarction (MI) and ischemia, angina attacks (AA) in stable angina (stA) or variant angina (varA) or silent ischemia. In hypertensive patients various anti-hypertensive drugs were investigated in crossover studies (morning vs. evening dosing); however consistent data were only obtained for angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers. Whereas in dippers ACE inhibitors had a super-dipping effect when dosed at night, no consistent difference in BP lowering effect on the 24-hr BP profile was found with calcium channel blockers after morning and evening dosing. In non-dippers the calcium channel blockers isradipine and amlodipine consistently transformed non-dippers into dippers, after evening dosing. Diuretics are also able to normalize a non-dipping behaviour. Moreover, a circadian phase-dependency in pharmacokinetics has been demonstrated for various cardiovascular active drugs such as beta-blockers, calcium channel blockers, oral nitrates and ACE inhibitors, modified by the pharmaceutical formulation. There is evidence that in hypertensive dippers anti-hypertensive drugs should be given in the early morning, whereas in non-dippers it may be necessary to add an evening dose or even to use a single evening dose in order to not only reduce high BP but also to normalize a disturbed non-dipping 24 hr BP profile. In CHD, calcium channel blockers-mainly short acting and non-retarded preparations-seem to be less effective than beta-adrenoceptor antagonists in reducing ischemic events during the night and early morning. However, the role of formulation and/or subclasses of the calcium channel blockers remains to be elucidated. In order to get more insight into the circadian regulation of the cardiovascular system animal models of primary and secondary hypertension have been studied in various strains of normotensive and hypertensive rats and mice. At least in rodents there is ample evidence that the 24-hr rhythms in BP and HR are under the control of biological clock(s) as they persist under constant darkness (i.e. in free-run conditions) with a period deviating from 24 hr; these rhythms are abolished by lesioning of the "master clock" located in the suprachiasmatic nuclei (SCN). In conclusion, chronobiological and chronopharmacological studies are important experimental and clinical approaches to get a better insight into the physiological and pathophysiological regulation of the cardiovascular system including their rhythmic organisation. Circadian time-dependent clinical studies also have implications for drug therapy in hypertension and CHD.
Background and aim
Inflammatory myopathies are heterogeneous in terms of etiology, (immuno)pathology, and clinical findings. Endothelial cell injury, as it occurs in DM, is a common feature of ...numerous inflammatory and non-inflammatory vascular diseases. Vascular regeneration is mediated by both local and blood-derived mechanisms, such as the mobilization and activation of so-called proangiogenic cells (PACs) or early endothelial progenitor cells (eEPCs). The current study aimed to evaluate parameters of eEPC integrity in dermatomyositis (DM), compared to necrotizing myopathy (NM) and to non-myopathic controls.
Methods
Blood samples from DM and NM patients were compared to non-myositis controls and analyzed for the following parameters: circulating CD133
+
/VEGFR-2
+
cells, number of colony-forming unit endothelial cells (CFU-ECs), concentrations of angiopoietin 1, vascular endothelial growth factor (VEGF), and CXCL-16. Muscle biopsies from DM and NM subjects underwent immunofluorescence analysis for CXCR6, nestin, and CD31 (PECAM-1). Finally, myotubes, derived from healthy donors, were stimulated with serum samples from DM and NM patients, subsequently followed by RT-PCR for the following candidates: IL-1β, IL-6, nestin, and CD31.
Results
Seventeen (17) DM patients, 7 NM patients, and 40 non-myositis controls were included. CD133
+
/VEGFR-2
+
cells did not differ between the groups. Both DM and NM patients showed lower CFU-ECs than controls. In DM, intramuscular CD31 abundances were significantly reduced, which indicated vascular rarefaction. Muscular CXCR6 was elevated in both diseases. Circulating CXCL-16 was higher in DM and NM in contrast, compared to controls. Serum from patients with DM but not NM induced a profound upregulation of mRNS expression of CD31 and IL-6 in cultured myotubes.
Conclusion
Our study demonstrates the loss of intramuscular microvessels in DM, accompanied by endothelial activation in DM and NM. Vascular regeneration was impaired in DM and NM. The findings suggest a role for inflammation-associated vascular damage in the pathogenesis of DM.
