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Biomedical subjects

A Unbehaun

Publications and source records attributed to A Unbehaun.

14 recordsLinked to original sources
PubMed2001

Hypochlorite-modified low density lipoprotein inhibits nitric oxide synthesis in endothelial cells via an intracellular dislocalization of endothelial nitric-oxide synthase.

Hypochlorous acid/hypochlorite, generated by the myeloperoxidase/H(2)O(2)/halide system of activated phagocytes, has been shown to oxidize/modify low density lipoprotein (LDL) in vitro and may be involved in the formation of atherogenic lipoproteins in vivo. Accordingly, hypochlorite-modified (lipo)proteins have been detected in human atherosclerotic lesions where they colocalize with macrophages and endothelial cells. The present study investigates the influence of hypochlorite-modified LDL on endothelial synthesis of nitric oxide (NO) measured as formation of citrulline (coproduct of NO) and cGMP (product of the NO-activated soluble guanylate cyclase) upon cell stimulation with thrombin or ionomycin. Pretreatment of human umbilical vein endothelial cells with hypochlorite-modified LDL led to a time- and concentration-dependent inhibition of agonist-induced citrulline and cGMP synthesis compared with preincubation of cells with native LDL. This inhibition was neither due to a decreased expression of endothelial NO synthase (eNOS) nor to a deficiency of its cofactor tetrahydrobiopterin. Likewise, the uptake of l-arginine, the substrate of eNOS, into the cells was not affected. Hypochlorite-modified LDL caused remarkable changes of intracellular eNOS distribution including translocation from the plasma membrane and disintegration of the Golgi location without altering myristoylation or palmitoylation of the enzyme. In contrast, cyclodextrin known to deplete plasma membrane of cholesterol and to disrupt caveolae induced only a disappearance of eNOS from the plasma membrane that was not associated with decreased agonist-induced citrulline and cGMP formation. The present findings suggest that mislocalization of NOS accounts for the reduced NO formation in human umbilical vein endothelial cells treated with hypochlorite-modified LDL and point to an important role of Golgi-located NOS in these processes. We conclude that inhibition of NO synthesis by hypochlorite-modified LDL may be an important mechanism in the development of endothelial dysfunction and early pathogenesis of atherosclerosis.

Antioxidants↗
PubMed2001

L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin.

Ascorbic acid has been shown to stimulate endothelial nitric oxide (NO) synthesis in a time- and concentration-dependent fashion without affecting NO synthase (NOS) expression or l-arginine uptake. The present study investigates if the underlying mechanism is related to the NOS cofactor tetrahydrobiopterin. Pretreatment of human umbilical vein endothelial cells with ascorbate (1 microm to 1 mm, 24 h) led to an up to 3-fold increase of intracellular tetrahydrobiopterin levels that was concentration-dependent and saturable at 100 microm. Accordingly, the effect of ascorbic acid on Ca(2+)-dependent formation of citrulline (co-product of NO) and cGMP (product of the NO-activated soluble guanylate cyclase) was abolished when intracellular tetrahydrobiopterin levels were increased by coincubation of endothelial cells with sepiapterin (0.001-100 microm, 24 h). In contrast, ascorbic acid did not modify the pterin affinity of endothelial NOS, which was measured in assays with purified tetrahydrobiopterin-free enzyme. The ascorbate-induced increase of endothelial tetrahydrobiopterin was not due to an enhanced synthesis of the compound. Neither the mRNA expression of the rate-limiting enzyme in tetrahydrobiopterin biosynthesis, GTP cyclohydrolase I, nor the activities of either GTP cyclohydrolase I or 6-pyruvoyl-tetrahydropterin synthase, the second enzyme in the de novo synthesis pathway, were altered by ascorbate. Our data demonstrate that ascorbic acid leads to a chemical stabilization of tetrahydrobiopterin. This was evident as an increase in the half-life of tetrahydrobiopterin in aqueous solution. Furthermore, the increase of tetrahydrobiopterin levels in intact endothelial cells coincubated with cytokines and ascorbate was associated with a decrease of more oxidized biopterin derivatives (7,8-dihydrobiopterin and biopterin) in cells and cell supernatants. The present study suggests that saturated ascorbic acid levels in endothelial cells are necessary to protect tetrahydrobiopterin from oxidation and to provide optimal conditions for cellular NO synthesis.

Ascorbic Acid↗
PubMed2000

Vascular response to angiotensin II in atherosclerosis: role of the baroreflex.

High-cholesterol alimentation is associated with an induction of angiotensin-converting enzyme and angiotensin II receptor expression within the vascular wall of the aorta. Despite an enhanced pressure response to angiotensin II in atherosclerotic conscious rabbits, angiotensin II-induced contraction was reduced in isolated vascular rings from the aorta and unchanged in those from the iliac artery. We, therefore, investigated whether cholesterol-induced atherosclerosis enhances overall vascular responsiveness to angiotensin II in intact animals and whether an altered arterial baroreflex sensitivity can explain the discrepancy between experiments in intact animals and isolated blood vessels. Rabbits were maintained on a high-cholesterol diet (2 g/d cholesterol plus 20 mL/d sunflower seed oil, n=11) or on a standard diet (n=12) for 12 weeks. Total serum lipids markedly increased (P<0.05). Tissue examinations 6 weeks after termination of the high-cholesterol diet revealed distinct atherosclerosis and elevated cholesterol content in the aorta (P<0.05). A high-cholesterol diet did not change baseline hemodynamic parameters. However, angiotensin II-induced increases in total peripheral resistance were larger in the atherosclerotic animals (86.3+/-13.0 versus 41.9+/-9.7 mm Hg. L(-1). min, P<0.05). In addition, the blood pressure pulse interval relationship was markedly reduced (slope: 0.80+/-0.14 versus 0. 49+/-0.06 ms/mm Hg, P<0.05), which suggested that the baroreflex blunted the angiotensin II response to a lesser extent in atherosclerotic animals. In conclusion, the overall vascular responsiveness to angiotensin II is increased in the atherosclerotic rabbit as indicated by the larger increase in total peripheral resistance. An attenuation of the arterial baroreflex sensitivity may contribute to this effect.

Angiotensin II↗
PubMed1999

Rhythms and complexity of respiration during sleep in pre-term infants.

The aim of this study is to test rhythmic and complex properties of respiratory control in former ventilated, pre-term infants during quiet and active sleep. The children had a higher risk for sudden infant death due to bronchopulmonary dysplasia (BPD). Twelve infants suffering from BPD and 12 control infants, matched regarding their post-conceptional age, were examined polygraphically during quiet (QS) and active sleep (AS). The respiratory rate (RR), the ratio (LF/HF) between the low-frequency power (LF) and the high-frequency power (HF) of the spectra of the thoracic respiratory effort, and the frequency of the dominant peak within LF (LFF) and HF (HFF) were computed. The correlation dimension (D2) of the respiratory signal was calculated to determine the complexity of the respiratory control. The transcutaneous pO2 (tcpO2) and pCO2 and the oxygen saturation (sO2) were analysed. Infants with BPD had significantly higher RR and HFF during QS (median: BPD 48 breaths min-1; control 32 breaths min-1). tcpO2 and sO2 were significantly lower in the BPD group. No differences were found in LF/HF, LFF or D2 between groups, either in QS or in AS. D2 ranged between 1.8 and 3.8, showing significantly higher values during AS. LFF was found to be lower during active sleep (AS 0.04-0.05 Hz; QS about 0.06 Hz). We propose that in infants with BPD the lower lung compliance and the higher resistance, and possibly also the hypoxaemia, contribute to the acceleration of breathing. The behaviour of RR, spectral parameters and D2 indicates a specific, functional setting rather than a regulatory impairment in infants with BPD.

Bronchopulmonary Dysplasia↗
PubMed1997

The transcriptional activation pattern of lipopolysaccharide binding protein (LBP) involving transcription factors AP-1 and C/EBP beta.