The objective of this study was to investigate the effects of recorded lullabies and taped maternal voice in premature infants.
Sixty-two preterm infants in a stable condition with 30<37 weeks of ...gestation and <10 days of postnatal age were randomly assigned to hear (A) recorded lullabies or (B) taped maternal voice for 30 min each evening during 14 consecutive days or (C) receive no standardized acoustic stimulation (control group). Heart rate and respiratory rate were recorded daily before, during and after the intervention (A and B) or a comparable period with no intervention (C), whereas activity was measured on days 1, 7 and 14 of the intervention using accelerometers.
Both interventions led to a significant decrease in heart rate and respiratory rate during and after the stimulation when compared with the control group. The changes were more pronounced in infants with higher gestational ages (P=0.001). Lower activity was measured during the intervention when compared with the control group (P<0.01).
Standardized acoustic stimulation with recorded lullabies and taped maternal voice led to a decrease in heart rate and respiratory rate, and was associated with lower activity. Whether this indicates a reduced stress reaction needs to be investigated in further studies.
The objective of the present study was to determine the prevalence of symptoms generally attributed to hypertension and the relationship between symptoms and blood pressure categories. Routine office ...blood pressure measurement in the morning was obtained and morning symptoms were reported using a standardized questionnaire in a multicenter study from general practitioners in Germany. Dizziness and headaches were significantly (P<0.001) more prevalent in 2154 untreated hypertensives (19.6 and 17.0%) as compared with 1399 normotensives (13.6 and 7.4%), whereas tiredness was less in hypertensives (12.0 vs 17.0%, P<0.01). In untreated and in 52 469 treated hypertensives, the overall prevalence of symptoms increased constantly with blood pressure levels from 26.1% in untreated male patients with mild hypertension to 54.3% of female patients with severe treated hypertension, with a higher prevalence in women (+7% vs men) and in patients with concomitant diseases (+13% vs patients without concomitant diseases). The prevalence of symptoms in older patients with untreated isolated systolic hypertension was not different from younger normotensives. There was a tight positive correlation between systolic and diastolic blood pressure and dizziness (R=0.73 and 0.76) as well as headaches (R=0.83 and 0.90) for all blood pressure levels in all patient groups. Typical hypertension-attributed symptoms like dizziness and headaches are more prevalent in hypertensives and they are closely related to blood pressure levels in untreated and treated hypertensives. Morning symptoms in hypertensives may suggest that there is inadequate control of blood pressure. More attention should be paid to perceived symptoms in hypertensives.
Hypertension is a side effect of systemically administered glucocorticoids, but the underlying molecular mechanism remains poorly understood. Ingestion of dexamethasone by rats telemetrically ...instrumented increased blood pressure progressively over 7 days. Plasma concentrations of Na+ and K+ and urinary Na+ and K+ excretion remained constant, excluding a mineralocorticoid-mediated mechanism. Plasma NO2-/NO3- (the oxidation products of NO) decreased to 40%, and the expression of endothelial NO synthase (NOS III) was found down-regulated in the aorta and several other tissues of glucocorticoid-treated rats. The vasodilator response of resistance arterioles was tested by intravital microscopy in the mouse dorsal skinfold chamber model. Dexamethasone treatment significantly attenuated the relaxation to the endothelium-dependent vasodilator acetylcholine, but not to the endothelium-independent vasodilator S-nitroso-N-acetyl-D,L-penicillamine. Incubation of human umbilical vein endothelial cells, EA.hy 926 cells, or bovine aortic endothelial cells with several glucocorticoids reduced NOS III mRNA and protein expression to 60-70% of control, an effect that was prevented by the glucocorticoid receptor antagonist mifepristone. Glucocorticoids decreased NOS III mRNA stability and reduced the activity of the human NOS III promoter (3.5 kilobases) to ≈ 70% by decreasing the binding activity of the essential transcription factor GATA. The expressional down-regulation of endothelial NOS III may contribute to the hypertension caused by glucocorticoids.