Lipopolysaccharide (LPS) Binding Protein (LBP) is an acute phase protein with the ability to recognize bacterial LPS and transport it to the CD14 molecule or into HDL particles. It is synthesized in hepatocytes and secreted into the blood stream. LBP levels significantly rise during the acute phase response and levels of LBP may be important for an appropriate host reaction to bacterial challenge and for developing the sepsis syndrome. In order to elucidate the mechanisms of LBP regulation we investigated its transcription pattern and performed promoter studies under experimental conditions mimicking an acute phase scenario. In human hepatoma cell lines stimulation with IL-1 beta, IL-6, TNF-alpha and dexamethasone leads to strong transcriptional activation of the LBP gene in a dose- and time-dependent manner. IL-6 alone induces LBP significantly, whereas IL-1 beta mainly increases the IL-6 effect when applied in combination. Our results furthermore show that AP-1 and C/EBP beta are transcription factors involved in the activation of the LBP gene, as revealed by Luciferase reporter gene analysis and electromobility shift assays. Elucidating the mechanism of transcriptional activation of LBP potentially may help in understanding host-pathogen response patterns and mechanisms involved in the acute phase reaction and in the pathophysiology of sepsis.

Acute-Phase Proteins↗
PubMed1997

Control of transcriptional activation of the lipopolysaccharide binding protein (LBP) gene by proinflammatory cytokines.

The lipopolysaccharide binding protein (BLP) is of major importance for endotoxin recognition, presentation and subsequent cytokine induction in immune cells. As a member of a growing family of structurally and functionally related proteins, LBP is synthesized in hepatocytes and constitutively secreted into the bloodstream. During the acute-phase response, however, LBP levels rise substantially. In this article the mechanisms of induction of LBP protein synthesis are highlighted. Induction of LBP in hepatocytes is the result of transcriptional and posttranscriptional mechanisms, as shown by nuclear run-on and RNA half-life experiments. Cloning of the 5' flanking region of the LBP gene gave results consistent with the LBP promoter as a typical acute-phase protein promoter. Reporter-gene assays employing the Luciferase gene and mutation variants of the LBP promoter revealed that integrity of a common acute-phase promoter motif, binding STAT-3, is essential for activation of the LBP promoter. Elucidating the transcriptional activation mechanism could show the way how to therapeutically lower LBP levels in high-risk patients in order to reduce their susceptibility to Gram-negative septic shock.

Acute-Phase Proteins↗
PubMed1996

Interaction of heart-rate fluctuations and respiration in 12 to 14-year-old children during sleeping and waking.

Our study was designed to investigate and quantitatively characterise the interaction of breathing and instantaneous heart rate. Comparisons were made during consciousness at rest, and during non-REM sleep. 31 12-14-year-old healthy children were subjected to a 24-h polygraphic electrocardiogram, respirogram, electrooculogram and actogram measurements. The data were analysed by means of power spectral analysis and coherence spectra. The peak frequency of high-frequency heart rate fluctuations was always clearly related to the breathing frequency, i.e., respiratory sinus arrhythmia is present in both states. Moving squared coherence analysis demonstrates the stability of the cardiorespiratory coupling to remain constant during wakefulness or non-REM sleep. However, coherence increases from waking state to non-REM sleep. The lower coherence during waking state may be explained by greater additional central and peripheral influences on the cardiorespiratory coupling or by increased non-linear properties of the transfer system due to operating point shifting.

Adolescent↗
PubMed1996

The lipopolysaccharide-binding protein is a secretory class 1 acute-phase protein whose gene is transcriptionally activated by APRF/STAT/3 and other cytokine-inducible nuclear proteins.

Acute-phase reactants (APRs) are proteins synthesized in the liver following induction by interleukin-1 (IL-1), IL-6, and glucocorticoids, involving transcriptional gene activation. Lipopolysaccharide-binding protein (LBP) is a recently identified hepatic secretory protein potentially involved in the pathogenesis of sepsis, capable of binding the bacterial cell wall product endotoxin and directing it to its cellular receptor, CD14. In order to examine the transcriptional induction mechanisms by which the LBP gene is activated, we have investigated the regulation of expression of its mRNA in vitro and in vivo as well as the organization of 5' upstream regulatory DNA sequences. We show that induction of LBP expression is transcriptionally regulated and is dependent on stimulation with IL-1beta, IL-6, and dexamethasone. By definition, LBP thus has to be viewed as a class 1 acute-phase protein and represents the first APR identified which is capable of detecting pathogenic bacteria. Furthermore, cloning of the LBP promoter revealed the presence of regulatory elements, including the common APR promoter motif APRE/STAT-3 (acute-phase response element/signal transducer and activator of transcription 3). Luciferase reporter gene assays utilizing LBP promoter truncation and point mutation variants indicated that transcriptional activation of the LBP gene required a functional APRE/STAT-3 binding site downstream of the transcription start site, as well as an AP-1 and a C/EBP (CCAAT enhancer-binding protein) binding site. Gel retardation and supershift assays confirmed that upon cytokine stimulation APRF/STAT-3 binds to its recognition site, leading to strong activation of the LBP gene. Unraveling of the mechanism of transcriptional activation of the LBP gene, involving three known transcription factors, may contribute to our understanding of the acute-phase response and the pathophysiology of sepsis and septic shock.

Acute-Phase Proteins↗
PubMed1996

Developmental aspects of the interaction between the controls of heart rate and respiratory rhythm--linear and nonlinear components of diverse activity states in childhood.

Heart beat and respiration are rhythmical phenomena with separate intrinsic frequencies which necessarily have to be effectively tuned by a network of interactive processes. Their linear and nonlinear components may ripen in different ways during childhood thus leading to unstable transitions or risk of dangerous events. This study investigates the development from newborns to children mainly between sleep and wakefulness. 42 healthy untrained children underwent a 24 hours monitoring of ECG, respiration, actogram, and EOG. Linear parameters such as respiratory rate, heart period duration (HPD), total and high frequency spectral power (TP, HFP), low/high frequency power quotient (LF/HF) and coherence were calculated in wake state, REM- and non-REM sleep. The largest Lyapunov exponent (LLE) was evaluated as nonlinear parameter and proved by the surrogate data method. The childrendata were compared to newborndata at days 1 and 180. In wake children, all values except TP differ from that in non-REM and except LLE from that in REM. All linear parameters differ between REM and non-REM. Similar differences exist for quiet to active sleep in newborns at day 1. At day 180 only LF/HF and coherence differ. Development from day 1 to 180 exists in quiet sleep for LF/HF and coherence, in active sleep additionally for LLE and from day 180 to children except for LF/HF and coherence. The results show clear differences in the linear parameters of the activity states. Wakefulness, REM- and non-REM sleep, therefore, follow varied rhythmical controls. The behaviour of LF/HF points to changes in the intensity of vagal participation and that of the coherence accentuates the differing tightness of the coupling. The clearly existing nonlinear components have a separate value only in wakefulness hinting at larger complexity at that state. The development within the first 180 days indicates an increase of vagal participation and tightness of coupling in quiet sleep, in active sleep also an increase in complexity. From that day no further development in vagal and coupling effects has been detected among children. The complexity remains unchanged, only the power parameters expressing heart rate variability increase. (Fig. 3, Tab. 3, Ref. 13.)

Adolescent↗
PubMed1996

[Nonlinear dynamics in regulation of heart rate in healthy infants].

The aim of this study was to investigate qualitatively and quantitatively non-linear and linear characteristics of heart rate identifying their connection to sleep states during the first 6 months of life. 16 newborns were examined polygraphically in a longitudinal study (first day, first and sixth month). After R-peak detection of a limb lead ECG and R-R interval calculation, time series of the instantaneous heart rate (IHR) were constructed. They were analyzed qualitatively with regard to the structure of the Poincaré maps and the occurrence of bifurcations as well as quantitatively by calculating the correlation dimension (D2) and the Lyapunov exponent (LLE). In some cases, bifurcations in the IHR time series occurred. The Poincaré maps showed mainly clear structures in the shape of limited point clusters. D2 was in the range of 1.5 to 2.5 and was larger in quiet than in active sleep. LLE was always positive, although higher values in active sleep than in quiet sleep were exhibited in the first month of life only. D2 and LLE values during active sleep were age-dependent. The results of the study indicate a non-linear component in the heart rate control of healthy newborns. The change in D2 and LLE in connection with postnatal age and sleep states expresses a modulation of these system components during the postnatal maturation and during vegetative sleep organisation.