The nitric oxide (NO) system is involved in the regulation of the cardiovascular system in controlling central and peripheral vascular tone and cardiac functions. It was the aim of this study to ...investigate in wild-type C57BL 6 and endothelial nitric oxide synthase (eNOS) knock-out mice (eNOS- -) the contribution of NO on the circadian rhythms in heart rate (HR), motility (motor activity MA), and body temperature (BT) under various environmental conditions. Experiments were performed in 12 12 h of a light:dark cycle (LD), under free-run in total darkness (DD), and after a phase delay shift of the LD cycle by −6 h (i.e., under simulation of a westward time zone transition). All parameters were monitored by radiotelemetry in freely moving mice. In LD, no significant differences in the rhythms of HR and MA were observed between the two strains of mice. BT, however, was significantly lower during the light phase in eNOS- - mice, resulting in a significantly greater amplitude. The period of the free-running rhythm in DD was slightly shorter for all variables, though not significant. In general, rhythmicity was greater in eNOS- - than in C57 mice both in LD and DD. After a delay shift of the LD cycle, HR and BT were resynchronized to the new LD schedule within 5-6 days, and resynchronization of MA occurred within 2-3 days. The results in telemetrically instrumented mice show that complete knock-out of the endothelial NO system-though expressed in the suprachiasmatic nuclei and in peripheral tissues-did not affect the circadian organization of heart rate and motility. The circadian regulation of the body temperature was slightly affected in eNOS- - mice.
1 Division of Neurosurgical Research, Department of Neurosurgery, and 2 Institute of Pharmacology and Toxicology, Faculty of Clinical Medicine Mannheim, University of Heidelberg, Mannheim, Germany
...Submitted 8 December 2004
; accepted in final form 6 May 2005
Cardiovascular parameters such as arterial blood pressure (ABP) and heart rate display pronounced circadian variation. The present study was performed to detect whether there is a circadian periodicity in the regulation of cerebral perfusion. Normotensive Sprague-Dawley rats (SDR, 15 wk old) and hypertensive (mREN2)27 transgenic rats (TGR, 12 wk old) were instrumented in the abdominal aorta with a blood pressure sensor coupled to a telemetry system for continuous recording of ABP, heart rate, and locomotor activity. After 512 days, a laser-Doppler flow (LDF) probe was attached to the skull by means of a guiding device to measure changes in brain cortical blood flow (CBF). After the animals recovered from anesthesia, measurements were taken for 34 days. The time series were analyzed with respect to the midline estimating statistic of rhythm (i.e., mean value of a periodic event after fit to a cosine function), amplitude, and acrophase (i.e., phase angle that corresponds to the peak of a given period) of the 24-h period. The LDF signal displayed a significant circadian rhythm, with the peak occurring at around midnight in SDR and TGR, despite inverse periodicity of ABP in TGR. This finding suggests independence of LDF periodicity from ABP regulation. Furthermore, the acrophase of the LDF was consistently found before the acrophase of the activity. From the present data, it is concluded that there is a circadian periodicity in the regulation of cerebral perfusion that is independent of circadian changes in ABP and probably is also independent of locomotor activity. The presence of a circadian periodicity in CBF may have implications for the occurrence of diurnal alterations in cerebrovascular events in humans.
circadian rhythm; cerebral perfusion; arterial blood pressure; locomotor activity; radiotelemetry
Address for reprint requests and other correspondence: L. Schilling, Div. of Neurosurgical Research, Dept. of Neurosurgery, Univ. Hospital Mannheim, Theodor Kutzer-Ufer 1-3, D-68135 Mannheim, Germany (e-mail: lothar.schilling{at}nch.ma.uni-heidelberg.de )
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 rhythms in the functions of the body are well established, e.g. in cardiovascular (blood pressure, heart rate, blood flow, etc.), pulmonary, hepatic and renal functions. Also the symptoms ...and the onset of diseases are not randomly distributed within 24 hours of a day (e.g. coronary infarction, angina pectoris attacks, silent ischaemia, asthmatic attacks). Accordingly, the effects and/or pharmacokinetics of drugs can display significant daily variations. Recent data on the chronopharmacodynamics and chronopharmacokinetics of H
2-blockers, antiasthmatics (theophylline,
β-agonists, glucocorticoids), cardiovascular active drugs (
β-blockers, organic nitrates, calcium channel blockers, ACE-inhibitors) are described as representative examples. The data demonstrate that biological rhytms can have an impact on drug therapy.
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