Child Development↗
PubMed1996

[Sleep structure in relation to respiration and heart rate in children in puberty].

The different expression of respiratory sinus arrhythmia in REM- versus nonREM-sleep indicates a dependence of cardiorespiratory interaction on patterns of sleep. Investigations of the intensity of respiratory entrainment on heart rhythmicity during various stages of sleep will provide an insight into the coupling of cardiorespiratory interaction and sleep patterns. 42 healthy children (12 to 15 years old) were polygraphically investigated over 24 h. An ECG, EOG, and actogram were performed, respiratory movements were observed, and the skin temperature was taken. The power spectra of the instantaneous heart rate and the respirograms were calculated. The analysis of coherence was carried out to determine how pronounced the cardiorespiratory interaction is. REM-sleep, nonREM-phases, and wakefulness were compared. The spectral parameters of instantaneous heart rate show differences between both stages of sleep and the waking state. Due to a dependence of spectral power on breathing patterns, drawing quantitative conclusions is not possible. The analysis of coherence provides more information about sleep patterns within the cardiorespiratory interaction. It is very pronounced during non-REM-sleep (0.80 +/- 0.07; mean +/- standard deviation). Heart rhythmicity proceeds independent of breathing during REM-sleep (0.52 +/- 0.11). The coupling is weaker than during wakefulness (0.64 +/- 0.09).

Adolescent↗
PubMed1995

[Circadian rhythms in the spectrum of heart rate variability].

Heart rate shows a circadian rhythm. This has not yet been sufficiently investigated for its variability till now, which challenges the analysis of rhythms of the variability and their validity in long time records. For this purpose, time series of heart period duration (HPD) and sinus arrhythmia (SA) were measured in 30 children in a boarding-school (14 male, 16 female, 12 to 14 years of age) from the ECG for 5 min/h during 24 h. Fast Fourier transform provided the spectra and the power density. HPD, SA, power maxima and their frequencies were analyzed for circadian rhythms according to Halberg. Times of meals and sleep were uniform. Power and frequencies of the spectra showed individual patterns, stable throughout the day in 2 diverse groups. SA, high- (HF) and middle frequent (MF) spectral parts show circadian oscillations in frequency or power with acrophases during day or night, often in contrast to HF and MF. This proves the existence of circadian rhythms of heart rate variability for SA, HF and MF. In some cases, the individual 24-h patterns are superimposed by effects of external zeitgeber, e.g. meals.

Adolescent↗
PubMed1995

[Correlation between respiration and heart rate in 12- to 14-year-old children during sleep and wakefulness].

The coupling of respiratory and cardiac rhythm is determined by interactions of oscillating brain stem centers and external physical and psychical influences. Not well known are effects of sleep and wakefulness which will be investigated over the day. From the ECG and respirogram of 42 healthy children (11 female, 31 male, 12 to 14 years) during 24 h the time series of instantaneous heart rate (HR) and respiratory rhythm and from this by FFT the density spectra of power, the maximal power and related frequency in the respiratory range were ascertained. Differences between nonREM sleep and wakefulness and the strength of coupling were determined by coherence analysis. In all probands the maximal power of HR and of the coherence were higher during nonREM sleep than in wakefulness. Both values were stable during each state. The maximum related frequencies of HR and respiration shifted parallel between sleep and wakefulness. The results mean augmentation in nonREM sleep following to improved transfer of respiratory activity to the control of HR. The increased coherence hints at a stronger linear coupling which is stable during each state. The changes of cardiorespiratory coupling may be effected by stronger non-linear parts in the interactions during wakefulness.

Adolescent↗